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TRANSCRIPT
Health Technology A
ssessment 2006;Vol. 10: N
o. 12A
decision analysis for sampling and treating infected diabetic foot ulcers
A series of systematic reviews toinform a decision analysis for samplingand treating infected diabetic footulcers
EA Nelson, S O’Meara, D Craig, C Iglesias, S Golder, J Dalton, K Claxton, SEM Bell-Syer, E Jude, C Dowson, R Gadsby, P O’Hareand J Powell
Health Technology Assessment 2006; Vol. 10: No. 12
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A series of systematic reviews toinform a decision analysis for samplingand treating infected diabetic footulcers
EA Nelson,1* S O’Meara,1 D Craig,2 C Iglesias,1
S Golder,2 J Dalton,1 K Claxton,3 SEM Bell-Syer,1
E Jude,4 C Dowson,5 R Gadsby,6 P O’Hare7
and J Powell8
1 Department of Health Sciences, University of York, UK2 Centre for Reviews and Dissemination, University of York, UK3 Department of Economics and Centre for Health Economics,
University of York, UK4 Tameside General Hospital, Ashton-under-Lyne, UK5 Department of Biological Sciences, University of Warwick, UK6 Warwick Diabetes Care, University of Warwick, UK7 Warwick Medical School, University of Warwick, UK8 Faculty of Medicine, Imperial College, London, UK
* Corresponding author
Declared competing interests of authors: none
Published April 2006
This report should be referenced as follows:
Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al. A series of systematicreviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.Health Technol Assess 2006;10(12).
Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE,Excerpta Medica/EMBASE and Science Citation Index Expanded (SciSearch®) and Current Contents®/Clinical Medicine.
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Objectives: To review systematically the evidence onthe performance of diagnostic tests used to identifyinfection in diabetic foot ulcers (DFUs) and ofinterventions to treat infected DFUs. To use estimatesderived from the systematic reviews to create adecision analytic model in order to identify the mosteffective method of diagnosing and treating infectionand to identify areas of research that would lead tolarge reductions in clinical uncertainty.Data sources: Electronic databases covering periodfrom inception of the database to November 2002.Review methods: Selected studies were assessedagainst validated criteria and described in a narrativereview. The structure of a decision analytic model wasderived for two groups of patients in whom diagnostictests were likely to be used.Results: Three studies that investigated theperformance of diagnostic tests for infection onpopulations including people with DFUs found thatthere was no evidence that single items on a clinicalexamination checklist were reliable in identifyinginfection in DFUs, that wound swabs perform poorlyagainst wound biopsies, and that semi-quantitativeanalysis of wound swabs may be a useful alternative toquantitative analysis. However, few people with DFUswere included, so it was not possible to tell whetherdiagnostic performance differs for DFUs relative towounds of other aetiologies. Twenty-three studiesinvestigated the effectiveness (n = 23) or cost-effectiveness (n = 2) of antimicrobial agents for DFUs.
Eight studied intravenous antibiotics, five oralantibiotics, four different topical agents such asdressings, four subcutaneous granulocyte colonystimulating factor (G-CSF), one evaluated oral andtopical Ayurvedic preparations and one comparedtopical sugar versus antibiotics versus standard care.The majority of trials were underpowered and weretoo dissimilar to be pooled. There was no strongevidence for recommending any particular antimicrobialagent for the prevention of amputation, resolution ofinfection or ulcer healing. Topical pexiganan cream maybe as effective as oral antibiotic treatment withofloxacin for the resolution of local infection. Ampicillinand sulbactam were less costly than imipenem andcilastatin, a growth factor (G-CSF) was less costly thanstandard care and cadexomer iodine dressings may beless costly than daily dressings. A decision analyticmodel was derived for two groups of people, those forwhom diagnostic testing would inform treatment –people with ulcers which do not appear infected butwhose ulcer is not progressing despite optimalconcurrent treatment – and those in whom a firstcourse of antibiotics (prescribed empirically) havefailed. There was insufficient information from thesystematic reviews or interviews with experts topopulate the model with transition probabilities for thesensitivity and specificity of diagnosis of infection inDFUs. Similarly, there was insufficient information onthe probabilities of healing, amputation or death in theintervention studies for the two populations of interest.
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Abstract
A series of systematic reviews to inform a decision analysis forsampling and treating infected diabetic foot ulcers
EA Nelson,1* S O’Meara,1 D Craig,2 C Iglesias,1 S Golder,2 J Dalton,1 K Claxton,3
SEM Bell-Syer,1 E Jude,4 C Dowson,5 R Gadsby,6 P O’Hare7 and J Powell8
1 Department of Health Sciences, University of York, UK2 Centre for Reviews and Dissemination, University of York, UK3 Department of Economics and Centre for Health Economics, University of York, UK4 Tameside General Hospital, Ashton-under-Lyne, UK5 Department of Biological Sciences, University of Warwick, UK6 Warwick Diabetes Care, University of Warwick, UK7 Warwick Medical School, University of Warwick, UK8 Faculty of Medicine, Imperial College, London, UK* Corresponding author
Therefore, we were unable to run the model to inform the most effective diagnostic and treatmentstrategy.Conclusions: The available evidence is too weak to beable to draw reliable implications for practice. Thismeans that, in terms of diagnosis, infection in DFUscannot be reliably identified using clinical assessment.This has implications for determining which patientsneed formal diagnostic testing for infection, on whetherempirical treatment with antibiotics (before the resultsof diagnostic tests are available) leads to betteroutcomes, and on identifying the optimal methods ofdiagnostic testing. With respect to treatment, it is notknown whether treatment with systemic or localantibiotics leads to better outcomes or whether any
particular agent is more effective. Limited evidencesuggests that both G-CSF and cadexomer iodinedressings may be less expensive than ‘standard’ care,that ampicillin/sulbactam may be less costly thanimipenem/cilastatin, and that an unlicensed cream(pexiganan) may be as effective as oral ofloxacin.Further research is needed to ascertain thecharacteristics of infection in people with DFUs thatinfluence healing and amputation outcomes, todetermine whether detecting infection prior totreatment offers any benefit over empirical therapy,and to establish the most effective and cost-effectivemethods for detecting infection, as well as the relativeeffectiveness and cost-effectiveness of antimicrobialinterventions for DFU infection.
Abstract
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Health Technology Assessment 2006; Vol. 10: No. 12
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List of abbreviations .................................. vii
Executive summary .................................... ix
1 Background ................................................ 1The impact of diabetic foot ulcers ............. 1Quality of life ............................................. 1General management of DFU ................... 2Wound infection and healing ..................... 2Management of infection in DFU .............. 3Methods used in this project ...................... 5Initial representation of pathway of care ............................................................. 5
2 Research questions .................................... 9
3 Review methods ......................................... 11Search strategy ........................................... 11Study selection ........................................... 13Data extraction ........................................... 15Critical appraisal of included studies ........ 15Data analysis ............................................... 17Decision analytic model ............................. 17
4 Results ........................................................ 19Literature search results ............................. 19Studies included in the diagnostic review ... 19Results of diagnostic review ....................... 19Effectiveness studies ................................... 26Overall summary ........................................ 47Decision analytic modelling ....................... 48
5 Discussion ................................................... 61Diagnostic studies ...................................... 61Effectiveness studies ................................... 64
Strengths and weaknesses of the review .... 68Integration of this review with previous work ............................................................ 69Decision analytic model ............................. 69
6 Conclusions ................................................ 71Implications for clinical practice ............... 71Implications for research ........................... 71
Acknowledgements .................................... 73
References .................................................. 75
Appendix 1 Search strategies .................... 87
Appendix 2 Expert advisory panel ........... 113
Appendix 3 Data extraction forms ............ 115
Appendix 4 Data extraction tables ............ 125
Appendix 5 Quality assessment ................ 199
Appendix 6 Summary of excluded studies ......................................................... 203
Appendix 7 Experts’ views on definition and management of clinically infected diabetic foot ulcers ..................................... 211
Health Technology Assessment reportspublished to date ....................................... 223
Health Technology Assessment Programme ................................................ 235
Contents
A/C amoxycilin and clavulanate
A/S ampicillin and sulbactam
CCT controlled clinical trial
CFU colony-forming unit
CI confidence interval
CONSORT Consolidated Standards ofReporting Trials
CRD Centre for Reviews andDissemination
DFU diabetic foot ulcer
DNA deoxyribonucleic acid
DNPU diabetic neuropathic plantar ulcer
DPN diabetic peripheral neuropathy
EQ-5D EuroQol quality of lifequestionnaire
G-CSF granulocyte colony-stimulatingfactor
HEED Health Economics EvaluationDatabase
HRQoL health-related quality of life
I/C imipenem and cilastatin
LR likelihood ratio
+LR positive likelihood ratio
–LR negative likelihood ratio
MRSA methicillin-resistant Staphylococcusaureus
NHS EED National Health ServiceEconomic Evaluation Database
NICE National Institute for Health andClinical Excellence
NPV negative predictive value
P/C piperacillin and clindamycin
P/T piperacillin and tazabacam
PCR polymerase chain reaction
PPV positive predictive value
QALY quality-adjusted life-year
QUADAS Quality Assessment of Studies ofDiagnostic Accuracy Included inSystematic Reviews
QUOROM Quality of Reporting of Meta-Analyses
RCT randomised controlled trial
rh-G-CSF recombinant human granulocytecolony-stimulating factor
rhPDGF recombinant human platelet-derived growth factor
ROC receiver operating characteristic
RR relative risk
RVP retrograde venous perfusion
SD standard deviation
SEK Swedish kroner
SPSS Statistics Package for SocialSciences
STARD Standards for Reporting ofDiagnostic Accuracy
T/C ticarcillin and clavulanate
VAS visual analogue scale
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List of abbreviations
All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case the abbreviation is defined in the figure legend or at the end of the table.
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BackgroundAround 6% of people with diabetes have a footulcer or have a history of one. Diabetic foot ulcers(DFUs) are associated with increased mortality,illness and reduced quality of life. Diagnosinginfection in DFU accurately and administeringantibiotics may be important as infection can leadto amputation. However, using antimicrobialagents inappropriately could be costly, and lead toincreased bacterial resistance. This reviewconcentrates on the diagnosis of infection and themanagement of DFUs with antimicrobial agents.
ObjectivesThe objectives of this study were:
� To review systematically the evidence on theperformance of diagnostic tests used to identifyinfection in DFUs and of interventions to treatinfected DFUs.
� To use estimates derived from the systematicreviews to create a decision analytic model inorder to identify the most effective method ofdiagnosing and treating infection and toidentify areas of research that would lead tolarge reductions in clinical uncertainty.
MethodsData sourcesElectronic searches were made of 19 databasescovering the period from inception of each databaseto November 2002. In addition, handsearches ofbook chapters, conference proceedings, a journaland bibliographies of retrieved studies were carriedout. Internet searches were also made.
Study selectionStudies that dealt with the following areas wereselected.
Diagnosis Studies of the diagnosis of infection in people withDFUs or venous leg ulceration where a referencestandard was compared with an alternativeassessment.
EffectivenessRandomised controlled trials (RCTs) or controlledclinical trials (CCTs) of the effect ofmicrobiological analysis or antimicrobial agents inpeople with DFUs.
Cost-effectivenessEconomic evaluations of eligible interventionsstudied in which costs and effectiveness weresynthesised.
ModellingEconomic or decision analytic models in which the progress of patients with DFUs was described in sufficient detail to allow replication of themodel.
Data extractionQuality checklists and data extraction forms foreach study design were completed by one reviewerand checked by a second. Interviews were heldwith experts to inform gaps in the evidence.
Data synthesisStudies were described in a narrative review. Thestructure of a decision analytic model was derivedfor two groups of patients in whom diagnostic testswere likely to be used.
ResultsDiagnosisThree studies investigated the performance ofdiagnostic tests for infection on populationsincluding people with diabetic foot ulcers. Onestudy investigated the performance of clinicalassessment, another investigated the performanceof punch biopsy versus wound swab andquantitative analysis and the third comparedquantitative and semi-quantitative wound swabs inpeople with chronic wounds, including DFUs, forthe identification of infection. These studies, all ofwhich looked at identifying infection in chronicwounds, found that:
� There was no evidence that single items on aclinical examination checklist were reliable inidentifying infection in DFUs.
� Wound swabs performed poorly against woundbiopsies.
Executive summary
x
� Semi-quantitative analysis of wound swabs maybe a useful alternative to quantitative analysis.
For the three diagnostic studies few people withDFUs were included, so it was not possible to tellwhether diagnostic performance differs for DFUsrelative to wounds of other aetiologies.
EffectivenessTwenty-three studies investigated the effectiveness(n = 23) or cost-effectiveness (n = 2) ofantimicrobial agents for DFU. Eight studiedintravenous antibiotics, five oral antibiotics, fourdifferent topical agents such as dressings, foursubcutaneous granulocyte colony stimulatingfactor (G-CSF), one evaluated oral and topicalAyurvedic preparations and one compared topicalsugar versus antibiotics versus standard care.
The majority of trials were underpowered andwere too dissimilar to be pooled. There was nostrong evidence for recommending any particularantimicrobial agent for the prevention ofamputation, resolution of infection or ulcerhealing. Topical pexiganan cream may be aseffective as oral antibiotic treatment with ofloxacinfor the resolution of local infection.
Ampicillin and sulbactam were less costly thanimipenem and cilastatin, a growth factor (G-CSF)was less costly than standard care and cadexomeriodine dressings may be less costly than dailydressings.
Decision analytic modelA decision analytic model was derived for twogroups of people, those for whom diagnostictesting would inform treatment – people withulcers which do not appear infected but whoseulcer is not progressing despite optimalconcurrent treatment – and those in whom a firstcourse of antibiotics (prescribed empirically) havefailed. There was insufficient information from thesystematic reviews or interviews with experts topopulate the model with transition probabilitiesfor the sensitivity and specificity of diagnosis ofinfection in DFUs. Similarly, there was insufficientinformation on the probabilities of healing,amputation or death in the intervention studies
for the two populations of interest. Therefore, wewere unable to run the model to inform the mosteffective diagnostic and treatment strategy.
ConclusionsImplications for healthcareThe available evidence was too weak to be able todraw reliable implications for practice. This meansthat, in terms of diagnosis, infection in DFUscannot be reliably identified using clinicalassessment. This also has implications fordetermining which patients need formaldiagnostic testing for infection, whether empiricaltreatment with antibiotics (before the results ofdiagnostic tests are available) leads to betteroutcomes, and identifying the optimal methods ofdiagnostic testing. With respect to treatment, wedo not know whether treatment with systemic orlocal antibiotics leads to better outcomes orwhether any particular agent is more effective.Limited evidence suggests that both G-CSF andcadexomer iodine dressings may be less expensivethan ‘standard’ care, that ampicillin/sulbactammay be less costly than imipenem/cilastatin, andalso that an unlicensed cream (pexiganan) may beas effective as oral ofloxacin.
Implications for researchQuestions to be answered are:
• What characteristics of infection in people withDFUs influence healing and amputationoutcomes?
• Does detecting infection prior to treatmentoffer any benefit over empirical therapy?
• If detecting infection offers clinical benefit, thenwhat are the most effective and cost-effectivemethods for detecting infection, e.g. clinicalassessment, wound swabbing or wound biopsyand microbiological analysis, or noveltechniques such as electronic nose/tongue andpolymerase chain reaction analysis?
• What are the relative effectiveness and cost-effectiveness of antimicrobial interventions forDFU infection, e.g. combinations of broad-spectrum antibiotics, larval therapy, growthfactors and topical agents/dressings?
Executive summary
The impact of diabetic foot ulcersDiabetic foot ulcers (DFUs) are costly andassociated with increased mortality, thedevelopment of morbidity and reduced quality oflife. It has been estimated that the proportion ofpeople with diabetes in the UK who have ever hadfoot ulceration is around 6%.1 Currie andcolleagues analysed routine inpatient data from ahospital in Cardiff, UK, and estimated that thecost per admission for DFU was £1451 and thatthe extrapolated annual national cost would be£17 million (price year 1994).2 A prognostic studyconducted in the USA showed that presence offoot ulceration was related to a higher risk ofshort-term mortality (mean follow-up 692 days) inpeople with diabetes.3
A large proportion of DFUs may fail to heal andare associated with the development of infection(including osteomyelitis) and/or gangrene and anincreased risk of lower extremity amputation.4,5
A review of European studies examining theincidence of amputations in diabetic patientsreported estimates ranging from 5.7 to 20.5 amputations per 100,000 total populationper year.1 Although the variation in estimates may be due to differences between thecharacteristics of the various populations studied,it is also likely to be explained by differences inthe ways in which amputation rates are recordedand expressed.1
Amputation can be performed at several differentlevels, including the following: toe excision; toeand ray excision (longitudinal amputation of a toeand its metatarsal); tarsometatarsal (Lisfranc)disarticulation (amputation of junction of tarsusand metatarsus); midtarsal (Chopart)disarticulation (amputation through thetalonavicular and calcaneocuboid joints, leavingonly the hindfoot); Syme ankle disarticulation;transtibial (below knee); knee disarticulation(through knee); and transfemoral (above knee).6,7
The excision must be proximal to the level ofdamaged tissue. Other considerations indetermining the level of amputation includedegree of tissue oxygen perfusion, predictedpatient adherence with after-care and lack ofprotective sensation.7
It has been suggested that amputation should notbe viewed as failure of management, but rather asa means of restoring a patient’s functional status.However, this may depend upon the level ofamputation performed. Partial foot excision isconsidered to have several advantages, includingpreservation of weight-bearing and proprioceptiveabilities, less alteration of body image and modestpostoperative requirements for footwearmodification or application of a small prosthesisor orthosis. Such devices may help restore near-normal ambulatory function.7 The term‘proprioceptive’ refers to the capability ofreceiving stimuli originating in muscles, tendonsand other internal tissues.8 However, the short-and long-term success of amputation can dependupon the underlying morbidity at the time ofsurgery and also future morbidity. A non-systematic review of mainly surgical case seriessuggested postoperative re-ulceration rates ofaround 25%.9 In addition, it has been noted that aproportion of patients undergo repeatedamputations of either a higher level of the samelimb or the contralateral limb.5,10,11
Quality of lifeStudies have shown that diabetic people with footulceration suffer from reduced quality of life interms of pain, restricted mobility, time lost fromwork and reduction in social activities, leading tosocial isolation and loneliness.12–14
A number of studies have attempted to assess theimpact of amputation on quality of life in diabeticpatients. Three studies reported the surprisingfinding that some amputees experienced a betterquality of life than those with a DFU, at least insome domains.15–17 In studies where informationwas given about the level of amputation, theincreased quality of life scores in amputees relativeto people with a foot ulcer were seen only in thosewith minor amputations (toe ortransmetatarsal).15,17 This finding may beexplained by the possibility that those with a DFUdevelop depression associated with theacknowledgement of a poorer state of health.18 Inaddition, reduced mobility has been shown to beassociated with reduced quality of life in diabetic
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Chapter 1
Background
patients.13 Those with a DFU often have a regimenof reduced mobility imposed upon them, owing tothe requirement to reduce pressure on the affectedfoot, whereas amputees who have had a prosthesisfitted are normally encouraged to mobilise.18
General management of DFUThe management of the patient with a DFUrequires input from a multidisciplinary team whoprovide different aspects of care, as follows:
� patient education� optimisation of blood glucose control� correction (where possible) of arterial
insufficiency� reduction of pressure on the foot, for example,
through the use of pressure-relieving/redistributing orthoses such as totalcontact casts
� optimal skin care� optimal care of wounds, with respect to
cleansing and dressings� debridement of non-viable tissue� reduction of pain associated with ulceration
(particularly arteriopathic ulcers)� surgical intervention, including debridement,
drainage of pus, revascularisation oramputation, as considered necessary
� maintenance of mobility and independence� prevention of wound infection, where possible� early detection and treatment of wound
infection.
Care may take place in various settings, includingprimary care, specialist outpatient clinics, hospital(acute care) and rehabilitation centres. Currentrecommendations state that diabetic patientsshould be screened regularly and entered on to aregister. Those deemed to be at risk of footproblems should be referred to a diabetes footcare team consisting of a physician, a nursespecialist and a podiatrist.19,20 However, manyhospitals in the UK have yet to implement such ateam.21 A recent survey of consultantdiabetologists (79/160 usable questionnairesreturned) indicated that 67% of respondents hadaccess to a designated diabetic foot clinic.However, the staff members of the clinics were notdescribed.22
Wound infection and healingThe presence of a combination ofpathophysiological factors means that people with
diabetes are particularly susceptible to footinfection. These factors include impairedglycaemic control, neuropathy, altered footanatomy, lower extremity oedema, peripheralvascular disease, immunodeficiency, impairedwound healing, altered flora on unbroken skin andan increased incidence of skin disorders leading tobreaks in the skin.23,24 Foot ulceration may beviewed as one of a number of clinical signs thatcan alert the clinician to the development ofdiabetic foot infection, a broader clinical problemthan ulceration alone. Other indicative lesionsinclude cellulitis, abscess, osteomyelitis and aninflamed appearance of the soft tissue of the foot.Other local signs of diabetic foot infection includepain, swelling, sinus tract formation, crepitation(thought to suggest presence of soft tissue gas andnecrosis) and fluctuance (thought to indicateundrained suppuration). Systemic signs andsymptoms of infection (fever, rigors, vomiting,tachycardia, confusion, malaise) and metabolicdisturbances such as severe hyperglycaemia mayalso indicate a locally developing infection of thefoot.24,25 Although we recognise that diabetic footinfection may occur in conjunction withulceration, this project will focus on themanagement of foot ulceration with regard toinfection. Therefore, infections of the foot wherethere is no ulcer present will not be considered forthe purposes of this project.
Moist chronic skin ulcers are an ideal medium formicrobiological growth and the identified floracan include both aerobic and anaerobic bacteria,and fungi.24 Results from studies of microbiologicalcultures from DFUs have indicated that the mostfrequently identified isolates are as follows:
� Aerobes – Staphylococcus aureus, Staphylococcusepidermidis, coagulase-negative Staphylococcusspecies, group B Streptococcus, Enterococcus spp.,Escherichia coli, Pseudomonas aeruginosa, Proteusmirabilis and other Proteus species26–36
� Anaerobes – Bacteroides melaninogenicus,Bacteroides fragilis, Peptostreptococcus species andPeptococcus species27–29,32,33,35–37
� Fungi – Candida tropicalis and Candida albicans.27
Anaerobes are sometimes mentioned as importantcausative organisms in DFU infection.Microbiological surveys in DFUs show a widerange of anaerobe prevalence, expressed as aproportion of the total number of isolates found(5–58%).26–36 This variation may depend upon thesetting of the study, the methods used forcollecting, transporting and analysing specimensand patient or wound characteristics. It may also
Background
2
reflect the possible difficulties of culturinganaerobes from routine swabs and/or failure to useprolonged anaerobic culture methods.38
Some authors suggest that infection in DFUs maybe caused by the presence of more than oneisolate.30,39 In a Canadian study, the mean numberof organism types per lesion varied according tothe setting of treatment: 2.1 isolates for auniversity hospital, 2.3 for a community hospitaland 3.4 for a district hospital.30 In a smaller studybased in the UK and Ireland, the mean number ofisolates cultured from patients attending a diabeticclinic was 4.5 per wound.39
It is possible that different microorganisms thatare present in the same wound may interact withone another, for example aerobes and anaerobes.An emerging area of research interest is thepossible impact of biofilms on outcomes in chronicwounds. A biofilm has been defined as “a layeredculture of microorganisms growing on a surfacethat they have created themselves by secretingpolysaccharides and glycoproteins”.8 Thestructured communities of bacteria within abiofilm are thought to have increased resistance toantimicrobial agents compared with bacteria livingas planktonic forms (meaning free-living bacteriaas opposed to those contained within biofilmcommunities).40,41 Biofilms have been cultured inanimal models.41 In a case series of 15 patientswho had undergone vascular grafts, 13 hadbiofilms cultured from their graft sites duringfollow-up times ranging from 5 months to14 years.42 It has been proposed that the presenceof biofilms may have an adverse impact ondiabetic foot infections and that therapies otherthan antimicrobial agents may need to beconsidered such as enzymatic therapy or inhibitionof bacterial communication.40 However, furtherresearch is required in this area to establish theimpact of biofilms on outcomes in DFUs and todetermine the optimum methods of management.
The eradication of causative microorganisms hasbeen deemed to be an important outcome in themanagement of infection in DFUs, as reflected inthe literature and through expert opinion.43–47
However, wound healing has also been identifiedas an important outcome, and may be of greaterimportance to patients than outcomes such as theresolution of infection.13,48,49
The relationship between bacterial colonisation andhealing in chronic wounds is currently unclear.50–53
Although it has been proposed that higher bacterialcounts may be associated with failure to heal,51,54,55,
some sources suggest that the presence of bacteriais unimportant.50,52 However, other findingsindicate that the presence of four or more bacterialgroups may be associated with delayed healing.56
Results from some studies suggest that the presenceof specific microorganisms may be detrimental towound healing, including �-haemolytic streptococciand Staphylococcus aureus.51 However, most of thisliterature relates to venous leg ulcers. An earliersystematic review did not find any such data onDFUs.48
Management of infection in DFUGeneral treatment considerationsThe resolution of infection in DFUs requires abroad consideration of several aspects of clinicalmanagement, including optimisation of glycaemiccontrol, surgery (debridement, drainage andrevascularisation) and the treatment of associatedand concurrent deep soft tissue infection and/orosteomyelitis.
Prolonged, poorly controlled hyperglycaemia isassociated with progressive adverse changes invarious types of body tissue and abnormalities ofthe immune system. Impaired glycaemic control isthought to contribute to increased rates ofinfection, and to generate more serious infections.It is therefore generally recommended thatattention be given to optimising blood glucoselevels in any diabetic patient with an infected footor ulcer.57
Surgical procedures may also have a role inmanaging infected DFUs. Sharp or surgicaldebridement may help counter wound infectionthrough the removal of necrotic tissue, which canfoster microorganisms.24,25,58 Surgical drainage ofpus can be deemed necessary if the infected ulceris associated with a deeper soft tissue infection.24
The presence of vascular disease impairs thedelivery of antibiotics and oxygen to areas ofinfection.58 Vascular reconstruction surgery to treatperipheral arterial disease may help resolveinfection by improving the blood flow to the foot,thereby improving the supply of nutrients anddrugs to infected tissue.24,25,58
Long-term and refractory infection of DFUs maybe associated with the presence of underlyingosteomyelitis.58 Findings from a small, non-randomised study suggested that conservativesurgical treatment of osteomyelitis added tomedical treatment may produce an increasedhealing rate of foot ulcers compared with medical
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treatment alone.59 The potential importance ofthe above therapies in treating infected DFUs isacknowledged. However, this project will focus onthe diagnosis of infection and use of antimicrobialagents in the management of DFUs.
Diagnosis of infection in DFUsDiagnostic aspects of infection in DFUs focus onthe identification of infection through clinicaljudgement and/or laboratory techniques. Theacquisition of microbiological specimens isrequired in order to culture potentially causativemicroorganisms and study their sensitivities toantibiotic therapy; however, when more than onebacterial species is identified it is difficult todetermine which is/are causing the infection.Acquisition techniques include the wound swab,curettage, tissue biopsy and fine-needleaspiration.24,60 Two more recently developed,potentially useful techniques are the electronicnose/tongue and polymerase chain reaction (PCR).The electronic nose/tongue is a type of electronicsensor used to detect the presence of bacteria. Ithas been used in rhinological research61 and for invitro studies.62 PCR is a system for the in vitroamplification of DNA, amplification in this contextbeing an increase in the number of copies of aspecific DNA fragment.8 This technique has beenused for detecting resistant staphylococcalinfection following cardiac surgery63 and in burnspatients.64 It may be useful in cases wheresuspected bacterial presence cannot easily bedetected using culture techniques,65 where thecultivation of a causative microorganism isconsidered to be risky66 or where a pathogen isknown to be slow-growing.67 Relevant evidencerelating to these newer techniques, and also themore established bacterial acquisition methods,will be sought and assessed in this review. Of thecurrently available techniques, it could be arguedthat wound swabs are the most important as theyare performed more frequently than the othermethods. There is an important related debateabout whether techniques and procedures used forswabbing and plating out (spreading a specimenonto a nutrient surface) are always optimal.56
The interactions between clinical assessment,microbiological sampling and antibiotic prescribingare of importance in the management of DFU.There is some debate in the literature as towhether it would be advisable to wait forbacteriology results prior to prescribing antibioticsin order to ensure that the correct agent isadministered, or whether to give antibiotics beforethe result has been reported. Early treatmentwithout the test result might be beneficial as it may
promote faster healing and help to reduceamputation rates. However, it could also mean thatthe wrong antibiotics are prescribed, which mayencourage bacterial resistance. Another approachis not to rely on cultures at all, but to treat thewound according to clinical judgement.24,25
Several different study designs may be consideredfor primary evaluations of diagnostic tests. It ispossible to combine diagnostic and treatmentcomponents of clinical management in a diagnosticrandomised controlled trial (RCT). Such studiescombine an evaluation of the performance ofdiagnostic tests and subsequent treatmentstrategies in a sequential design, capturing theeventual effect of diagnostic procedures on clinicaloutcomes. Just as in evaluations of the clinicaleffectiveness of a therapy, this design is consideredoptimal.68,69 Diagnostic RCTs have been conductedin areas such as acute appendicitis70–71 anddevelopmental hip dysplasia.72
Alternative designs in diagnostic research includecase–control and cohort studies. When comparedwith a diagnostic RCT, these study designs aremore prone to bias. Important types of bias indiagnostic research include the following:68,69
� Spectrum bias (occurs when the group recruitedto the study is not representative of thepopulation to which the test will be applied inclinical practice).
� Absent, inappropriate or imperfect referencestandard.
� Rapid developments in technology, meaningthat study findings rapidly become obsolete.
� Disease progression bias (patients may getbetter or worse over time owing to the time lagbetween the application of the index andreference tests).
� Partial verification bias (only some patientsreceive the reference test).
� Differential verification bias (inconsistentreference standards used).
� Incorporation bias (index test is part of thereference standard).
� Treatment paradox (improvement of conditiondue to treatment given, usually following theresults of the index test).
� Review bias (failure to blind to findings of indexand/or reference test).
� Clinical review bias (interpretation influencedby availability of clinical data).
� Inappropriate handling of unclear results in thedata analysis (i.e. failure to report them clearly).
� Arbitrary choice of threshold value (especially ifdetermined post hoc).
Background
4
Diagnostic cohort and case–control studies areseen more frequently in the literature thandiagnostic RCTs, and therefore evidence fromthese designs is likely to be of value, provided thatthe potential impact of important sources of biascan be taken into account.68,69
Systemic antimicrobial agentsSystemic treatments for infection in DFUs revolvearound the prescription of antibiotics. Systemicagents can be administered orally for mild tomoderate infections or intravenously for moreserious infections, and usually fall into thefollowing groups:73
1. penicillins, for example flucloxacillin andamoxicillin
2. cephalosporins, cephamycins and other �-lactams, for example cefalexin and cefazolin
3. tetracyclines (oral route only), for exampletetracycline
4. aminoglycosides (given by the intramuscular orintravenous route), for example gentamicinand netilmycin
5. macrolides, for example erythromycin andclarithromycin
6. quinolones, for example ciprofloxacin.
There are also several other drugs available,including clindamycin, metronidazole andtrimethoprim.73 A previously published systematicreview including only studies reporting objectivelyassessed wound healing outcomes found two smallRCTs of oral antibiotics used with DFUs. In termsof wound healing, oral amoxycillin combined withclavulanic acid proved to be no better thanplacebo,74 and no statistically significant differencewas observed between clindamycin andcephalexin.75 Despite this paucity of existingevidence, current recommendations for DFU careinclude systemic antibiotics as considerednecessary in conjunction with cleansing,debridement, wound dressings, pressure relief andgood glycaemic control.23,49,76–79
Topical antimicrobial agentsTopical preparations may be divided into twocategories, according to their function. One groupconsists of lotions with antimicrobial properties,used to irrigate or cleanse wounds. These usuallyhave only a brief contact time with the woundsurface, unless they are used as a pack or soak.They include the hypochlorites (e.g. Eusol),hexachlorophene (hexachlorophane) – a constituentof some soaps and other skin cleansers – andsubstances such as potassium permanganate andgentian violet (both used in solution).73
The second group consists of preparationsdesigned to stay in contact with the wound surfacefor a longer period of time, ideally until the nextdressing change. These include creams, ointmentsand impregnated dressings. Most topicalantibiotics come into this category, and includemupirocin, fusidic acid and neomycin sulfate.Other preparations include silver-based products,such as silver-sulfadiazine.73
Products that fall into both categories includepovidone-iodine, chlorhexidine and hydrogenperoxide.73
An emerging topical agent is pexiganan acetate, apeptide antibiotic.24
Methods used in this projectSystematic reviews may be based on evaluations ofdiagnostic tests and evaluations of clinicaleffectiveness. On occasions, a series of suchreviews may be required to answer a complexresearch question, as opposed to the single reviewsthat are often seen in the literature. Systematicreviews are most commonly used to addressindividual and focused research questions aboutthe effects of healthcare interventions.80 However,health professionals usually view patients in thecontext of a more complex sequence of decisionsand associated interventions. Decision analysis is atechnique that allows representation of this morecomplicated scenario.81
Clinical decision analysis is a modelling techniquethat represents the different pathways of care thatare possible for a given patient together with thecomplex sequence of decisions involved in thatcare. It is a useful technique for helping healthprofessionals to identify the optimum pathway ofcare under conditions of uncertainty.82 Some ofthe advantages of clinical decision analytic modelsinclude the option of being able to undertakesensitivity analyses if there is uncertainty aroundimportant model parameters, patient preferencescan be incorporated into the model and decisions,preferences and utilities can be made explicit.82
Initial representation of pathwayof careIn order to make the linkages between thediagnostic and effectiveness questions explicit, wewill describe a theoretical pathway of care,highlighting the decisions made by clinicians at
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Background
6
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various stages. Figure 1 is a simple representationof the decisions made in the treatment of apotentially infected DFU. This pathway wasconstructed at the start of the project to helprepresent the interdependence of the variousdecisions that can be made. It was amendedduring the project from the literature and the finalpathway is shown in Figure 8 (p. 59). This pathwayintegrates the methods of diagnosis of infection,the decision to treat immediately or await resultsof an antibiogram and the effectiveness and cost-effectiveness of individual antimicrobial agents (anantibiogram has been defined as an examinationthat measures the biological resistance ofsubstances causing disease, performed prior tochemotherapy so as to make it more efficient).83
This simplified pathway does not take into accountthe transitions of an ulcer from uninfected toinfected status or the pathway of care for thoseulcers that are unhealed at the end of this episode.It does serve, however, to illustrate thecombination of clinical questions and decisionsthat inform the care of a person with a diabeticfoot ulcer. At the very left of the pathway, at thepoint where a patient enters the system, a clinicalassessment is undertaken to assess for the presenceof infection. The clinical pathway followeddepends on the result of this assessment.
A person with an ulcer that appeared infectedwould follow the route A–B. At this point, theclinician decides whether to take a microbiologicalsample to inform therapy or to treat empirically. Aclinician makes this decision when they reach boxB, that is, do the advantages of waiting forbacteriology results outweigh the benefits ofimmediate, empirical treatment? The route F–Jrepresents empirical treatment, whereas the routeG–I–J represents taking a sample to inform choiceof antimicrobial agent.
If the decision is made to take a sample to informmicrobiological therapy, then the clinician makes achoice from a number of types of sampling
techniques, such as biopsy, swab or near-patienttesting techniques for bacteria such as theelectronic nose. The clinician makes the decisionabout choice of sample at box G. We need to knowwhether, for example, a wound swab is a validindicator of the presence of infection. Followingthe collection of a bacteriological sample, asubsequent decision may need to be maderegarding the sample processing, for example,qualitative culture and sensitivity, quantitative orsemi-quantitative culture or techniques using DNAreplication to expand and identify bacterialpopulations. The decision about the processingand analysis of the sample is made at box I.
A person with an ulcer that appeared uninfectedand yet failed to heal may also be offeredantimicrobial therapy as the clinician may suspectthat the wound is in fact infected withoutdisplaying signs and symptoms of infection. Thepathway A–C–D would represent this situation. Atpoint D in the pathway, the clinician decideswhether to treat empirically or to take amicrobiological sample to inform therapy.
A patient whose ulcer is not clinically infected andwhose ulcer is healing satisfactorily will not usuallybe offered antimicrobial agents and would followthe pathway A–C–E–K.
At each decision point, there is the potential forthe results of the systematic reviews of theperformance of diagnostic tests or the clinical andcost-effectiveness of antimicrobial therapy to guideclinical decisions/sampling policies. Patientpreferences may also be taken into account. Thepoints at which the review questions (1–5, seeTable 1) are addressed are also highlighted inFigure 1.
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The aim of this research is to define theoptimum management strategies for infected
DFUs with reference to clinical examination,microbiological sampling of the wound andantimicrobial therapy.
This research had two objectives:
1. to undertake a series of systematic reviews ofthe evidence relating to the diagnosis andtreatment of infection in DFU
2. to use estimates derived from the systematicreviews to create a decision analytic model
Five linked systematic reviews were conducted,three concerning aspects of diagnosis, onefocusing on effectiveness of microbiologicalanalysis and the other on both clinical and cost-effectiveness of antimicrobial treatment. Theresearch questions and corresponding systematicreviews are outlined in Table 1.
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Chapter 2
Research questions
TABLE 1 Research questions and corresponding systematic reviews
Question Systematic review of
1. How can clinicians determine whether a sample should … the sensitivity and specificity of clinical examination in be taken from a DFU? the identification of infection in DFUs
2. What sampling techniques are the most accurate for … the sensitivity and specificity of different sampling people with DFUs? techniques (wound swab, biopsy, wound lavage and/or
curettage, near-patient testing techniques) in theidentification of infection in DFUs
3. What laboratory techniques are the most accurate for … the sensitivity and specificity of techniques of analysing samples from DFUs? microbiological analysis (qualitative, quantitative, semi-
quantitative) in the identification of infection in DFUs
4. What impact does microbiological analysis have on … the effects of microbiological analysis on the treatment therapy? of infection, pain (in patients without neuropathy), exudate
associated with DFUs, the impact on healing, impact onHRQoL and the development of complications
5. What is the effectiveness and cost-effectiveness of … the clinical effectiveness and cost-effectiveness of management of infection in DFU? techniques for treating infection in DFUs including wound
healing and the transfer of drug-resistant organisms to staffand other patients
Search strategySearch strategies and bibliographicdatabases usedWe searched 19 electronic databases, two Internetsources of ongoing research, six conferenceproceedings, one journal and three books forprimary research or systematic reviews, and nineInternet sources for clinical practice guidelines orreviews. All sources were searched for diagnostic,effectiveness and modelling studies. For thediagnostic questions we searched for systematicreviews of diagnostic studies, primary diagnosticstudies, and economic evaluations of diagnosticstudies. For the effectiveness questions, we searchedfor systematic reviews of trials [RCTs and/orcontrolled clinical trials (CCTs)], primary studies(RCTs and/or CCTs) or economic evaluations ofintervention studies. For the modelling question wesearched for decision analytic or economic models.The sources are listed in Table 2.
The searches were carried out in three stages. Thefirst set of searches aimed to retrieve papers relatingto clinical effectiveness, the second papers relatingto economic effectiveness and the third to diagnostictesting. All three sets of retrieved records were thenimported into reference manager software(Endnote) and labelled as either ‘rct’, ‘econ’ or ‘diag’depending on the search strategy from which theywere retrieved. These records were then de-duplicated and any records that were retrieved frommore than one of the search types labelled as such.
Diagnostic searchesLiterature searches were carried out on samplingand microbiological techniques for the diagnosisof DFUs. Databases were searched from the dateof inception of each database to the most recentdate available.
Internet databases� Allied And Complementary Medicine (AMED)
(1985–2002 November).Searched: 23 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� British Nursing Index (BNI) (1994–2002September).Searched: 23 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� CINAHL (1982–2002 October, week 4).Searched: 23 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� EMBASE (1980–2002, week 46).Searched: 24 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� MEDLINE (1966 to 2002 October, week 5).Searched: 24 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� PREMEDLINE (up to 21 November 2002).Searched: 24 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
HandsearchesSix conference proceedings, the Diabetic Footjournal and three books were handsearched.
Clinical effectiveness searchesThe following sources were searched for studiesrelating to the impact of microbiological analysison therapy and the effectiveness of differenttreatments. The literature searches were designedto retrieve systematic reviews and trials only.However, some databases cannot be reliablyrestricted by study type and in these cases thesearch was not limited by study design, and theresults of the searches were entered into anEndnote Library. A range of free text terms andsubject headings were used as appropriate. Detailsof the search strategies are contained inAppendix 1.
CRD internal administration databases (searched:12 November 2002 using CAIRS software)� Database of Abstracts of Reviews of Effectiveness
(DARE).� Health Technology Assessment Database (HTA).
Internet databases� Allied And Complementary Medicine (AMED)
(1985–2002 November).Searched: 12 November 2002 OvidWebGateway at http://gateway.ovid.com/athens.
� British Nursing Index (BNI) (1994–2002August).Searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� CINAHL (1982–2002 October, week 4).Searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
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Chapter 3
Review methods
� Cochrane Controlled Trials Register (CCTR)(2002: Issue 4).Searched: 12 November 2002 on InternetExplorer using the “new generation software” athttp://www.update-software.com/cochrane/.
� Cochrane Database of Systematic Reviews(CDSR) (2002: Issue 3).Searched: 12 November 2002 on InternetExplorer using the ‘new generation software’ athttp://www.update-software.com/cochrane/.
� EMBASE (1980–2002, week 44).Searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� MEDLINE (1966–2002 October, week 4).Searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� PREMEDLINE (up to 5 November 2002).Searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
HandsearchesSix conference proceedings, the Diabetic Footjournal and three books were handsearched.
No date or language restrictions were applied toany of the literature searches. The bibliographies
Review methods
12
TABLE 2 Sources for primary studies, reviews and guidelines
Electronic databasesAllied and Complementary Medicine Database (AMED)British Nursing Index (BNI)Cochrane Controlled Trials Register (CCTR)Cochrane Database of Systematic Reviews (CDSR)Cochrane Specialised Wounds RegisterCumulative Index to Nursing and Allied Health Literature (CINAHL)Database of Abstracts of Reviews of Effects (DARE)DH-DataEconLitEMBASEHealth Economic Evaluation Database (HEED)Health Management Information Service Database (HELMIS)Health Technology Assessment (HTA) databaseIndex to Scientific and Technical Proceedings (ISTP)King’s Fund DatabaseMEDLINEMEDLINE In Process NHS Economic Evaluation Database (NHS EED)System for Information on Grey Literature in Europe (SIGLE)
Additional sources to identify ongoing researchControlled Clinical Trials (http://controlled-trials.com)National Research Register (NRR) (http://www.nrr.nhs.uk/search.htm)
Handsearching conference proceedings3rd International Conference on the Diabetic Foot, Noordwijkerhout, The Netherlands, 1999Diabetic Foot Study Group meeting: Fiuggi, Italy, 2000; Crieff, Scotland, 2001; Balaton, Hungary, 20028th and 9th Malvern Diabetic Foot Conferences, 2000 and 2002
Handsearching journals and booksJournal: The Diabetic FootBooks: The Foot in Diabetes. Boulton AJM, Connor H and Cavanagh PR, editors. 3rd edition, Wiley, Chichester, 2000Levin and O’Neal’s The Diabetic Foot. Bowker JH and Pfeifer MA, editors. 6th edition, Mosby, St Louis, MO, 2001The Evidence Base for Diabetes Care. Williams R, Herman W, Kinmonth AL and Wareham NJ, editors. 2002
Internet searches to identify review/guideline documentsClinical Evidence (http://www.clinicalevidence.com/)Health Evidence Bulletins Wales (http://www.uwcm.ac.uk/uwcm/lb/pep)Health Services Technology Assessment Text (HSTAT) (http://text.nlm.nih.gov/)National Coordinating Centre for HTA (http://www.hta.nhsweb.nhs.uk)National Guideline Clearing House (http://www.ahcpr.gov/clinic/assess.htm)National Institute for Health and Clinical Excellence (NICE) web page (published appraisals)
(http://www.nice.org.uk/nice-web/)ScHARR Lock’s Guide to the Evidence (http://www.shef.ac.uk/uni/academic/R-Z/scharr/ir/scebm.html)Scottish Intercollegiate Guidelines Network (SIGN) (http://www.sign.ac.uk)Turning Research Into Practice (TRIP) (http://tripdatabase.com)
of all included studies were examined in order toidentify any additional relevant studies.
Cost-effectiveness and modelling searchesThose databases restricted by study design in theclinical effectiveness searches were searched againwith a search strategy designed to retrieve cost-effectiveness studies, decision models or economicmodels. Two specialist databases were alsosearched, the NHS Economic Evaluation Database(NHS EED) and the Health Economic EvaluationDatabase (HEED); no economic filter wasnecessary for these databases.
CRD internal administration databases� NHS EED (searched 13 November 2002 on
CAIRS software).
CD-ROM resources� EconLit (1969–2002 October)
Searched: 12 November 2002 on ARCSilverPlatter
� HEED (Issue: November 2002) Searched: 13 November 2002 on stand-aloneCD-ROM
Internet databases� Allied and Complementary Medicine Database
(AMED) (1985–2002 November).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� British Nursing Index (BNI) (1994–2002August).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� CINAHL (1982–2002 October week 4).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� EMBASE (1980–2002 week 44).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� MEDLINE (1966–2002 October, week 5).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
� PREMEDLINE (up to 11 November 2002).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.
HandsearchesSix conference proceedings, the Diabetic Footjournal and three books were handsearched.
Generic searchesThere were a number of databases for which it wasnot practical to justify searching separately forclinical, cost-effectiveness and diagnosis studiesbecause the database was either too small to
warrant such a detailed search or the interfaces forthe database were too simplistic. A general searchfor papers on DFUs was therefore sufficient forthe following databases and the papers were thensifted for relevance.
Internet resources and databases (searched: 26 August 2002)� Health Evidence Bulletins Wales
http://www.uwcm.ac.uk/uwcm/1b/pep� Health Services Technology Assessment Text
(HSTAT) http://text.nlm.nih.gov/
� Index to Scientific and Technical Proceedings(ISTP) (1990 onwards)http://wos.mimas.ac.uk/
� National Coordinating Centre for HealthTechnology Assessmenthttp://www.hta.nhsweb.nhs.uk
� National Guideline Clearinghousehttp://www.ahcpr.gov/clinic/assess.htm
� National Institute for Health and ClinicalExcellence (NICE) (published appraisals)http://www.nice.org.uk/nice-web/
� Scottish Intercollegiate Guidelines Network(SIGN) Guidelineshttp://www.sign.ac.uk/
� Turning Research Into Practice (TRIP) Indexhttp://www.ceres.uwcm.ac.uk/framset.cfm?section=trip
CD-ROM resources� Health Management Information Consortium
(HMIC) Databases: HELMIS 1984–1998/DH-Data and King’s Fund Database1983–2002/King’s Fund Database 1979–2002.Searched: 09 November 2002 on ARCSilverPlatter).
� National Research Register (NRR) (2002,Issue 4).Searched: 13 November 2002 on stand-aloneCD-ROM.
� SIGLE (1967–2002 July, week 3).Searched: 06 November 2002 on ARCSilverPlatter.
Study selectionReferences identified from the search strategieswere de-duplicated and entered into abibliographic software package (ProCite Version 5for Windows). Titles and abstracts, where available,were examined by two reviewers. If either reviewerconsidered a reference to be potentially relevant,the full report was retrieved. Full reports werescreened for inclusion with close reference to the
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inclusion criteria described below. At both stagesof study selection, two reviewers made decisionsindependently and met subsequently to discussdisagreements. Any disagreements were resolvedby discussion. No restrictions were applied interms of the date of publication or the language ofthe report.
Inclusion criteria for systematic reviewsof diagnosis (questions 1–3)1. The study must compare the results of an
independent gold standard (as defined in thestudy) with an alternative assessment.
2. The target population must comprise patientswith diabetes mellitus aged 18 years or olderwith a foot ulcer. Since it was expected that thebody of literature relating to diagnosis ofinfection in DFUs would be small, trialsrecruiting adults with venous leg ulcers werealso eligible for inclusion for questions 1–3. Itwas considered that although the focus of thisproject should remain the management ofpatients with infected DFUs, it is possible thatuseful information may be obtained from thevenous leg ulcer literature as techniques forobtaining and analysing samples are likely tobe similar, regardless of wound aetiology.
3. Sufficient data must be presented in the paperto enable completion of a 2 × 2 diagnostic table(true positives, false positives, true negatives,false negatives), thus allowing outcomes such assensitivity, specificity, predictive values andlikelihood ratios to be calculated.
Inclusion criteria for systematic reviewof impact of microbiological analysis ontherapy or outcomes (question 4)1. The study must be an RCT or a CCT of one or
more strategies of managing suspected infectionof DFUs, such as empirical therapy versusmicrobiological analysis and the use ofappropriate antimicrobial regimens. A CCT wasdefined as a prospective non-randomisedcomparative study with concurrent studygroups.
2. The target population must comprise patientswith diabetes mellitus aged 18 years or olderwith a foot ulcer. Studies recruiting solely peoplewith diabetic foot infection or osteomyelitiswithout ulceration were not included.
3. The study must compare policies of prescribingantimicrobial agents (i.e. wait for result ofmicrobiological analysis before administrationversus administration without test result).Evaluations of relevant strategies/policiesdelivered in any healthcare setting wereconsidered for inclusion in the review.
4. At least one of the following outcome measuresmust be reported: (a) mortality (all or related to amputation)(b) incidence and type of amputation(c) incidence of osteomyelitis(d) pain (in patients without neuropathy)(e) proportion of ulcers healing(f) time to complete healing(g) change in ulcer area (absolute or relative)(h) healing rate(i) change in ulcer depth or volume (absolute
or relative)(j) ulcer recurrence(k) number and duration of hospital
admissions for diabetic foot problems(l) bacterial profile of ulcer(m) acquisition of resistant organisms(n) relationship between ulcer healing and
bacteriology(o) change in mobility(p) change in level of
dependence/independence(q) impact on health-related quality of life.
The most important outcomes were considered tobe those relating to mortality, amputation andwound healing. However, evaluations reportingany of the outcomes described above wereconsidered for inclusion. In addition, data onadverse events and adherence were recorded,where available. Large cohort/population studieswould be needed to identify rare adverse events,such as the acquisition of resistance, and we didnot search for these as there are poorly developedmethods of searching for these study designs andthere was insufficient time within this project toundertake this.
Inclusion criteria for systematic reviewof clinical effectiveness (question 5: part 1)1. The study must be an RCT or a CCT of one or
more antimicrobial regimens (the comparatorcan include no intervention, placebo orstandard care). A CCT was defined as aprospective non-randomised comparative studywith concurrent study groups.
2. The target population must comprise patientswith diabetes mellitus aged 18 years or olderwith a foot ulcer. Studies recruiting solelypeople with diabetic foot infection orosteomyelitis without ulceration were excluded.
3. The study must evaluate an antimicrobial agentused with the primary intention of treatinginfection in DFUs. Evaluations of relevantinterventions delivered in any healthcare
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setting were considered for inclusion in thereview. Evaluations of interventions possiblyinfluencing healing that might be usedconcurrently with antimicrobial agents (e.g.pressure relief, optimisation of blood glucosecontrol, improvement of blood supply to thefoot) were excluded.
During the process of screening studies foreligibility, it was noted that several trials includedmixed populations, for example, people with softtissue infection who did not all necessarily havefoot ulceration or diabetes. Separate outcomes forthe patients with DFU were not always reported inthe papers and, in some cases, authors were notable to supply the stratified data. Recognising thatuseful evidence could still be gleaned from amixed population study where the majority ofpatients had a DFU, a post hoc decision was takento include such studies in the review on conditionthat it could be ascertained that at least 80% ofrecruited patients had a DFU.
4. At least one of the following outcome measuresmust be reported:(a) mortality (all or related to
amputation)(b) incidence and type of amputation(c) incidence of osteomyelitis(d) pain (in patients without neuropathy)(e) proportion of ulcers healing(f) time to complete healing(g) change in ulcer area (absolute or
relative)(h) healing rate(i) change in ulcer depth or volume (absolute
or relative)(j) ulcer recurrence(k) number and duration of hospital
admissions for diabetic foot problems(l) bacterial profile of ulcer(m) acquisition of resistant organisms(n) relationship between ulcer healing and
bacteriology(o) change in mobility(p) change in level of
dependence/independence(q) impact on health-related quality of life.
The most important outcomes were considered to be those relating to mortality, amputation and wound healing. However, evaluationsreporting any of the outcomes described abovewere considered for inclusion. In addition, data on adverse events and adherence with the treatment regimen were recorded, whereavailable.
Inclusion criteria for systematic reviewof economic evaluations (question 5:part 2)Economic evaluations were considered forinclusion if they focused on the diagnosis and/ortreatment of infected DFUs and if they reported asynthesis of associated costs and benefits.Evaluations of any diagnostic test or antimicrobialtreatment strategy in infected diabetic foot ulcerswere eligible. Any type of economic evaluation waseligible, including cost-effectiveness analysis,cost–benefit analysis, cost–utility analysis or cost-minimisation analysis.
Data extractionDetails of eligible studies were extracted andsummarised using a structured data extractiontable (see Appendix 3). If data were missing fromreports, then attempts were made to contact theauthors to obtain sufficient data to carry out dataextraction and critical appraisal. Multiplepublications of the same study were regarded as asingle report and all relevant details wererecorded. Two reviewers verified data extractionindependently. Disagreements were resolved bydiscussion.
Critical appraisal of includedstudiesThree separate checklists were used for diagnosticstudies, effectiveness studies and economicevaluations. Two reviewers performed criticalappraisal of each individual included studyindependently. Disagreements in judgementsabout methodological quality were resolvedthrough discussion.
Critical appraisal of diagnostic studiesA 12-item checklist known as QUADAS (QualityAssessment of Studies of Diagnostic AccuracyIncluded in Systematic Reviews)84 was used (Table 3). This was generated using evidence-basedmethods combined with a Delphi procedure. Thechecklist was accompanied by a guide forcompletion that aims to minimise subjectivejudgement.84 Where an item is scored as ‘unclear’,this refers to the quality of reporting within thepaper rather than the methodological quality ofthe diagnostic evaluation.
Critical appraisal of effectivenessstudiesThe methodological quality of all included RCTswas assessed using a validated five-point scale,85
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and the allocation concealment criterion describedby Schulz,86 as follows:
1. Randomisation. Score: 0 or 1 or 2 One point was given if the study describedusing words such as random or randomisation.One extra point was given if the method ofrandomisation was described and wasappropriate. One point was deducted if themethod of randomisation was described andwas considered to be inappropriate.
2. Double-blinding. Score: 0 or 1 or 2One point was given if the study was describedas double-blind. One extra point was given ifthe method of double-blinding was describedand was appropriate. One point was taken awayif the method of double-blinding was describedand was inappropriate.
3. Withdrawals. Score: 0 or 1One point was given if the number and reasonsfor withdrawals in each group were stated.
4. Allocation concealment. Score: A or B or C(A) Adequate: if adequate measures were taken
to conceal allocation.(B) Unclear: if report of allocation
concealment was not reported or did notfit in category A or C.
(C) Inadequate: trials in which allocationconcealment was inadequate.
The critical appraisal of CCTs included the pointsabove, with the exception of the first(randomisation). In CCTs, the following additionalitems were assessed: method of allocation totreatment groups; degree of baselinecomparability between treatment groups; andappropriateness of adjustment during dataanalysis for observed imbalances betweentreatment groups.
Critical appraisal of economicevaluationsThe following checklist was used:87
1. Was a well-defined question posed inanswerable form?
2. Was a comprehensive description of thecompeting alternatives given?
3. Was the effectiveness of the programmes orservices established?
4. Were all the important and relevant costs andconsequences for each alternative identified?
5. Were costs and consequences measuredaccurately in appropriate physical units?
6. Were costs and consequences valued credibly?7. Were costs and consequences adjusted for
differential timing?8. Was an incremental analysis of costs and
consequences of alternatives performed?
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TABLE 3 Critical appraisal of diagnostic studies checklist – the QUADAS84 tool
Item Yes No Unclear
1. Was the spectrum of patients representative of the patients who will receive the test in practice?
2. Were selection criteria clearly described?3. Is the reference standard likely to correctly classify the target condition?4. Is the time period between reference standard and index test short enough
to be reasonably sure that the target condition did not change between the two tests?
5. Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis?
6. Did patients receive the same reference standard regardless of the index test result?
7. Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)?
8a. Was the execution of the index test described in sufficient detail to permit replication of the test?
8b. Was the execution of the reference standard described in sufficient detail to permit its replication?
9a. Were the index test results interpreted without knowledge of the results of the reference standard?
9b. Were the reference standard results interpreted without knowledge of the results of the index test?
10. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice?
11. Were uninterpretable/intermediate test results reported?12. Were withdrawals from the study explained?
9. Was allowance made for uncertainty in theestimates of costs and consequences?
10. Did the presentation and discussion of studyresults include all issues of concern to users?
Data analysisQuestions 1–3: diagnosisThe included studies were summarised using anarrative description. Meta-analysis wasconsidered where studies were considered to besufficiently similar with respect to patientcharacteristics and the index and reference testsused. In this case, standard methods forcombining primary studies were to be followed.88
Statistical analysis of the receiver operatingcharacteristic (ROC) curve was performed usingSPSS version 12.0.2 and the plot was generatedusing Excel 2000.
It was planned to analyse studies recruitingpatients with venous leg ulcers separately to thoseof DFU patients. Findings from venous leg ulcerstudies were interpreted with great caution whenconsidering any implications for DFUs. For DFUs,it was planned to group studies according to thetype of diabetes (type 1 and type 2) and type offoot ulcer (neuropathic and neuroischaemic).
Question 4: effect of microbiologicalanalysisThe included studies were summarised using anarrative description. Meta-analysis wasconsidered if studies were deemed to besufficiently similar with respect to patientcharacteristics, interventions and outcomes.
Question 5(1): clinical effectivenessThe included studies were summarised using anarrative description. Meta-analysis wasconsidered if studies were deemed to besufficiently similar with respect to patientcharacteristics, interventions and outcomes.
Methods of meta-analysis for questions4 and 5(1)The method of synthesising the studies woulddepend upon the quality, design andheterogeneity of studies identified. Clinicalheterogeneity would be explored by examiningfactors that may impact on outcomes such as caresetting and test, patient and ulcer characteristics.Statistical heterogeneity was assessed using a �2
test. In the absence of clinical heterogeneity andin the presence of statistical heterogeneity, a
random effects model was used for pooling. Thesummary statistic used depended on the event rateobserved. Where the event rate was over 30%, therelative risk (RR) was employed. When the eventrate was less than 30%, a summary odds ratio wascalculated. Where there was no clinical orstatistical heterogeneity, a fixed effects model wasapplied.
Question 5(2): cost-effectivenessEach included economic evaluation was describedin a narrative fashion. In addition, the use of asummary grading for each evaluation wasconsidered, according to the direction of cost-effectiveness estimates. A matrix was used (Box 1)in order to indicate when a clear decision may bemade on the basis of the evidence presented (i.e.better health outcomes with lower costs, or poorerhealth outcomes with higher costs, cells G and C,respectively). Situations where decisions were lessfavoured (either costs are lower or healthoutcomes are better) were represented by cells D,B, F and H. Cases where a financial or clinicaltrade-off was required are shown in cells A and I.Cell E represents a case where no differences wereobserved between the competing strategies. Theposition of each individual evaluation within thematrix has been shown.87,89 Although this methodgives a useful summary of results, and isparticularly helpful when the results of severaleconomic evaluations are presented, the findingsof each individual economic evaluation should beinterpreted in the light of methodological quality(see checklist above).
Decision analytic modelThe first step in the construction of the model wasto conduct a review of the literature to identify anymodels that described the natural history ofpatients with DFUs, and to identify studies thatcould inform the transitions within a decisionanalytic model. We searched for economic modelsor decision analytic models, that is, studies inwhich a mathematical structure had been used torepresent the health and/or economic outcomes ofpatients with a DFUs. Table 2 describes the sourcesused to identify research. The results of allsearches were scrutinised to identify potentiallyrelevant studies. We planned to model explore thecost-effectiveness of different strategies formanaging people with DFUs. The modelcombines information on the precision ofdiagnostic tests with clinical consequences ofundertaking those tests, for example, whichtreatment strategies are chosen (cost, amputation
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rates, healing times) to variations in the methodsof sampling, analysis and treatment regimens. Inthis way, the area of greatest uncertainty can beidentified and this can be used to identify priorityareas of future research. For example, it may bepossible to recognise whether the priority shouldbe to investigate the sensitivity and specificity ofmethods of sampling, or to assess the impact ofantibiotic therapy on the likelihood of healing.
Hence, the decision analysis combines informationon the precision of diagnostic tests with clinicalconsequences of undertaking those tests, forexample, which treatment strategies are chosen.
A full description of the methods for constructingthe decision analytic model and the outputs isgiven in the section ‘Decision analytic modelling’(p. 48).
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Incremental effectiveness+ 0 –
+ A B C
Incremental costs 0 D E F
– G H I
Decision strongly favoured Key: Effectiveness CostG = Accept treatment + Better HigherC = Reject treatment 0 Same Same
– Poorer LowerDecision less favouredD = Accept treatmentB = Reject treatmentF = Reject treatmentH = Accept treatment
No obvious decisionA = Is the added benefit worth the cost?I = Is the reduced effect acceptable given reduced costs?E = Neutral cost and effect. Other reasons to adopt treatment?
BOX 1 Permutation matrix for possible outcomes of economic evaluations for studies of intervention versus comparator87,89
Literature search resultsA total of 4225 studies were identified as beingpotentially relevant to the reviews in ourdiagnostic, effectiveness and economics searches,of which 14% were identified in more than onesearch (see Figure 2).
Diagnostic studies are summarised first, then theeffectiveness studies and cost-effectiveness studies.Finally, the decision analytic model results aredescribed. Data extraction sheets and summaryquality assessment tables are summarised inAppendix 5. Studies thought to be relevant fromtitle and/or abstract but excluded after scrutiny forthe diagnostic, effectiveness and economicsearches are summarised in the excluded studiestables in Appendix 6.
Studies included in the diagnosticreviewIn the diagnostic review search we identified 2762study citations, of which 219 were retrieved (threeincluded and 216 excluded). The reasons forexclusion were as follows:
Reasons for exclusion NPopulation not DFU 12 × 2 data not available 9Study of inter-observer variation 2No verification of infection 6Description of signs/symptoms 1Description of diagnostic techniques 1Osteomyelitis diagnosis 43Diabetic foot infection (not ulcer infection) 8Systematic review of osteomyelitis 2Prevalence studies/other reasons 163
Results of diagnostic reviewThree eligible diagnostic studies wereidentified.90–92 All three recruited patients with avariety of chronic wounds (including DFUs), andwere conducted in the USA. One study evaluatedthe diagnostic performance of clinical examinationusing tissue biopsy as the reference standard (relatesto review question 1),90 one study assessed woundswab against tissue biopsy as a method of specimenacquisition (relates to review question 2)91 and thethird focused on methods of laboratory analysis ofthe wound swab, namely semi-quantitative analysisversus quantitative analysis as the referencestandard (relates to review question 3).92
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Chapter 4
Results
Possiblediagnostic studies, n = 2762
Possibleeconomicstudies, n = 747
PossibleRCTs,n = 1310
878
2116153
422
168 2322
FIGURE 2 Results of search strategy: number of ‘possible’ RCTs, diagnostic studies and economic studies
Each of the studies was described individually, in anarrative fashion. All studies reported 2 × 2diagnostic data and we calculated additionaldiagnostic outcomes (sensitivity, specificity,predictive values, likelihood ratios) as required.Where cells in 2 × 2 tables contained zero, a valueof 0.5 was used in order to permit calculations. Aseach study addressed a different research question,data were not pooled. The numbers recruitedaccording to wound aetiology were reported in allthree studies (see Appendix 4, data extractiontables). A summary of the quality assessment ofthe diagnostic studies is given in Appendix 5. Inone study, separate outcome data were providedon venous leg ulcers (n = 7), but the very smallnumber of DFUs did not merit separate analysis(n = 2).90 For the other two studies, data werereported for the overall sample of wounds ofmixed aetiologies, without further breakdown. Interms of patient characteristics related to the DFU(type 1 or type 2 diabetes and presence ofneuropathy/ischaemia), insufficient data wereavailable from the papers to consider subgroupanalyses according to these factors. One studyreported the type of diabetes90 and none of thestudies reported numbers of patients with DFUwho had neuropathy and/or ischaemia.
Review question 1: What is thediagnostic performance of clinicalexamination in the identification ofinfection in DFU? Gardner andcolleagues (2001)90
In a cross-sectional study, people with chronicwounds of various aetiologies were recruited viafour centres: an acute care veterans’ facility, along-term care veterans’ facility, a mixed acutecare and long-term care veterans’ facility and achronic wound clinic at a university medicalcentre. At three of the four study sites, only peoplewith a white blood cell count of >1500 cells/mm3
or a total lymphocyte count of >800 cells/mm3,plus a platelet count of >125,000/mm wereeligible for inclusion. People with wounds ofarterial aetiology were excluded at all study sites.Of the overall sample of 36 participants, 19 hadpressure ulcers, seven had venous leg ulcers, sixhad wounds from a secondary incision and twoeach had non-healing traumatic wounds andDFUs. Punch biopsy was the reference test and theindex test consisted of the use of a clinical signsand symptoms checklist constructed from twoother checklists. One of these checklists containedsigns of infection that the study authors defined as‘classic’: pain, erythema, oedema, heat andpurulent exudate. The second checklist consistedof a list of signs and symptoms specific to
secondary wounds proposed by other authors:93
serous exudate plus concurrent inflammation,delayed healing, discoloration of granulationtissue, friable granulation tissue, pocketing of thewound base, foul odour and wound breakdown.The inter-rater reliability of the items on thechecklist was assessed using wound observationsmade independently by the principal investigatorand one of five specifically trained nurses,representing each study site (� range from 0.53 to1.00). The authors did not report outcomes forone clinical sign, pocketing of the wound base, asthere was no agreement owing to non-occurrenceof the sign within the study sample.90 At thechronic wounds clinic, the biopsy was performedwithin 8 hours of data collection for clinical signsand symptoms; the time interval between tests wasless than 1 hour for the other study sites (GardnerSE, University of Iowa School of Nursing: personalcommunication, 2003). Infection was defined asthe presence of at least 105 organisms per gram ofviable wound tissue, or wounds containing �-haemolytic Streptococcus at any level. Diagnosticmeasures were calculated for each individualclinical sign or symptom and verified againsttissue biopsy findings. The results that follow arefor the overall sample of wounds of variousaetiologies. Explanations for the diagnosticoutcomes used have been provided. Results areshown in Table 4 and in Appendix 4.
Sensitivity and specificity are properties of a testthat are concerned with the correct classification ofpeople according to their disease status. It isassumed that the result of the reference test iscorrect, and therefore that a positive result fromthe reference test equates to presence of thedisease and that a negative result denotes absenceof the disease. Sensitivity can be defined as theproportion of participants with the target diseasewho have a positive result for the disease from theindex test.94 In this study, the highest sensitivityvalues were seen for two separate clinical signs,presence of friable granulation and delayedhealing. They both correctly identified around80% of patients with a wound infection. However,the respective specificity values were 76% and64%, suggesting that the diagnostic performanceof these two signs may be less than optimal.Although increasing pain and wound breakdownboth had 100% specificity, they were associatedwith low sensitivity levels.
Predictive values are an estimate of the probabilityof disease, given the result of a test. They aredetermined by the prevalence of disease in thepopulation being tested. Positive predictive value
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(PPV) is defined as the probability of disease in apatient with a positive index test result.94 For thesymptom of increasing pain and the sign of woundbreakdown, the probability of patients with eitherof these clinical indicators having a woundinfection was 100%, whereas the probability forthose with purulent exudate was 18% (lowestvalue). Negative predictive value (NPV) is theprobability of not having the disease when the testresult is negative.94 In this study, the probability ofnot having a wound infection in the absence ofboth friable granulation and delayed healing wasaround 90% (highest values), around 80% forincreasing pain, oedema, serous exudate plusconcurrent inflammation or discolouration, withthe lowest value being 64% for purulent exudate.
Likelihood ratios (LRs) are another way ofexpressing the performance of a diagnostic test.Whereas sensitivity, specificity and predictivevalues use probability in their estimations, LRs arebased on the use of odds. They estimate howmany times more (or less) likely a test result is tobe found in diseased compared with non-diseasedparticipants.94
For this study, the range of values for positiveLR (+LR) included 1.14 for heat and 22.73 forwound breakdown, meaning that, for example,wound breakdown is almost 23 times more likelyto be observed in the presence of wound infectionthan in the absence of it. The +LR for increasingpain was around 18. The negative LR (–LRs)ranged from 0.97 for heat to 0.24 for friablegranulation. These values gives odds of around1:1.02 that absence of heat would occur in thepresence of an infection compared with absence ofinfection, and odds of around 1:4.2 that absence
of friable granulation would occur in the presenceof an infection compared with absence ofinfection. A proposed ‘rule of thumb’ suggests that +LRs greater than 10 or –LRs less than 0.1 give convincing diagnostic evidence, and that values above five and below 0.2, respectively,provide strong diagnostic evidence.88 Going by this, it seems that increasing pain and woundbreakdown may be useful individually asdiagnostic tests. However, these findings should be interpreted with caution owing to thesmall size of the study and the heterogeneity ofthe group recruited with respect to woundaetiology.
The LR values for one particular clinical sign,purulent exudate, merit special consideration (seedata extraction table in Appendix 4, pp. 126–30).The calculated values are the opposite to whatwould normally be expected, that is, the +LR inthis case is less than 1 (0.51), and the –LR isgreater than 1 (1.28). This may be explained asfollows. For the +LR, the ratio is derived from thevery low sensitivity rate for this test (18%) and therelatively high number of false positives expressedas a proportion of the total without disease asverified by the reference standard. For the –LR theratio is derived from the large proportion of falsenegatives relative to the total with disease and thespecificity of 64%. These findings are as would beexpected for a test that excludes disease asopposed to identifying it. The conclusion fromthese data is that purulent exudate is a particularlypoor test for identifying wound infection, and thatabsence of this clinical sign is more likely toindicate infection than its presence. The valuesobtained for related diagnostic outcomes supportthis conclusion. In terms of sensitivity, only 18% ofpatients with a wound infection were correctly
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TABLE 4 Diagnostic outcomes for individual clinical signs and symptoms90
Sign or symptom Se (%) Sp (%) PPV NPV +LR –LR
Increasing pain 36 100 100 78 18.18 0.64Erythema 55 68 43 77 1.71 0.67Oedema 64 72 50 82 2.27 0.50Heat 18 84 33 70 1.14 0.97Purulent exudate 18 64 18 64 0.51 1.28Serous exudate plus concurrent inflammation 55 72 46 78 1.95 0.63Delayed healing 81 64 50 89 2.27 0.28Discoloration 64 56 39 78 1.45 0.65Friable granulation 82 76 60 90 3.41 0.24Foul odour 36 88 57 76 3.03 0.72Wound breakdown 46 100 100 81 22.73 0.55
+/–LR, positive/negative likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; Se, sensitivity; Sp, specificity.
identified with purulent exudate, and forspecificity, 64% without a wound infection hadabsence of this clinical sign. In addition, theprobability of patients with purulent exudatehaving a wound infection was 18% (PPV), and theprobability of not having an infection in theabsence of this sign was 64% (NPV). Anotherclinical sign that is noteworthy in this respect isthe presence of heat around the wound. Heat had+LR and –LR values that were very close to one,indicating limited diagnostic usefulness (+LR1.14, –LR 0.97). Other outcomes for heat were asfollows: sensitivity 18%; specificity 84%; PPV 33%;and NPV 70%. Again, the small size of this studymeans that findings should be viewed withcaution.
The author was contacted to request data stratifiedaccording to wound type. Data on sensitivity forclinical signs and symptoms for venous leg ulcerswere provided (n = 7).95 The values ranged from100% for oedema or delayed healing to 25% forincreasing pain, heat, serous exudate plusconcurrent inflammation, discoloration or foulodour (see data extraction tables for the full rangeof values). The sensitivity for purulent exudate was67%, somewhat higher than the value calculatedfor the overall sample.
A summary of the quality assessment of this studyis given in Appendix 5. The selection criteria forpatients were clearly described, all patientsreceived both index and reference tests, the indextest did not form part of the reference test,execution of both tests was described in sufficientdetail to permit replication and there did notappear to be any uninterpretable test results orstudy withdrawals. Owing to the general scarcity ofresearch in this area, it was unclear whether thereference test (tissue biopsy) would correctlyclassify wound infection. It was also unclear fromthe paper whether interpretation of test resultswas blind and whether the same clinical datawould be available when test results wereinterpreted as would be available when the test isused in clinical practice. Standard practice maynot involve examination of a gauze swab appliedto the wound for 1 hour as an assessment forpresence of exudate. For three of the four studysites, tissue biopsy was obtained less than 1 hourafter clinical assessment (Gardner SE, Universityof Iowa School of Nursing, personalcommunication, 2003), and this would seem to bea short enough time interval to be confident thatthe infection status of the wound would not havechanged between tests. However, the time lag waslonger in the fourth site (8 hours) and it is
possible that the infection status of the woundcould have changed during this time. In terms ofthe spectrum composition (patient characteristicsof the sample recruited for the study), theselection criteria used in three out of the fourstudy sites (white blood cell count>1500 cells/mm3 or total lymphocyte count>800 cells/mm3; platelet count >125,000 mm)may have meant that the group recruited were notrepresentative of the patients who would receivethe test in clinical practice.
SummaryA wide range of values was seen for sensitivity,specificity and predictive values for the individualsigns and symptoms. It is arguable that highsensitivity is most important in this context, inorder to rule out disease, due to the potentiallyserious consequences of DFU infection.Interpretation of the derived LRs suggests that thesigns and symptoms checklist is not a usefulmethod of identifying infection in chronic wounds, with the possible exceptions of increasing pain and wound breakdown. Thedifferent values observed for the small subgroup ofpatients with venous leg ulcers relative to thewhole sample may be due to chance or differentialperformance of the tool when used with specificwound types. Generalisability of findings ishindered owing to the participant eligibilitycriteria used and aspects of the method ofassessment. Interpretation of study findings isfurther impeded by possible sources of bias andthe current lack of information on an optimumreference standard.
Review question 2: What is thediagnostic performance of specimenacquisition techniques in theidentification of infection in DFU?Bill and colleagues (2001)91
Patients attending a university-based chronicwound centre were recruited to a cross-sectionalstudy if they had a cutaneous wound at any bodysite, present for at least 6 months. Of the overallsample of 38 participants, 18 had pressure ulcers,10 had DFUs and five each had venous leg ulcers and arterial ulcers. Punch biopsy taken from the centre of the wound was the referencetest and wound swab with quantitative analysis was the index test. Tissue biopsy was carried out immediately after the wound swab wasobtained. The authors defined soft tissue infectionas the presence of more than >105 colony-formingunits (CFUs) per gram of tissue for tissue biopsyand greater than >105 CFUs cm2 for swabculture.91
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Although the authors did not calculate diagnosticoutcomes, they reported sufficient data topopulate a 2 × 2 diagnostic table for the overallsample. From these data, the sensitivity, specificity,PPV, NPV, +LR and –LR for wound swab withrespect to wound tissue biopsy as the referencestandard were calculated.
The estimated sensitivity for wound swab was 79%and specificity was 60%, as verified by tissuebiopsy. In terms of predictive values, PPV was 85%and NPV was 50%. The +LR was 1.96, meaningthat a positive wound swab result is almost twice as likely to occur in people with a woundinfection compared with those without aninfection. The –LR was 0.36, giving odds ofaround 1:2.8 that a negative wound swab wouldoccur in the presence of an infection comparedwith absence of infection. Going by the rule ofthumb described previously, it seems that thewound swab as used in this evaluation is not auseful diagnostic test.
The authors were contacted and requested toprovide 2 × 2 diagnostic data on the patients withDFUs, but data were unavailable.
The main issues around quality assessment (seeAppendix 5) were lack of evidence as to whethertissue biopsy is a valid reference standard, nodescription of blind test verification and lack ofclarity as to whether the same clinical data wereavailable when test results were interpreted aswould be available when the test is used inpractice. On a positive note, the selection criteriaand baseline characteristics of participants wereclearly described, the time lag between tests wasvery short, patients were sampled consecutivelyand all patients received the reference test. Theindex test did not form part of the referencestandard, and the execution of both tests wasdescribed in sufficient detail to permit replication.There did not appear to have been anyuninterpretable tests or withdrawals from thestudy.
SummaryThe sensitivity for wound swab was 79%, meaningthat the swab would fail to detect approximatelyone in five wound infections. The derived LRssuggest that the wound swab is not a usefulmethod of identifying infection in chronic wounds.Interpretation of study findings is impeded bypossible sources of bias and the current lack ofinformation on an optimum reference standardthat should be used to verify the diagnosticperformance of wound swab.
Review question 3: What is thediagnostic performance of differentlaboratory analysis techniques in theidentification of infection in DFU?Ratliff and Rodeheaver (2002)92
Patients attending a university-based wound careclinic were recruited if they had any type ofcutaneous wound present at any body site formore than 6 months. Of the overall sample of 124 participants, 44 had pressure ulcers, 27 hadulcers due to venous insufficiency, 29 hadneuropathic or diabetic ulcers, eight had lowerextremity ulcers due to arterial disease and 16 hadwounds due to other aetiologies (not described in the paper). The aim of this study was to assessthe diagnostic performance of semi-quantitativeanalysis of wound swab using quantitative analysis as the reference standard. All patients hadtwo wound swabs taken, using similar techniquesand materials (calcium alginate-tipped swabs).Quantitative techniques for analysing specimensobtained from wound swabs involve identifying thetype, and counting the numbers ofmicroorganisms present. Semi-quantitativetechniques entail classifying a level of bacterialgrowth by observing growth on four quadrants ofan agar plate where each quadrant has beenstreaked in sequence using a sterile loop for eachquadrant, thus making dilutions of the originalstreak on to each sequential quadrant. The greater the quantity of bacteria on the originalswab, the more quadrants will display bacterial growth. In this study, the swab forquantitative analysis was obtained after the swab for semi-quantitative analysis; however, thetime interval between acquisitions of the twospecimens was not stated. Soft tissue infection wasdefined as the presence of at least 105 CFUs cm2
for swab culture, derived from quantitativeanalysis.
The authors presented 2 × 2 diagnostic data fordifferent diagnostic thresholds of semi-quantitativeand quantitative analyses (quantitative range from102 to 107 CFUs cm2 for swab culture). In thepaper, sensitivity and specificity were reported fora reference standard level of 105 CFUs cm2. Wecalculated additional diagnostic outcomes(predictive values and LRs) and also generatedoutcomes for a range of possible diagnosticthresholds for the semi-quantitative analysis, ineach case using the stipulated reference standardlevel of 105 CFU cm2 for the quantitative analysis.Referring to the spread of bacterial growth acrossquadrants of an agar plate, the range of diagnosticthresholds for semi-quantitative analyses aredescribed and illustrated in Box 2.
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The outcomes for the different levels of semi-quantitative analysis are given in Table 5.
As may be expected, sensitivity was higher withless stringent definitions of infection, whereasspecificity decreased. As seen from Table 5,different values of sensitivity and specificity arederived when different diagnostic thresholds areused. When several different thresholds have beenproduced, these can be displayed on an ROC plotin order to help determine the optimumcombination of sensitivity and specificity (andtherefore the optimum diagnostic threshold touse). An ROC curve was generated for the fourdifferent levels of cut-off that were used for semi-quantitative analysis of wound swab (Figure 3). Thetrue positive rate (sensitivity) is plotted against thefalse positive rate (1 – specificity). Table 6 showsthe coordinates used to plot the ROC curve. Anuninformative test would be represented by a
diagonal line sloping upwards from left to rightacross the graph. Coordinates appearing closest tothe top left-hand corner of the graph indicate themost informative combination of sensitivity andspecificity values, and therefore indicate theoptimum diagnostic threshold to use.88 Accordingto these principles, it appears from this plot thatthreshold C is the most useful. However, asdiscussed in the original paper, it is necessary toconsider the clinical implications of different ratesof false positives and false negatives. For example,extrapolating from this study using the diagnosticthreshold C (Tables 5 and 6), 21% of patientswould have a false negative test result using semi-quantitative analysis and would experience a delayin receiving antimicrobial treatment. In addition,10% of patients would have false positive resultsand would receive antimicrobial therapyunnecessarily.92 Consideration of the effect of suchrates on clinical outcomes and costs may help
Results
24
A. Observed bacterial growth in any quadrant (QI, or Q1 + Q2, Q1 + Q2 + Q3, or Q1 + Q2 + Q3 + Q4: the least strict definition of infection)
B. Observed bacterial growth in at least 2 quadrants: Q1 + Q2, or Q1 + Q2 + Q3, or Q1 + Q2 + Q3 + Q4
C. Observed bacterial growth in at least three quadrants: Q1 + Q2 + Q3, or Q1 + Q2 + Q3 + Q4 (the definition of infection used by the study authors)
D. Observed bacterial growth in all four quadrants: i.e. Q1 + Q2 + Q3 + Q4 (most strict definition of infection)
BOX 2 Semi-quantitative descriptions of infection
TABLE 5 Diagnostic outcomes for semi-quantitative analysis of wound swab when different diagnostic thresholds (levels of growth) are used
Level of growtha Se (%) Sp (%) PPV (%) NPV (%) +LR –LR
A 100 37 54 100 1.58 0.026B 100 63 67 100 2.73 0.015C 79 90 86 85 8.04 0.23D 26 99 93 64 18.75 0.75
+/–LR, positive/negative likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; Se, sensitivity; Sp, specificity.a A, observed bacterial growth in quadrant I, quadrants I and II, quadrants I, II and III or quadrants I, II, III and IV;
B, observed bacterial growth in quadrants I and II, quadrants I, II and III or quadrants I, II, III and IV; C, observed bacterialgrowth in quadrants I, II and III or quadrants I, II, III and IV; D, observed bacterial growth in quadrants I, II, III and IV.
clinicians to determine the optimum diagnosticthreshold to use.
ROC curve plots enable the area under the curveto be estimated. This value is the probability of thediagnostic test correctly classifying a patient withor without an infection. The greater the area, themore accurate is the test, with perfect performancerepresented by a value of 1.0. A value of 0.5represents an uninformative test.96,97 For semi-quantitative analysis of wound swabs, theestimated area under the ROC curve was 0.92[95% (CI) 0.87 to 0.97], meaning that theprobability that cases were correctly classified was 92%.
In terms of predictive values, PPVs increased withthe more strict criteria and NPVs decreased(Table 5). +LRs, an estimate of how many moretimes a positive test result is likely to be found indiseased people compared with non-diseasedpeople, increased with increasing stringency ofdiagnostic criteria. According to the rule of thumbmentioned earlier for interpretation of +LRs, thestrictest diagnostic criterion provided convincingdiagnostic evidence (threshold D), the secondstrictest criterion provided strong diagnosticevidence (threshold C), whereas the values derivedfrom the two least strict criteria were lessinformative (thresholds A and B). For –LRs,thresholds A and B (the less strict definitions of
Health Technology Assessment 2006; Vol. 10: No. 12
25
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
0.0
Threshold C
0.0
0.2
0.4
0.6
0.8
1.0
0.2 0.4 0.6 0.8 1.0
Threshold D
Threshold B
Threshold A
Sens
itivi
ty (t
rue
poiti
ve r
ate)
1 – specificity (false positive rate)
FIGURE 3 ROC plot for detecting wound infection using semi-quantitative analysis of wound swab with reference to quantitativeanalysis of swab as the reference standard
TABLE 6 Coordinates used to plot the ROC curve
Level of growtha Sensitivity (true positive rate) 1 – Specificity (false positive rate)
A 1.000 0.634B 1.000 0.366C 0.792 0.099D 0.264 0.014
a See Table 5.
infection) showed convincing diagnostic evidence,whereas for the two stricter definitions of infection(thresholds C and D), the values derived were notinformative according to the rule of thumb.However, for diagnostic threshold C, the valueapproached usefulness (see Table 5).
A summary of the quality assessment for this studyis given in Appendix 5. The patient selectioncriteria were clearly described and the spectrum ofpatients recruited appeared to be representative ofthose who would receive the test in clinicalpractice. All patients received both tests, the indextest was not a component of the reference test,both tests were reported in sufficient detail topermit replication and there did not appear to beany uninterpretable results or study withdrawals.However, the time lag between tests was notstated. In addition, it was not clear whether thereference standard (quantitative analysis of woundswab) could correctly identify wound infection,whether blind interpretation of test results wasperformed or whether the same clinical data wereavailable when test results were interpreted aswould be likely to be available in clinical practice.
SummaryFindings suggest that semi-quantitative analysismay be a useful alternative to quantitative analysis,particularly for settings where the equipment andmaterials necessary for the latter are not available.Overall, threshold C gave the best diagnosticperformance (see Box 2). Interpretation of studyfindings is hindered by possible sources of biasand the current lack of information on anoptimum reference standard.
Effectiveness studiesOur searches identified 1903 citations, of which163 were potentially relevant to questions 4 and 5,namely effectiveness/cost-effectiveness ofmicrobiological analysis or antimicrobial agents.
Excluded studiesThe 140 effectiveness studies that were thought tobe potentially relevant to review questions 4 and 5,which were found to be ineligible after retrieval,are summarised in the excluded studies table inAppendix 6.
The reasons for exclusion were as follows: studynot an RCT or CCT of an antimicrobial, n = 98;study did not report data for diabetic foot ulcersseparately and <80% of patients had diabetic footulcers, n = 40. Two systematic reviews were
identified in the search and these werehandsearched for RCTs/CCTs.98,99
Review question 4: What impact doesmicrobiological analysis have ontherapy?Included studiesWe found no trials answering this question. Suchstudies would have compared a policy of taking amicrobiological sample (e.g. swab) or not at thepoint at which a patient was deemed to have aninfection and hence would have allowed us toevaluate the impact that microbiological analysishas on clinical outcomes.
Review question 5: What is theeffectiveness and cost-effectiveness ofmanagement of infection in DFU?Included studiesWe identified 23 trials (21 RCTs and two CCTs),including 25 comparisons, addressing thisquestion.
Quality of included studiesDetails of study quality assessment are given inAppendix 5. The methodological quality of allincluded RCTs was assessed using the criteriareported in the Jadad five-point scale85 and theallocation concealment criterion described bySchulz and colleagues.86
Results using the four assessment criteria are asfollows. Nine studies reported appropriatemethods of randomisation, 12 trials were simplydescribed as ‘randomised’ and two allowed thepatients to choose the groups to which they wereallocated. Two studies reported an appropriateprocedure for allocation concealment; in 17studies it was unclear if the person randomisingthe participants was aware of the allocation, in twostudies allocation was open and two studies wereCCTs, in which patients chose their treatment.Three trials described appropriatedouble–blinding, five described the trial asdouble-blind, in 13 trials there was no informationon double-blinding and in the two CCTs thepatients and clinicians were not blinded. Thirteenstudies reported the number and reason forwithdrawals, nine studies did not report reasonsfor withdrawal by group and one reported nowithdrawals.
Gough and colleagues100 and Peterson andcolleagues101 both described appropriate methodsfor allocation concealment, described appropriatemethods of generating the randomisationsequence, and both reported reasons and number
Results
26
of withdrawals by study group. In addition, bothstated they were double-blind, with the trial byGough and colleagues100describing how this wasachieved . Other trials may have been designed,performed and analysed to the highest standardsbut failed to report this in the study publication.Although these two trials were of high quality, theweight given to their findings is moderated by thefact that both are small (40 and 48 patients) andtherefore underpowered.
OutcomesThere was a wide variation across studies of theoutcome measures used. Twenty-one outcomeswere reported and no single outcome was reportedin all trials (Table 7). Adverse events, includingdeath, were reported in 16 trials. Amputation wasreported in 11 trials, clinical diagnosis of cure ofinfection in nine trials and proportion of ulcershealed in 11 trials. The large number of outcomesused and the lack of consistency in reportingoutcomes mean that the data on effectiveness aredifficult to synthesise.
The incidence of osteomyelitis, pain, ulcerrecurrence, mobility, level of independence,number of hospital admissions or health-relatedquality of life were not reported in any of theincluded studies. A large number of outcomes,which we had not specified in the review protocol,were reported in the studies and these are
identified in Table 7 as shaded columns. Clinicalcure of infection and the need for vascularreconstruction were not initially included in thereview outcomes. As these outcomes were reportedin nine and five trials, respectively, and we felt theymay report clinically important outcomes, wedecided, post hoc, to report these outcomes wherethey were available. If clinical assessments ofinfection status were found by the diagnosticreviews to be a valid indication of infection status(question 1), which was not the case, then thisoutcome would be a valid outcome measure.Vascular reconstruction may be seen as a procedureused to avert amputation, and therefore we felt thatit may also provide clinically relevant information.
PopulationThere was wide variation in the types of patientsrecruited to the trials and the ulcer characteristicsand settings are summarised in Table 8. There wasno information on the severity of ulceration in14 trials. One trial used its own ulcer gradingsystem and the remainder (eight trials) used theWagner classification system (Box 3)102 or theUniversity of Texas San Antonio Diabetic WoundClassification System (Box 4)103 The latterclassification system takes account of infection andischaemia in addition to ulcer depth. Three trialsstated that they included people with a grade1 ulcer, six included grade 2 ulcers, four grade3 ulcers and two grade 4 ulcers (as some trials
Health Technology Assessment 2006; Vol. 10: No. 12
27
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Grade Lesion0 No open lesions; may have deformity or cellulitis 1 Superficial diabetic ulcer (partial or full thickness) 2 Ulcer extension to ligament, tendon, joint capsule or deep fascia without abscess or osteomyelitis3 Deep ulcer with abscess, osteomyelitis or joint sepsis4 Gangrene localised to portion of forefoot or heel5 Extensive gangrenous involvement of the entire foota Source: Frykberg.104
BOX 3 Wagner ulcer classification systema
Stage Grade
0 1 2 3
A Pre- or postulcerative Superficial wound, not Wound penetrating to Wound penetrating tolesion completely involving tendon, capsule tendon or capsule bone or joint
or bone
B With infection With infection With infection With infection
C With ischaemia With ischaemia With ischaemia With ischaemia
D With infection and With infection and With infection and With infection and ischaemia ischaemia ischaemia ischaemia
BOX 4 University of Texas San Antonio Diabetic Wound Classification System
recruited patients with a range of ulcer severity,this total is greater than eight).
Four studies did not provide sufficient informationto allow us to determine whether the patients hadulcers with established infection. Twelve studies
stated that the ulcer was infected and sevenevaluated antimicrobial agents on apparentlyuninfected ulcers.
Three studies did not report information on thesite of treatment (inpatient or outpatient), 14 were
Results
28
TABLE 7 Outcome measures reporteda
Limb Infection outcomes Ulcer healing Organisationoutcomes outcomes outcomes
Study ID
Intravenous interventionsBouter (1996)106 × × ×Bradsher (1984)43 × × ×Erstad (1997)107 × × × × ×Grayson (1994)44 × × × × × × ×Lipsky (2004)109 × × ×Seidel (1991)110 × × × × × ×Seidel (1993,1994)111,112 × ×Tan (1993)108 × × ×
Oral interventionsChantelau (1996)74 × × ×Lipsky (1990)75 × × × ×Lipsky A114 × × × × ×Lipsky B114 × × × × ×Peterson (1989)101 × × ×
Subcutaneous interventionsGough (1997)100 × × × × × × × × ×Kastenbauer (2003)118 × × × × × ×de Lalla (2001)119 × × × × ×Yonem (2001)120 × ×
Topical interventions Apelqvist (1995)138 × × × × ×Marchina (1997)123 ×Markevich (2000)105 ×Rhaiem (1998)124 × × ×Vandeputte (1996)125 × × × × ×
Other interventionsDwivedi (2000)127 ×
a Shaded cells indicate outcomes listed in the protocol for this review as being relevant.
Am
puta
tion
Vas
cula
r re
cons
truc
tion
Req
uire
d su
rgic
al d
ebri
dem
ent
Clin
ical
cur
e of
infe
ctio
n
Dur
atio
n of
ant
ibio
tic
ther
apy
Erad
icat
ion
of p
atho
gens
Req
uire
d ad
diti
onal
ant
ibio
tics
Cur
e of
ost
eom
yelit
is
Bac
teri
olog
y
Tim
e to
res
olut
ion
of c
ellu
litis
Tim
e to
cle
ar s
wab
Pro
port
ion
wit
h re
solu
tion
of c
ellu
litis
Infe
ctio
n su
mm
ary
scor
e
Pro
port
ion
of u
lcer
s he
aled
Tim
e to
hea
ling
Are
a or
vol
ume
chan
ge
Cha
nge
in g
rade
Tim
e to
dis
char
ge
Cos
ts
Adv
erse
eve
nts
conducted on inpatients, five on outpatients andone on both inpatients and outpatients. The siteof treatment was related to the presence ofestablished infection (Table 8). Eleven studies ofestablished infection in ulcers were undertaken inhospital inpatients and only one treated peoplewith infected ulcers as outpatients.75 One studyapparently reported treatment of people withoutestablished infection as inpatients.105 There weretwo studies in which the setting was not clear andan additional four studies in which the status ofthe patient regarding ulcer infection was not clear.Therefore, it is not clear whether the relationshipbetween infection status and site of treatment isclear cut.
Interventions and comparisonsA number of intervention types were included inthis review: intravenous, oral, subcutaneous,topical and other methods. The ‘other’ groupincluded, for example, studies comparing oral andtopical administration methods with a topicalintervention, or where there were mixed methodsof administration.
Comparisons of methods of administrationincluded studies of intravenous versus intravenousadministration, oral versus oral, topical versustopical, oral versus topical and subcutaneousversus standard care or placebo. The variouscomparisons made are summarised in Table 9.
Owing to the heterogeneity in intervention andoutcomes, it was not possible to undertake anymeta-analyses.
Effectiveness of intravenousinterventionsEight studies are included in this group. Fourtrials made straight comparisons betweenintravenous regimens,44,106–108 one compared tworegimens in which therapy started as intravenousand was changed to oral as the patient’s conditionimproved,109 two trials (three reports) comparedtwo different methods of infusion of antibiotics(retrograde venous perfusion and regularintravenous infusion)110–112 and one compared anintravenous antibiotic with a comparator giveneither IV or intramuscularly.43
Health Technology Assessment 2006; Vol. 10: No. 12
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© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
TABLE 8 Characteristics of study settings and patient characteristics
Study Setting Ulcer grade Infected
Bouter (1996)106 IP Wagner grade 2, 3 or 4 YBradsher (1984)43 IP No information Yde Lalla (2001)119 IP Wagner grades 3 and 4 YErstad (1997)107 IP Used own grading system – most were grade 2 and 3 – cellulitis Y
+ skin break or cellulitis + deep ulcer or cellulitis and puncture plus suspected osteomyelitis
Gough 1997100 IP No data on grade YGrayson (1994)44 IP No data on grade but did provide data on baseline coma YKastenbauer (2003)118 IP Wagner grade 2 or 3 YLipsky (2004)109 IP No data on grade YPeterson (1989)101 IP No data on grade YRhaiem (1998)124 IP No data on grade NSeidel (1991)110 (CCT) IP No data on grade, 12/40 had osteomyelitis UnclearSeidel (1993,1994)111,112 IP No data on grade, Unclear Tan (1993)108 IP No data on grade YYonem (2001)120 IP Wagner grade 2 or less YMarkevich (2000)105 IP Grade 2 and 3 NApelqvist (1996)122 OP Wagner grade 1 or 2 NDwivedi (2000)127 OP No data on grade Unclear Lipsky A114 OP No data on grade NLipsky B114 OP No data on grade NLipsky (1990)75 OP No data on grade YChantelau (1996)74 OP + IP Grade 1A to 2A (Texas) UnclearMarchina (1997)123 Unclear 1st or 2nd degree (not defined) NVandeputte (1996)125 Unclear No data on grade N
IP, inpatient; OP, outpatient; Y, yes; N, no.
We found no trials comparing an intravenousantibiotic with a placebo. We found no studiescomparing an intravenous antibiotic against anoral, topical or subcutaneous intervention.
All comparisons were unique and each featuredtwo active treatment groups. In seven trials morethan one antibiotic was used, for exampleampicillin and sulbactam (A/S) or imipenem andcilastatin (I/C); only Bradsher and Snow made asimple comparison of two single antibiotics,ceftriaxone versus cefazolin.43 A/S was acomparator in three trials,44,107,109 I/C was acomparator in two trials44,106 and linezolid,109
piperacillin and clindamycin (P/C),106 piperacillinand tazobactam108 and ticarcillin and clavulanate(T/C)108 were each used in one trial. Onecomparison of two methods of infusion usedpiperacillin and gentamicin110 and the other usedpiperacillin and netilmycin.111,112
The trial results are summarised in Table 10.Further details on each trial are provided in thedata extraction tables in Appendix 4.
Description of the studiesBouter and colleagues (1996)106
Bouter and colleagues106 compared I/C with P/Cadministered intravenously in 46 hospitalisedpatients (mean age 71.4 years) with DFUs whoseankle/brachial index was at least 0.45. Theantibiotic treatment period was a minimum of10 days and the mean duration of therapy was
23–24 days. All patients underwent bed rest andthrombolytic therapy. Foot infections wereidentified as polymicrobial in more than half ofthe cases. There was no statistically significantdifference in the numbers of people with clinical‘cure’ (defined as the disappearance of initialinfection) between the two groups: 4/22 (18%) withI/C and 6/24(25%) with P/C (RR 1.38, 95% CI 0.48to 4.11). There was no statistically significantdifference in the prevalence of ‘bacterialeradication’, 9/22 (41%) for I/C and 16/24 (67%)for P/C (RR 1.63, 95% CI 0.94 to 3.02). Theincidence of adverse events was statisticallysignificantly higher in the P/C group (50%) thanin the I/C group (19%) (RR 3.67, 95% CI 1.33 to11.13), with diarrhoea being the single mostfrequently reported event. The trial wasunderpowered, however, so it was unable to detectall but massive differences in effectiveness asstatistically significant.
Bradsher and Snow (1984)43
Bradsher and Snow compared cefazolin givenintravenously with ceftriaxone administered eitherintravenously or intramuscularly in 84 inpatientswith suspected skin and soft tissue infection, ofwhom 20 had suppurative DFUs.43 Baselineinformation on demographics and bacteriology ispresented for the whole study population,including people with cellulitis, abscess,thrombophlebitis, pressure ulceration and surgicalwound infection. Results for the people with DFUs
Results
30
TABLE 9 Comparisons made in included studies.
i.v Oral Topical Placebo Standard care
i.v. antibiotics 1. Bouter106
2. Erstad107
3. Grayson44
4. Lipsky109
5. Seidel110
6. Seidel111
7. Tan108
Oral antibiotics 1. Lipsky75 1. Lipsky A114 1. Chantelau74
2. Peterson101 2. Lipsky B114
Subcutaneous growth 1. Gough174 1. de Lalla119
factors 2. Kastenbauer118 2. Yonem120
Topical antimicrobial 1. Apelqvist122 1. Rhaiem124
2. Marchina123 (sugar vs standard 3. Markevich105 care)4. Vandeputte125
Other antimicrobial 1. Bradsher43 1. Rhaiem124 1. Dwivedi 127
agents (i.v. versus either (sugar vs i.v. or i.m.) antibiotics)
Health Technology Assessment 2006; Vol. 10: No. 12
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© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
TA
BLE
10
Sum
mar
y of
com
paris
ons,
out
com
es a
nd re
sults
from
effe
ctive
ness
stu
dies
Stud
yC
ompa
riso
n A
Out
com
eD
ata
RR
, 95%
CI
Com
pari
son
B(d
icho
tom
ous
outc
omes
)M
ean d
iffe
rence,
95
% C
I
(conti
nuous
outc
om
es)
Intr
ave
nous
inte
rventi
ons
Bout
er (1
996)
106
Imip
enem
/cila
stat
in
Clin
ical
‘cur
e’ (d
isapp
eara
nce
of in
itial
infe
ctio
n)I/C
4/2
2 (1
8%)
RR 1
.38
Pipe
raci
llin/
clin
dam
ycin
P/C
6/2
4 (2
5%)
95%
CI 0
.48
to 4
.11
Imip
enem
/cila
stat
in‘B
acte
rial e
radi
catio
n’
I/C 9
/22
(41%
)RR
1.6
3Pi
pera
cilli
n/cl
inda
myc
inP/
C 1
6/24
(67%
) 95
% C
I 0.9
4 to
3.0
2Br
adsh
er (1
984)
43C
efaz
olin
‘In
fect
ion
elim
inat
ed’ a
t fo
llow
-up
I/C 4
/10
(40%
)RR
1.5
Cef
tria
xone
P/C
6/1
0 (4
0%)
95%
CI 0
.60
to 3
.74
Erst
ad (1
997)
107
Am
pici
llin/
sulb
acta
mA
ny a
mpu
tatio
nA
/S 8
/18
(44%
)RR
1.0
Cef
oxiti
nC
8/1
8 (4
4%)
95%
CI 0
.48
to 2
.09
Am
pici
llin/
sulb
acta
mC
linic
al ‘c
ure’
(res
olut
ion
of s
igns
and
sym
ptom
s A
/S 1
/18
(6%
)RR
0.1
4C
efox
itin
of in
fect
ion)
C 7
/18
(39%
)95
% C
I 0.0
2 to
0.7
6A
mpi
cilli
n/su
lbac
tam
Adv
erse
eve
nts
A/S
7/1
8 (3
9%)
RR 1
.17
Cef
oxiti
nC
6/1
8 (3
3%)
95%
CI 0
.5 t
o 2.
8
Gra
yson
(199
4)44
Am
pici
llin/
sulb
acta
mTo
tal n
umbe
r of
am
puta
tions
A/S
33/
48 (6
9%)
RR 0
.85
Imip
enem
/cila
stat
in
I/C 2
8/48
(58%
)95
% C
I 0.6
2 to
1.1
5A
mpi
cilli
n/su
lbac
tam
Clin
ical
‘cur
e’ (r
esol
utio
n of
sof
t tis
sue
infe
ctio
n)
A/S
28/
48 (5
8%)
RR 1
.04
Imip
enem
/cila
stat
inat
the
end
of t
reat
men
t I/C
gro
up 2
9/48
(60%
)95
% C
I 0.7
4 to
1.4
5A
mpi
cilli
n/su
lbac
tam
Clin
ical
‘cur
e of
infe
ctio
n’ r
ates
at
final
follo
w-u
pA
/S 2
7/48
(56%
)RR
1.2
2Im
ipen
em/c
ilast
atin
I/C
33/
48 (6
9%)
95%
CI 0
.89
to 1
.7A
mpi
cilli
n/su
lbac
tam
Adv
erse
eve
nts
A/S
16/
48 (3
3%)
Imip
enem
/cila
stat
in
I/C 1
7/48
(35%
)
Lips
ky (2
004)
109
Line
zolid
(i.v
. or
oral
)C
linic
al c
ure
rate
(res
olut
ion
of a
ll cl
inic
al s
igns
Li
nezo
lid 6
9% (1
31/1
90)
RR 0
.92
Am
pici
llin/
sulb
acta
m o
r an
d sy
mpt
oms
and
a he
alin
g w
ound
afte
r 5
days
A
S/A
C 6
3% (5
7/93
)95
% C
I 0.7
6 to
1.0
9am
oxic
illin
cla
vula
nate
of t
hera
py)
Line
zolid
(i.v
. or
oral
)A
mpi
cilli
n/su
lbac
tam
or
Mea
n to
tal d
urat
ion
of t
hera
py r
equi
red
Line
zolid
mea
n 17
.2da
ysD
iffer
ence
= –
0.7
days
amox
icill
in/c
lavu
lana
teA
S/A
C m
ean
16.5
days
95
% C
I –2.
66 t
o 1.
26Li
nezo
lid (I
V or
ora
l)D
urat
ion
of t
reat
men
t w
ith i.
v. a
ntib
iotic
s Li
nezo
lid m
ean
7.8
days
M
ean
diffe
renc
e 2.
6da
ysA
mpi
cilli
n/su
lbac
tam
or
AS/
AC
mea
n 10
.4da
ys95
% C
I 1.2
2 to
3.9
8am
oxic
illin
/cla
vula
nate
Line
zolid
(i.v
. or
oral
)W
ithdr
awin
g fr
om t
he s
tudy
due
to
an a
dver
se
Line
zolid
, n=
18
(7.5
%)
RR 2
.24
Am
pici
llin/
sulb
acta
m o
r ev
ent
AS/
AC
n =
4 (3
.3%
)95
% C
I 0.8
2 to
6.2
4am
oxic
illin
cla
vula
nate
cont
inue
d
Results
32 TA
BLE
10
Sum
mar
y of
com
paris
ons,
out
com
es a
nd re
sults
from
effe
ctive
ness
stu
dies
(co
nt’d
)
Stud
yC
ompa
riso
n A
Out
com
eD
ata
RR
, 95%
CI
Com
pari
son
B(d
icho
tom
ous
outc
omes
)M
ean d
iffe
rence,
95
% C
I
(conti
nuous
outc
om
es)
Seid
el (1
991)
110
i.v. a
ntib
iotic
sPe
ople
req
uirin
g am
puta
tion
due
to u
nder
lyin
g i.v
. 4/2
0RR
9 H
alda
ne a
ppro
xim
atio
nRV
P in
fusio
ns o
f ant
ibio
tics
oste
omye
litis
RVP
0/20
95%
CI 0
.52
to 1
57
i.v. a
ntib
iotic
sN
umbe
r of
ulc
ers
heal
edi.v
. 0/2
0RR
0.0
77 H
alda
ne
RVP
6/20
appr
oxim
atio
nRV
P in
fusio
ns o
f ant
ibio
tics
95%
CI 0
.005
to
1.28
i.v. a
ntib
iotic
s‘R
esol
ved’
ost
eom
yelit
isi.v
. 0/7
RR 0
.083
Hal
dane
RV
P in
fusio
ns o
f ant
ibio
tics
RVP
4/5
appr
oxim
atio
n95
% C
I 0.0
05 t
o 1.
27
Seid
el (1
993,
199
4)11
1,11
2i.v
. ant
ibio
tics
Am
puta
tion
rate
i.v. 4
/21;
19%
RR 1
.52
RVP
infu
sions
of a
ntib
iotic
sRV
P 3/
24; 1
2.5%
95%
CI 0
.42
to 5
.57
i.v. a
ntib
iotic
sU
lcer
s he
aled
i.v. 3
/21
(14%
)RR
0.4
3RV
P in
fusio
ns o
f ant
ibio
tics
RVP
8/24
(33%
)95
% C
I 0.1
3 to
1.2
8
Tan
(199
3)10
8Pi
pera
cilli
n/ta
zoba
ctam
(P/T
)C
linic
al ‘c
ure’
(def
ined
as
reco
very
from
infe
ctio
n)Pe
r pr
otoc
ol a
naly
sis (P
PA)
PPA
: RR
0.66
Tic
arci
llin/
clav
ulan
ate
P/T
56%
(9/1
6):
T/C
86%
(6/7
)95
% C
I 0.3
7 to
1.2
6 PP
AIn
tent
ion
to t
reat
ana
lysis
(IT
TA)
ITTA
: RR
0.87
P/T
29%
(9/3
1) T
/C 3
3% (6
/18)
95%
CI 0
.39
to 2
.07
if al
l miss
ing
data
ass
umed
to
equa
l ‘fa
iled
to a
chie
ve a
cure
’O
ral i
nter
vent
ions
Cha
ntel
au (1
996)
74A
mox
ycill
in+
clav
ulan
ic a
cid
Hea
ling
rate
s A
/C 6
/22
(27%
)RR
1.6
7(A
ugm
entin
®)
Plac
ebo
10/2
2 (4
5%)
95%
CI 0
.76
to 3
.83
Plac
ebo
Am
oxyc
illin
+cl
avul
anic
aci
d A
bsen
ce o
f mic
robe
s in
dee
p sw
ab w
ound
A
/C 7
/22,
32%
RR 0
.86
(Aug
men
tin®
)cu
lture
s ta
ken
at c
ompl
etio
n of
the
stu
dyPl
aceb
o 6/
22, 2
7%95
% C
I 0.3
5 to
2.0
9Pl
aceb
oLi
psky
(199
0)75
Clin
dam
ycin
hyd
roch
lorid
e In
fect
ion
‘cur
e’ r
ate
(sig
ns a
nd s
ympt
oms
reso
lved
) Pe
r pr
otoc
ol a
naly
sis (P
PA)
RR 0
.93
(Cle
ocin
) C
linda
myc
in 2
1/27
(78%
)95
% C
I 0.6
7 to
1.2
9C
epha
lexi
n (K
efle
x)
Cep
ahle
xin
21/2
9 (7
2%)
Clin
dam
ycin
hyd
roch
lorid
e U
lcer
s he
alin
gPe
r pr
otoc
ol a
naly
sisRR
0.8
3(C
leoc
in)
Clin
dam
ycin
10/
27 (3
7%)
95%
CI 0
.4 t
o 1.
73C
epha
lexi
n (K
efle
x)C
epha
lexi
n 9
/29
(31%
)
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
33
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
TA
BLE
10
Sum
mar
y of
com
paris
ons,
out
com
es a
nd re
sults
from
effe
ctive
ness
stu
dies
(co
nt’d
)
Stud
yC
ompa
riso
n A
Out
com
eD
ata
RR
, 95%
CI
Com
pari
son
B(d
icho
tom
ous
outc
omes
)M
ean d
iffe
rence,
95
% C
I
(conti
nuous
outc
om
es)
Clin
dam
ycin
hyd
roch
lorid
e Er
adic
atio
n of
bac
teria
l pat
hoge
nsPe
r pr
otoc
ol a
naly
sisRR
0.9
(Cle
ocin
) C
linda
myc
in 2
0/26
(77%
)95
% C
I 0.6
3 to
1.2
6C
epha
lexi
n (K
efle
x)C
epha
lexi
n 20
/29
(69%
)C
linda
myc
in h
ydro
chlo
ride
Adv
erse
eve
nts
Clin
dam
ycin
1RR
2.0
(Cle
ocin
) C
epha
lexi
n 2
95%
CI 0
.28
to 1
4.8
Cep
hale
xin
(Kef
lex)
Lips
ky A
114
Pexi
gana
n cr
eam
Num
ber
of a
mpu
tatio
nsPe
xiga
nan
6/24
6 (2
.4%
)RR
1.5
Oflo
xaci
n O
floxa
cin
4/24
7 (1
.6%
) 95
% C
I 0.4
6 to
4.9
2Pe
xiga
nan
crea
mC
linic
al ‘c
ure’
rat
es (n
o fu
rthe
r sig
ns o
r sy
mpt
oms
Pexi
gana
n 63
/243
(26%
)RR
1.0
8O
floxa
cin
of in
fect
ion)
at
day
10
Oflo
xaci
n 67
/240
(28%
) 95
% C
I 0.8
1 to
1.4
5Pe
xiga
nan
crea
m‘M
icro
biol
ogic
ally
res
olve
d in
fect
ion’
at
final
Pe
xiga
nan
75/1
85 (4
0%)
RR 1
.07
Oflo
xaci
nfo
llow
-up
Oflo
xaci
n 84
/193
(44%
)95
% C
I 0.8
5 to
1.3
6Pe
xiga
nan
crea
mA
dver
se e
vent
s le
adin
g to
pat
ient
with
draw
alPe
xiga
nan
28/2
47 (1
1%)
RR 0
.82
Oflo
xaci
nO
floxa
cin
23/2
46 (9
%)
95%
CI 0
.49
to 1
.38
Pexi
gana
n cr
eam
Serio
us a
dver
se e
vent
sPe
xiga
nan
28/2
47 (1
1.3%
)RR
0.7
2O
floxa
cin
Oflo
xaci
n 20
/246
(8.1
%)
95%
CI 0
.42
to 1
.23
Lips
ky B
114
Pexi
gana
n cr
eam
Clin
ical
‘cur
e’ r
ates
(def
ined
abo
ve) a
t da
y 10
Pexi
gana
n 34
/171
RR 1
.0O
floxa
cin
Oflo
xaci
n 34
/171
95%
CI
Pexi
gana
n cr
eam
Infe
ctio
n ‘re
solv
ed’
Pexi
gana
n 44
(26%
)RR
0.6
8O
floxa
cin
Oflo
xaci
n 30
(18%
)95
% C
I 0.4
5 to
1.0
2IT
T p
rinci
ple:
ass
ume
sam
ple
size
= 1
71 fo
r ea
chgr
oup
and
all m
issin
gpa
tient
s no
t cu
red
Pexi
gana
n cr
eam
Adv
erse
eve
nts
lead
ing
to p
atie
nt w
ithdr
awal
Pexi
gana
n 16
/171
(9%
)RR
0.9
4O
floxa
cin
Oflo
xaci
n 15
/171
(9%
) 95
% C
I 0.4
8 to
1.8
1
Pete
rson
(198
9)10
175
0 m
g N
umbe
r of
am
puta
tions
750
mg,
n=
4/24
(17%
)RR
1.5
1000
mg
twic
e da
ily c
ipro
floxa
cin
1000
mg,
n=
6/2
4 (2
5%)
95%
CI 0
.51
to 4
.49
750
mg
Adv
erse
eve
nts
whi
ch r
esul
ted
in d
iscon
tinua
tion
2 in
100
0 m
g gr
oup
RR 5
Hal
dane
10
00 m
g tw
ice
daily
cip
roflo
xaci
nof
the
dru
g ap
prox
imat
ion
95%
CI 0
.25
to 9
9
cont
inue
d
Results
34 TA
BLE
10
Sum
mar
y of
com
paris
ons,
out
com
es a
nd re
sults
from
effe
ctive
ness
stu
dies
(co
nt’d
)
Stud
yC
ompa
riso
n A
Out
com
eD
ata
RR
, 95%
CI
Com
pari
son
B(d
icho
tom
ous
outc
omes
)M
ean d
iffe
rence,
95
% C
I
(conti
nuous
outc
om
es)
Sub-
cuta
neou
s in
terv
enti
ons
Gou
gh (1
997)
100
G-C
SFTo
e am
puta
tion
G-C
SF 0
/20
RR 5
Hal
dane
Pl
aceb
o (s
alin
e)Pl
aceb
o 2/
20
appr
oxim
atio
n 95
% C
I 0.3
to
98G
-CSF
Ulc
er h
eale
dG
-CSF
4/2
0 (2
0%)
RR 9
Hal
dane
Pl
aceb
o (s
alin
e)
Plac
ebo,
0/2
0ap
prox
imat
ion
95%
CI 0
.5 t
o 15
7
Kast
enba
uer
(200
3)11
8G
-CSF
Hea
led
at d
ay 1
0 G
-CSF
0/2
0RR
5 H
alda
ne
Plac
ebo
(sal
ine)
Con
trol
2/2
0 (1
0%)
appr
oxim
atio
n95
% C
I 0.3
to
98
de L
alla
(200
1)11
9G
-CSF
Am
puta
tion
rate
G-C
SF g
roup
3/2
0 (1
5%)
RR 0
.33
Stan
dard
car
eSt
anda
rd c
are
9/20
(45%
) 95
% C
I 0.1
1 to
0.9
5G
-CSF
‘Cur
ed’ o
r ha
d a
stab
le u
lcer
at
6 m
onth
sG
-CSF
13/
16RR
0.9
2St
anda
rd c
are
Stan
dard
car
e 15
/20
95%
CI 0
.63
to 1
.38
Yone
m (2
001)
120
G-C
SFPr
opor
tion
of p
atie
nts
requ
iring
am
puta
tion
G-C
SF 2
/15
(13%
)RR
0.6
7St
anda
rd c
are
Stan
dard
car
e 3/
15 (2
0%)
95%
CI 0
.15
to 2
.95
Topi
cal i
nter
vent
ions
Ape
lqvi
st (1
995)
138
Cad
exom
er io
dine
oin
tmen
t N
umbe
r of
pat
ient
s w
ho r
equi
red
surg
ical
St
anda
rd t
reat
men
t 5/
18 (2
8%)
RR fo
r su
rger
y 0.
64G
enta
mic
in o
r st
rept
odor
nase
/in
terv
entio
nC
adex
omer
iodi
ne 3
/17
(18%
)95
% C
I 0.1
9 to
2.0
7st
rept
okin
ase
or d
ry s
alin
e ga
uze
Cad
exom
er io
dine
oin
tmen
t U
lcer
hea
led
Cad
exom
er io
dine
5/1
7 (2
9%)
RR 2
.65
Gen
tam
icin
or
stre
ptod
orna
se/
Stan
dard
car
e 2/
18 (1
1%)
95%
CI 0
.68
to 1
0.89
stre
ptok
inas
e or
dry
sal
ine
gauz
e
Mar
chin
a (1
997)
123
Ant
isept
ic s
pray
(con
tent
not
C
ompl
etel
y he
aled
at
15 d
ays
Ant
isept
ic s
pray
50%
NA
desc
ribed
) Eo
sin/c
hlor
oxyl
enol
82%
2% e
osin
and
0.3
% c
hlor
oxyl
enol
sp
ray
Mar
kevi
ch (2
000)
105
Larv
aeU
lcer
hea
ling
Larv
al t
hera
py 5
/70
(7.1
%)
RR 2
.5H
ydro
gel
Hyd
roge
l 2/7
0 (2
.9%
)95
% C
I 0.5
8 to
10.
9 cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
35
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
TA
BLE
10
Sum
mar
y of
com
paris
ons,
out
com
es a
nd re
sults
from
effe
ctive
ness
stu
dies
(co
nt’d
)
Stud
yC
ompa
riso
n A
Out
com
eD
ata
RR
, 95%
CI
Com
pari
son
B(d
icho
tom
ous
outc
omes
)M
ean d
iffe
rence,
95
% C
I
(conti
nuous
outc
om
es)
Rhai
em (1
998)
124
Syst
emic
ant
ibio
tics
Hea
ling
rate
Syst
emic
ant
ibio
tics
16/4
0 (4
0%)
RR 1
.25
Suga
rSu
gar
8/16
(50%
)95
% C
I 0.6
4 to
2.2
3Su
gar
dres
sings
Suga
r dr
essin
gs 1
1/24
(46%
)RR
0.8
7St
anda
rd d
ress
ings
Stan
dard
dre
ssin
gs 1
6/40
(40%
)95
% C
I 0.5
to
1.59
Use
d w
ith s
yste
mic
ant
ibio
tics
Syst
emic
ant
ibio
tics
Ulc
er h
ealin
gSy
stem
ic a
ntib
iotic
s 11
/24
RR 1
.09
No
antib
iotic
s N
o an
tibio
tics
8/16
95%
CI 0
.55
to 2
.07
Also
sug
ar d
ress
ings
Vand
eput
te (1
996)
125
Hyd
roge
l dre
ssin
g N
eces
sity
for
ampu
tatio
n (o
ne o
r m
ore
toes
) H
ydro
gel 1
/15
(7%
)RR
5.4
Gau
ze a
nd c
hlor
hexi
dine
Chl
orhe
xidi
ne 5
/14
(36%
) 95
% C
I 0.9
8 to
32.
7H
ydro
gel d
ress
ing
Ulc
ers
heal
edH
ydro
gel 1
4/15
(93%
)RR
2.6
1G
auze
and
chl
orhe
xidi
neC
hlor
hexi
dine
5/1
4 (3
6%)
95%
CI 1
.45
to 5
.76
Hyd
roge
l dre
ssin
g In
cide
nce
of in
fect
ion
Hyd
roge
l gro
up 1
/15
(7%
)RR
7.5
Gau
ze a
nd c
hlor
hexi
dine
Chl
orhe
xidi
ne 7
/14
(50%
)95
% C
I 1.4
7 to
44.
1H
ydro
gel d
ress
ing
Syst
emic
/loca
l ant
ibio
tics/
requ
ired
Hyd
roge
l 1/1
5 (7
%)
RR 0
.067
Gau
ze a
nd c
hlor
hexi
dine
Chl
orhe
xidi
ne 1
4/14
(100
%)
95%
CI 0
.01
to 0
.31
Oth
er in
terv
enti
ons
Dw
ived
i (20
00)12
7A
yurv
edic
med
icin
e vs
Requ
ired
surg
ery
Act
ive
16%
NA
stan
dard
car
eSt
anda
rd c
are
30%
NA
, not
ava
ilabl
e.
are reported as ‘bacteriological response’. Sixpeople in the ceftriaxone group and four in thecefazolin group were described as having their‘infection eliminated’ at follow-up (RR 1.5, 95% CI0.60 to 3.74). The study reported the outcomes ofamputation, the need for other surgicalprocedures (such as incision and drainage ordebridement) and adverse events for all patientscombined (not stratified by patient type), hence itis difficult to determine whether these could begeneralised to the DFU population.
Erstad and colleagues (1997)107
Erstad and colleagues compared A/S versuscefoxitin, both administered intravenously, in adouble-blind RCT.107 Thirty-six hospitalisedpatients with at least a Wagner grade 1 diabeticfoot infection were treated for a minimumof 5 days, with initial follow-up at 2 weeks post-hospital discharge and again at 1 year. Thirty-three of the 36 (92%) had open ulcers. Followingtreatment, similar proportions of patients had hadamputations in each study group, i.e. 8/18 (44%).The RR for any amputation was 1.0 (95% CI 0.48to 2.09). There was also no statistically significantdifference between the levels of amputation in thetwo groups, i.e. number of either toe amputationsor toe and ray amputations. Some 33% (6/18) ofpeople allocated to cefoxitin had a toeamputation, whereas of those receiving A/S, 17%(3/18) had a toe amputation, RR for toeamputation 0.5 (95% CI 0.15 to 1.55). In thecefoxitin group, the proportion of people withcombined toe and ray amputations was 5.5%(1/18), in the A/S group it was 22% (4/18) (RR 4.0,95% CI 0.68 to 25.4). There was no statisticallysignificant difference in the rate ofrevascularisation in the cefoxitin (4/18; 22%) orA/S groups (2/18; 11%) (RR 0.5, 95% CI 0.12 to2.06). More people in the cefoxitin group (7/18;39%) were reported as having a clinical ‘cure’(defined as complete resolution of presentingsigns and symptoms of infection) than in the A/Sgroup (1/18; 6%) (RR 0.14, 95% CI 0.02 to 0.76).
The report also describes an outcome in which‘cure’ and ‘improved’ patients were pooled(without stating why this outcome was used), andfound no statistically significant difference in theproportions with this outcome (15/18; 83% A/S;16/18; 89% cefoxitin). A per protocol analysis ofthe rate of eradication of bacterial pathogensfound no statistically significant differencebetween groups: 8/11 (73%) in the cefoxitin groupand 6/6 (100%) in the A/S group (RR 1.38, 95% CI0.7 to 2.17). An intention-to-treat analysis foreradication of bacterial pathogens also found no
statistically significant difference between groups:8/18 (44%) in the cefoxitin group and 6/18 (33%)in the A/S group (RR 0.75, 95% CI 0.32 to 1.69).Adverse events, all described as gastrointestinal innature, were reported in 6/18 (33%) of thecefoxitin group and 7/18 (39%) of the A/S group(RR 1.17, 95% CI 0.5 to 2.8). The trial wasunderpowered (for all outcomes) in terms of itsability to detect clinically important differencesthat were statistically significant.
Grayson and colleagues (1994)44
A double-blind RCT with 93 patients (96 infections)compared the intravenous administration of A/Swith I/C in hospital inpatients with diabetes whohad a limb-threatening infection of the feet orlegs, of whom 92% (88) had a foot ulcer.44 A ‘limb-threatening infection of the feet or legs’ wasdefined as (as least) the presence of cellulitis, withor without ulceration or purulent discharge. Thetreatment period averaged 14 days and follow-upwas at 1 year. All patients had bed rest, surgicaldrainage and debridement of infected ulcers andnecrotic tissue. There were no statisticallysignificant differences between the A/S and the I/Cgroups for the total number of amputations [33/48(69%) A/S versus 28/48 (58%) I/C; RR 0.85, 95%CI 0.62 to 1.15; NB the denominator is number ofinfections rather than patients]. There was nostatistically significant difference in the number ofinfections requiring vascular reconstruction in theA/S (7/48; 15%) or I/C (15/48; 31%) groups (RR2.14, 95% CI 0.99 to 4.76). There was nostatistically significant difference in the rate ofclinical ‘cure’ (defined as the resolution of softtissue infection) at the end of treatment in the A/Sgroup (28/48, 58%) or I/C group (29/48, 60%) (RR1.04, 95% CI 0.74 to 1.45). Similarly, at finalfollow-up, clinical ‘cure of infection’ rates in thetwo groups were not statistically significantlydifferent: 27/48 in A/S (56%) and 33/48 (69%) inI/C (RR 1.22, 95% CI 0.89 to 1.7).
The authors reported that there was no statisticallysignificant difference in the number of doses orduration of antibiotic therapy; however, there wereinsufficient data provided in the paper to allow usto calculate the mean differences or CIs. They alsoreported no statistically significant difference inthe eradication of bacterial pathogens at day 5[17/48 (35%) in A/S versus 20/48 (42%) in I/C] andat end of therapy (32/48 in A/S versus 36/48 inI/C) (RR 1.125, 95% CI 0.87 to 1.46). Theproportion of patients with any adverse events was33% (16/48) in A/S versus 35% (17/48) in I/C, withhalf of these described as ‘significant’ (forexample, diarrhoea, rash, nausea or seizure).
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The trial was underpowered in terms of its abilityto detect clinically important differences asstatistically different for all reported outcomes. Asthere were no statistically significant clinicaldifferences between study groups, the concurrenteconomic analysis compared only the costs ofprimary, secondary treatment and hospital bedcosts using 1994 US dollar prices.113 The resultsrevealed that the mean total treatment cost waslower (by $3000 per patient; $14,000 versus$17,000) with A/S. Sensitivity analysis showed thatthe I/C treatment regimen would need to be 30%more effective than A/S in order to reach thecriteria for cost-effectiveness as defined in thisstudy (i.e. absolute risk difference for probabilityof success of around 30%). For the outcomesamputation, cure of infection at end of treatmentand cure of infection at final follow-up, andvascular reconstruction the difference in eventrates excludes the value where I/C would be 30%more effective than A/S, but larger trials areneeded to increase the precision of the estimatesof effectiveness and cost-effectiveness.
Using a matrix of cost-effectiveness87,89 in whichcosts and effectiveness outcomes are integrated,then A/S is preferred over I/C as there is noevidence of difference in effectiveness with reducedcosts, corresponding to cell H of the table in Box 1.
Lipsky and colleagues (2004)109
An open-label, multi-centre RCT comparedlinezolid (intravenously or orally administered)versus A/S (intravenously) or amoxicillin andclavulanate (A/C) (orally) in 361 patients withdiabetic foot infections, of whom 78% had footulcers.109 This study was identified by contact withexperts and was published in 2004. The methodof administration was switched (from intravenousto oral) at the investigators’ discretion and therapywas continued on both an inpatient and outpatientbasis for at least 7 days, but no more than 28 days.Data on 283 people with DFUs were presentedseparately. Vancomycin was added to the A/S orA/C regimen where necessary for the treatment ofmethicillin-resistant Staphylococcus aureus (MRSA)and all patients received wound dressings, but nottopical antimicrobial treatments. Investigatorscould administer aztreonam 1–2 g intravenously,every 8–12 hours, if required for the treatment ofGram-negative pathogens if the allocatedintervention was not effective against them.Wounds with callus or necrotic material weresharply debrided.
There was no statistically significant difference inthe overall clinical cure rate (resolution of all
clinical signs and symptoms and a healing woundafter 5 days of therapy) for those with infectedulcers, 69% (131/190) in linezolid and 61% (57/93)in A/S or A/C (RR 0.92, 95% CI 0.76 to 1.09).There was no statistically significant differencebetween groups in the mean total duration oftherapy required [mean 17.2 days, standarddeviation (SD) 7.9 in linezolid versus mean16.5 days (SD 7.9), difference –0.7 days, 95% CI–2.66 to 1.26]. Patients were treated withintravenous antibiotics for longer in the A/S orA/C group [mean 10.4 days (SD 5.7)] than thelinezolid group [mean 7.8 days (SD 5.5); meandifference 2.6 days, 95% CI 1.22 to 3.98]. Anumber of adverse events were reported, includingdiarrhoea, nausea, anaemia, thrombocytopenia,vomiting, decreased appetite and dyspepsia.Adverse events were reported for the whole studypopulation (of whom 78% had ulcers). There were64 events in 241 people with linezolid, of whom18 patients (7.5%) discontinued therapy becauseof the event, and 12 events in 120 people in theA/S or A/C group, of whom four (3.3%)discontinued therapy. As patients could experiencemore than one adverse event, and the study doesnot report the number of people in each groupwho experienced any event, we have calculated theRR of withdrawing from the study due to anadverse event (RR 2.24, 95% CI 0.82 to 6.24).
Seidel and colleagues (1991)110
Seidel and colleagues conducted two CCTs inwhich male inpatients with diabetic neuropathicplantar ulcers chose either conventionalintravenous or retrograde venous perfusion (RVP),that is, injection into a dorsal vein during arterialocclusion. In the first study, the RVP group hadone RVP infusion daily of gentamicin, buflomedil,dexamethasone, heparin and lignocaine inisotonic saline. This group also had anintramuscular injection of gentamicin, a long-acting buflomedil tablet and three intravenousinfusions of piperacillin.110 The standard infusiontechnique group had three infusions per day ofpiperacillin, gentamicin, buflomedil and heparinin dextran. Both groups received the sameregimen of local antibacterial therapy. Resultsincluded the number of people requiringamputation due to underlying osteomyelitis [0/20in the the RVP and 4/20 in the intravenous group;RR 9 (Haldane approximation used to avoid errorin the �2 tests if cell contains 0; it involves adding0.5 to all of the cells of contingency table), 95% CI0.52 to 157], although there were 10% more casesof osteomyelitis in this group at baseline, and thenumber of ulcers healed (6/20 in RVP and 0/20intravenous; RR 0.077, 95% CI 0.005 to 1.28).
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They also reported mean reduction in ulcer size(55% in RVP, 7.5% in intravenous), but the reportdoes not specify whether the accompanyingfigures (±8 and ±3.6) represent the standarderror, SD or range and therefore the CI for thedifference cannot be calculated. Of those withosteomyelitis, 4/5 in the RVP group and 0/7 in theintravenous group had ‘resolved’ [RR 0.083(Haldane approximation), 95% CI 0.005 to 1.27].Note that none of the outcomes were assessedblind to the study group. The authors state thatbacterial analysis was amongst the outcomemeasures, but no data were presented. A numberof adverse events were noted in the RVP group,including petechiae (tiny broken blood vessels:6/20), pain from arterial occlusion (5/20),haemorrhage (4/20) and stasis dermatitis (3/20).
Seidel and colleagues (1993)111 and (1994)112
In a later study, the same group comparedintravenous and RVP administration of antibioticsin 45 male inpatients with diabetic neuropathicplantar ulcers (DNPUs) over a 10-dayperiod.111,112 People in the intravenous group hadthree infusions per day of netilmycin, buflomedil,heparin, rheomacrodex and dexamethasone, plustwice daily piperacillin (intravenous). The RVPgroup had once daily infusions of netilmycin,buflomedil, dexamethasone, lidocaine andheparin, plus an evening injection (intravascular)of netilmycin, a buflomedil tablet, and twice dailypiperacillin (intravenous). All patients receivedsimilar wound cleansing and dressing, along withdietary and medical interventions for diabetes.There was no statistically significant difference inthe amputation rate in the two groups [3/24(12.5%) in RVP versus 4/21 (19%) in intravenous:RR 1.52, 95% CI 0.42 to 5.57]. The number ofulcers healed was not statistically significantlydifferent in the two groups: 8/24 (33%) RVP and3/21 (14%) intravenous (RR 0.43, 95% CI 0.13 to1.28). The study was underpowered to detectclinically important differences in amputation rateor healing as statistically significant.
Tan and colleagues (1993)108
Tan and colleagues reported a double-blind multi-centre RCT in 251 patients of whom 49 had footulcers.108 Results for people with DFUs werereported separately. They compared piperacillinand tazobactam (P/T) with T/C over a minimum of5 days in hospitalised patients with complicatedskin/skin structure infections. Treatment continuedfor at least 48 hours following the resolution ofsigns and symptoms, followed by early(24–72 hours) and late monitoring (10–14 days)after treatment completion. The number of
evaluable patients with foot ulcers (of whom themajority were diabetic; the exact proportion wasnot reported in the paper) was 16/31 (52%)receiving P/T and 7/18 (39%) receiving T/C.Reasons for non-evaluability are only available forthe complete treatment group, but these werefailure to meet diagnostic criteria for infection10%, no baseline pathogen 10%, inadequateclinical follow-up 9%, prestudy antibiotic 7%,concomitant infection 6%, resistant pathogen atbaseline 4% and ‘other reasons’ 11%; 55% of thoserecruited were therefore non-evaluable. Allpatients underwent surgical debridement ordrainage as part of their managementprogramme. The mean duration of therapy was8–9 days. Results for those evaluable patients withfoot ulcers showed no significant difference in therate of achieving a clinical ‘cure’ (defined asrecovery from infection) between the T/C and P/Tgroups. A per protocol analysis reported that the‘cure of infection’ rate with T/C was 86% (6/7) and56% (9/16) with P/T (RR 0.66, 95% CI 0.37 to1.26). An intention-to-treat analysis of ‘cure ofinfection’ rates found that 33% (6/18) with T/Cand 29% (9/31) with P/T had this outcome (if allpersons in whom data are missing are assumed tohave failed to achieve a cure of infection) (RR0.87, 95% CI 0.39 to 2.07). The high proportionof missing data from ulcer patients means thatthese results must be treated with caution.
The trial was underpowered in terms of its abilityto detect clinically important differences inoutcomes amongst people with foot ulcers asstatistically significant. The proportion of patientsexperiencing at least one adverse event wasreported for all patients in the trial (of whom 20%had an ulcer) and was 42% in both groups, withgastrointestinal events (diarrhoea) being afrequent cause (11% of people in each group hada gastrointestinal adverse event).
SummaryThe eight trials of intravenous antibiotics do notprovide robust evidence of the superiority of anyparticular antibiotic regimen over any other, orwhether retrograde perfusion is superior tostandard infusion techniques. Erstad colleaguesfound that cefoxitin was better than A/S for anoutcome of clinical cure (in a trial described asdouble-blind), but there was insufficient evidenceregarding differences for outcomes of amputation,revascularisation, bacterial eradication or adverseevents.107 Bouter and colleagues found that I/C wasassociated with fewer adverse events probablyrelated to the trial drug than P/C, although therewas insufficient evidence of any differences in
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effectiveness outcomes of bacterial eradication ofpathogens or clinical cure.106 Lipsky and colleaguesreported that the length of treatment with A/S orA/C was greater than that with linezolid, althoughthere was insufficient evidence regarding anydifferences in clinical cure of infection rates oradverse events.109 None of the six RCTs in thisgroup reported that their method of allocation wasmasked so that the person performing therandomisation was unaware of the schedule, butthree of them described themselves as doubleblind.44,107,108 Four of the six RCTs describedappropriate methods of randomisation.43,44,106,108
Only the study by Tan and colleagues108 reportedthat it was double-blind and reported anappropriate method to generate the allocationsequence.
The two CCTs by Seidel and colleagues allowedpatients to choose their mode of therapy –conventional intravenous or RVP therapy.Insufficient information is presented on thecharacteristics to allow one to examine anydifferences in patient selection at the outset.110–112
Even if the two groups were well matched at theoutset for characteristics known to be prognostic,the groups may not be comparable for unknownprognostic variables. In addition, those patientswho chose the novel treatment may differ fromthose who chose conventional therapy.
Effectiveness of oral interventionsFive studies are included in this group. One studycompared oral antibiotics with placebo,74 twocompared different orally administeredantibiotics75 ,101 and two studies compared atopical intervention with oral antibiotics (reportedin one document).114 We found no studies thatcompared an oral intervention with an intravenousor subcutaneous intervention.
Description of the studiesChantelau and colleagues (1996)74
Chantelau and colleagues74 compared oral A/C(Augmentin®) with an identical placebo over a 20-day period in a double-blind RCT involving 44patients with foot lesions graded 1A to 2A usingthe Texas classification system (Box 4).115 Allpatients received mechanical debridement, woundcleansing, dressing and pressure relief. Theauthors state that there was no statisticallysignificant difference in mean reduction in ulcersize, but insufficient data were reported to allowcalculation of effect size or CIs. There was nostatistically significant difference between healingrates [6/22 (27%) in A/C and 10/22 (45%) inplacebo; RR 1.67, 95% CI 0.76 to 3.83]. In
addition, there was no difference in the numbersof people whose deep swab wound cultures takenat completion of the study showed absence ofmicrobes [7/22, (32%) in A/C versus 6/22 (27%) inplacebo; RR 0.86, 95% CI 0.35 to 2.09] or isolates[4/22 (18%) in A/C versus 1/22 (5%) in placebo;RR 0.25, 95% CI 0.04 to 1.51] at the end of thestudy. Diarrhoea occurred in only one patient(active intervention group) and this was resolvedwithout withdrawal from the study. Five otherpatients were withdrawn at the beginning of thetrial owing to non-compliance or bacteriaunresponsive to the antibiotic. It was not clearwhether these patients were included in theanalysis. The trial was underpowered in terms ofits ability to detect clinically important differencesas statistically significant.
Lipsky and colleagues (1990)75
Lipsky and colleagues compared orallyadministered clindamycin hydrochloride (Cleocin)with cephalexin (Keflex) in an RCT amongst 60male outpatients with diabetes (data reported on56 people).75 Treatment was over 2 weeks, with3 months of follow-up. Patients with clinicallyinfected lower extremity lesions were included inthe study, with 89% and 93% in the respectivestudy groups having an ulcer. All patients hadlesions cleansed and debrided at the initialevaluation and this was followed by instructionsfor self-care. There was no statistically significantdifference in the infection ‘cure’ rate (where allsigns and symptoms resolved), in a per protocolanalysis, between clindamycin and cephalexingroup [21/27 (78%) in clindamycin versus 21/29(72%) in cepahlexin; RR 0.93, 95% CI 0.67 to1.29]. There was no statistically significantdifference in the proportion of ulcers healing in aper protocol analysis between clindamycin, 10/27(37%) and cephalexin, 9/29 (31%) (RR 0.83, 95%CI 0.4 to 1.73). Results for the eradication ofbacterial pathogens, using per protocol results,showed a similar cure rate in each of the studygroups [20/26 (77%) for clindamycin and 20/29(69%) for cephalexin; RR 0.9, 95% CI 0.63 to1.26]. Adverse events were noted in only threepatients (one in the clindamycin group and two inthe cephalexin group; RR 2.0, 95% CI 0.28 to14.8), presenting as mild diarrhoea and nausea.The trial was underpowered in terms of its abilityto detect clinically important differences asstatistically significant.
Lipsky and colleagues (unpublished) A114 and B114
Two trials by Lipsky and colleagues compared anoral and a topical intervention. These wereidentified by contact with experts. The comparison
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was of topically applied pexiganan cream(Locilex®) with ofloxacin (orally) over a 14–28-dayperiod with follow-up at 2 weeks after treatmenthad ended.114,116 The authors describe pexiganan cream as a broad-spectrumantimicrobial agent, structurally related to frogskin peptides. This product has not been licensedfor use.117 These double-blind RCTs recruitedoutpatients with a DFU in whom there were nosigns of extensive cellulitis, exposure ofbone/tendon or fever. All patients were offereddebridement and standard dressings. The authorspresent results at three time points (day 10, end oftreatment and follow-up), in 10 populations(including intention-to-treat, per protocol,intention-to-treat microbiology and per protocolmicrobiology). The primary outcome was ‘clinicaloutcome at day 10 in an evaluable population’.Other outcomes included clinical outcome at threetime points, microbiological outcome at three timepoints, therapeutic response at three time points,wound score, wound infection score, wound depth,absolute and relative wound area reduction (meanand median) and eradication of pathogens presentat baseline. The large number of outcomes (whichmay have been necessary for the submission to theFederal Drug Administration committee) may haveled to a Type I error, that is, concluding that thereis a statistically significant difference when noneexists.
Lipsky and colleagues (unpublished) A114
Results from the first of these studies (493participants) revealed no statistically significantdifference between the number of amputations inthe pexiganan group [4/247 (1.6%)] and theofloxacin group [6/246 (2.4%)] (RR 1.5, 95% CI0.46 to 4.92).
There was no statistically significant differencebetween the clinical ‘cure’ rates (defined as nofurther signs or symptoms of infection) at day 10[63/243 (26%) in pexiganan and 67/240 (28%) inofloxacin (RR 1.08, 95% CI 0.81 to 1.45], at endof treatment, [133/247 (54%) pexiganan and150/246 (61%) in ofloxacin (RR 1.13, 95% CI 0.97to 1.32] and at final follow-up [136/243 (56%) inpexiganan and 156/240 (65%) in ofloxacin (RR1.16, 95% CI 1.00 to 1.34)]. The mean reductionin wound area was similar in the two groups,namely 93.4 mm2 area reduction in pexiganan and96 mm2 area reduction in ofloxacin, butinsufficient data were provided to allow thecalculation of CIs. At final follow-up, the numbersof people with an outcome described as‘microbiologically resolved infection’ were 75/185 (40%) in pexiganan and 84/193 (44%) in
ofloxacin (RR 1.07, 95% CI 0.85 to 1.36). Therewere a similar number of adverse events leading to patient withdrawal from the study inpexiganan [28/247 (11%)] and ofloxacin [23/246(9%)] (RR 0.82, 95% CI 0.49 to 1.38), the mostfrequent causes being diarrhoea, nausea and pain. The incidence of serious adverse events such as cellulitis, infection or osteomyelitis was not statistically significantly different inpexiganan [28/247 (11.3%)] from ofloxacin[20/246 (8.1%)] (RR 0.72, 95% CI 0.42 to 1.23).
Lipsky and colleagues (unpublished) B114
The second study compared pexiganan andofloxacin in 342 patients. There was no statisticallysignificant difference in the number of people whohad an amputation: 7/171 (4%) in the pexiganangroup and 3/171 (2%) in the ofloxacin group (RR0.43, 95% CI 0.12 to 1.49). Clinical ‘cure’ rates(defined above) were not statistically significantlydifferent at day 10 (34/171 in pexiganan and34/171; RR 1.0, 95% CI 0.65 to 1.53) or at end oftreatment (84/171 in pexiganan and 80/171; RR 1.05, 95% CI 0.84 to 1.31). The mean reductionin wound area was 129 mm2 in pexiganan and142.6 mm2 in ofloxacin, but insufficient data wereprovided to allow the calculation of CIs.Microbiological response at 10 days was analysedboth per protocol and intention-to-treat. Forty-four patients (26%) had an outcome of ‘resolved’in pexiganan and 30 (18%) were ‘resolved’ inofloxacin. If one assumes that the sample size forthis analysis is 171 for each group and that noneof the patients for whom data are missing had amicrobiological ‘cure’, the RR of ‘resolved’ is 0.68(95% CI 0.45 to 1.02) using an intention-to-treatprinciple. This result is sensitive to the assumptionthat all missing data represented failures as theauthors present the microbiological cure asoccurring in 44/138 (32%) pexiganan and 30/140(21%) ofloxacin (RR 0.67, 95% CI 0.45 to 0.99).There was no statistically significant difference inthe proportion of patients classified as ‘resolved’in the two groups at end of treatment, that is,53/171 (31%) in pexiganan and 59/171 (34%) inofloxacin (RR 1.11, 95% CI 0.82 to 1.51) orfollow-up, 50/171 (29%) in pexiganan and 61/171(36%) in ofloxacin (RR 1.22, 95% CI 0.89 to 1.66).Adverse events leading to patient withdrawal inthis study involved similar proportions of patientsin each group: 16/171 (9%) from the pexiganangroup and 15/171 (9%) from the ofloxacin group(RR 0.94, 95% CI 0.48 to 1.81). The causes ofadverse events were the same as in the largerLipsky pexiganan study (described above). Seriousadverse events were observed in 22/171 (13%)
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pexiganan and 19/171 (11%) ofloxacin (RR forserious adverse events 0.86, 95% CI 0.49 to 1.52).
We did not pool the data from the Lipsky studiesas there was differential drop-out from the twoarms (ofloxacin and pexiganan) and we felt thatthis may have been misleading to use theper protocol data available. Given that thistreatment is not licensed for use currently, we didnot pursue acquiring the data from the studysponsors.
Peterson and colleagues (1989)101
Peterson and colleagues compared theeffectiveness of orally administered ciprofloxacinin an RCT in which 48 inpatients with lowerextremity DFUs were given different doses (750 or1000 mg twice daily) of ciprofloxacin, with follow-up at 12 months.101 Patients with osteomyelitiswere treated for 3 months and those with cellulitisfor 3 weeks. All patients received local wound care,comprising debridement, wound cleansing,dressing and pressure relief. Data were availableon 45 patients. There was no statistically significantdifference in the number of amputations betweenthe 750 and 1000 mg dose groups: 4/24 (17%) inthe 750 mg and 6/24 (25%) in the 1000 mg group(RR 1.5, 95% CI 0.51 to 4.49). A number ofadverse events occurred, of which two resulted indiscontinuation of the drug [both in the high-dosage group; RR 5 (Haldane approximation),95% CI 0.25 to 99]. Six patients in the high-dosegroup and two in the low-dose groups experiencednon-serious adverse events such as chemicalabnormalities (increased blood urea nitrogen orserum creatinine levels) thought to be associatedwith the treatment (RR 0.33, 95% CI 0.08 to 1.28).The trial was underpowered.
SummaryFive studies compared oral interventions, with onlythe two unpublished studies by Lipsky (reported inthe same document) comparing the sameinterventions (topical pexiganan and oralofloxacin) more than once.114 There is insufficientevidence from the studies to recommend anyparticular oral antimicrobial: none of the studiesreported significant difference on any outcomes,although trials by Chantelau and colleagues,74
Lipsky and colleagues75 and Peterson andcolleagues101 were so small that they were unlikelyto detect clinically important differences inoutcomes as statistically significant. The two large(unpublished) trials by Lipsky with 835 patients, inwhich an oral antibiotic was compared with anantimicrobial cream, found no difference inoutcomes in per protocol analyses.114
Peterson and colleagues described allocationconcealment, an appropriate method ofrandomisation (by the pharmacy).101 The otherfour trials did not make it clear whether allocationwas concealed. Both trials of pexiganan andofloxacin were described as double-blind.114
Effectiveness of subcutaneousinterventionsFour included studies evaluated subcutaneousadministration of recombinant humangranulocyte-colony stimulating factor (rhG-CSF,also known as filgrastim; Neupogen®) in additionto standard care versus placebo plus standardcare,100,118 or standard care alone.119,120
Granulocyte colony-stimulating factor (G-CSF) isan endogenous haemopoietic growth factor thatinduces terminal differentiation and release ofneutrophils from the bone marrow. There were nostudies comparing any subcutaneous interventionswith an intravenous, oral or topical treatment.
Description of the studiesGough and colleagues (1997)100
The double-blind RCT by Gough and colleaguescompared a subcutaneous injection of G-CSF witha placebo (saline solution) in 40 inpatients with aDFU with extensive cellulitis (the majorityoccurring in the forefoot) over a 7-day period.100
G-CSF dosage was initially 5 µg/kg/day (daily for2 days), and was then titrated against the patient’sneutrophil count, reduced to 2.5 µg/kg/day (dailyfor 2 days), and then given on alternate days (upto 7 days). All patients received an intravenouscombination of four antibiotics (ceftazidime,amoxycillin, flucloxacillin and metronidazole),appropriate glycaemic control, foam dressings andpodiatric treatment. Two patients in the placebogroup underwent toe amputation compared withnone in the G-CSF group [RR for amputation 5(Haldane approximation), 95% CI 0.3 to 98]. Twopatients in the placebo group required extensivedebridement under anaesthesia, compared withnone in the G-CSF group [RR for debridement 5(Haldane approximation), 95% CI 0.3 to 98]. The study is underpowered to detect clinicallyimportant differences in debridement oramputation outcomes as statistically significant.The median time to resolution of cellulitis was7 days in the G-CSF group (range 5–20) and12 days in the placebo group (range 5–93). Themedian time to negative swab was 4 days in the G-CSF group (range 4–10) versus 8 days in theplacebo group (range 5–93), and although therewere insufficient data available to allow us tocalculate the CIs for the difference in time, theauthors stated that the difference was statistically
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significant. There was no statistically significantdifference in the number of people whose ulcerhealed in the two groups; 4/20 (20%) patients inthe G-CSF group healed their ulcer, whereas nopatients in the placebo group had a healed ulcer,but this difference was not statistically significant[RR 9 (Haldane approximation), 95% CI 0.5 to157]. People in the G-CSF group were more likelyto have resolution of cellulitis at day 7 than theplacebo group [11/20 (55%) versus 4/20 (20%), RR2.75, 95% CI 1.1 to 7.3]. The median time tohospital discharge was reportedly lower in the G-CSF group than the placebo group [10 days(range 7–31) versus 17.5 1 days (range 9–100)] butinsufficient data were provided to calculate the CIfor the difference. The authors state that thisdifference is statistically significant at theconventional 95% level. There was leucocytosisamongst some G-CSF patients (at day 7 thepatients receiving G-CSF had higher counts oflymphocytes and monocytes than patients in thecontrol group). The median dose of G-CSFrequired over the study period was 302 µg/day(range 200–440).
It is noteworthy that the median duration of ulcersprior to trial entry in the G-CSF group was21 days (range 2–1278) compared with 39.5 days(range 2–1825) in the placebo group, indicatingthat the G-CSF group was more likely to heal frombaseline as the randomisation of a small numberof participants had failed to distribute ulcers oflong duration equally between the two groups. Aneconomic analysis of G-CSF versus placebo wasundertaken by Edmonds and colleagues,121 usingthe resource use data from the first 28 patients (of40), in the Gough trial,100 from a hospital ratherthan a societal perspective. A decision tree modelwas built to estimate the mean treatment cost foreach group. They estimated that the mean costsavings associated with G-CSF over placebo were£2666. Sensitivity analysis was undertaken toexamine the effect of changing assumptions aboutthe patient type, probability distribution, unit costand duration of hospital stay on cost-effectiveness.They identified that the savings ranged from £155to £3129 when patients with vascular problemsand/or tissue necrosis were excluded from thestudy. The authors pointed out that the results ofthe economic analysis should be interpreted withcaution as the two groups were treated differentlyafter randomisation; more patients in the placebogroup had a vascular problem than in the G-CSFgroup (seven versus four) and these required more costly diagnostic tests and interventions. The results therefore need to be confirmed in alarge RCT.
Given that there is no clear evidence of differencein effectiveness, but lower costs associated with G-CSF, then in an economic analysis G-CSF ispreferred – corresponding to cell H of the cost-effectiveness matrix in Box 1.87,89
Kastenbauer and colleagues (2003)118
A second study in this group118 was a single(patient)-blinded RCT that compared the samedose of G-CSF as Gough and Colleagues100 with aplacebo (sterile saline solution). Thirty-sevenhospital inpatients with a DFU (Wagner grade 2 or3) were treated over a 10-day period.102 Allpatients maintained bed rest and received the samestandard wound care, including debridement.Intravenous antibiotics (clindamycin andciprofloxacin) were administered, followed by oralantibiotics where necessary. Daily clinicalobservations were supplemented by the calculationof an Infection Summary Score (no informationwas provided on validation of this scale). Healingdata were presented as changes in Wagner grade,reduction in volume, resolution of cellulitis andcomplete ulcer healing. All five of the grade 3ulcers from the GCSF group and all three of thegrade 3 ulcers in the placebo group progressed tograde 2 ulcers by day 10. There were similarreductions in ulcer volume in the control group(125 µl) and the G-CSF group (120 µl), but therewas no data on the variance to allow the calculationof CIs of the change. Furthermore, the groups werenot comparable at baseline for ulcer volumes (203versus 358 µl) and this may have biased the result.The proportion of patients with unresolvedcellulitis at day 10 showed a greater number in theactive intervention group (approximately 27%versus 17%, data derived from graph). There wasno statistically significant difference in theproportion of patients achieving complete healingat day 10: 10% (2/20) in the control group versusnone in the G-CSF group [RR 5 (Haldaneapproximation), 95% CI 0.3 to 98]. Adverse eventsof worsened liver function and skin efflorescencewere noted in two patients in the G-CSF group.The trial was underpowered to detect clinicallyimportant differences as statistically significant.
de Lalla and colleagues (2001)119
An RCT by de Lalla and colleagues comparedconventional treatment (local treatment plussystemic antibiotic therapy) and additionalsubcutaneously administered G-CSF withconventional treatment alone in 40 hospitalisedpatients with a DFU over 21 days.119 Follow-up wascarried out at 9 weeks and 6 months. All patientshad either Wagner grade 3 or 4 ulcer (describedas limb threatening) and all received local
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treatment and empirical antibiotic therapy(intravenous or oral ciprofloxacin andclindamycin) where necessary. The amputationrate was statistically significantly higher in theconventional treatment group at the end oftreatment [9/20 (45%)] compared with the G-CSFgroup [3/20 (15%)] (RR 0.33, 95% CI 0.11 to0.95). There was no statistically significantdifference in the number of major amputationsperformed in the conventional treatment group[2/20 (10%) conventionally treated versus 0/20(0%) in the G-CSF group] [RR 0.2 (Haldaneapproximation) 95% CI 0.01 to 3.9]. There was noreported difference between groups in theproportion of ulcers ‘cured’ (complete closure ofthe ulcer without signs of underlying boneinfection) at 21 days (none healed in both groups)or 9 weeks, as 7/20 (35%) healed in both groups(RR 1.0, 95% CI 0.43 to 2.3). At 6 months 13/16people in the GCSF group were either ‘cured’ orhad a stable ulcer (four lost to follow-up)compared with 15/20 in the control group (RR0.92, 95% CI 0.63 to 1.38).
There was no statistically significant difference inthe mean/median duration of antibiotic therapy inthe G-CSF group (58.7 days, SD 23.7) or thestandard care group (68.9 days, SD 29.2), meandifference 10.2 days (95% CI –6.3 to 26.7 days). Inaddition, there were no statistically significantdifferences between groups in terms of theproportion of patients requiring oral/antibiotictherapy during the trial period [11/20 (55%)versus 13/20 (65%), RR for oral therapy requiredin standard care 1.18, 95% CI 0.7 to 2.04]. Therewas no statistically significant difference betweengroups in terms of proportion of patients
requiring adjustments to empirical therapy [9/20(45%) in standard care versus. 7/20 (35%) in G-CSF, RR 0.78, 95% CI 0.36 to 1.65]. Theauthors reported that there were no adverse eventsassociated with G-CSF but two patients in thisgroup required a reduced dose of G-CSF owing toan elevated neutrophil count.
Yonem and colleagues (2001)120
Yonem and colleagues evaluated subcutaneous G-CSF against ‘standard’ local wound care in 30people; all patients received intravenousciprofloxacin and metronidazole.120 The settingand length of treatment were not reported. Allparticipants had either pedal cellulitis or a footlesion (Wagner grade 2 or less) secondary todiabetes mellitus and were placed on a dailymultiple-dose injection of short-acting insulin.There was no statistically significant difference inthe proportion of patients requiring amputation[3/15 (20%) in standard care versus 2/15 (13%) inthe G-CSF group; RR 0.67, 95% CI 0.15 to 2.95].The number of days to resolution of infection was22.3 in standard care (SD 1.7) and 23.6 in G-CSF(SD 1.8) (mean difference 1.3 days; 95% CI 0.05 to2.55). This trial was underpowered to detectclinically important outcomes such as amputationas statistically significant. Adverse events were notreported.
Three of the four G-CSF studies reported the rateof compete ulcer healing, and Figure 4 summarisesthe results for the three studies.
Three of the four G-CSF studies reportedamputation rates, and Figure 5 summarises theresults for these three studies.
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Review: G-CSF – DFUComparison: 01 G-CSF versus placebo or standard careOutcome: 01 Healed
Studyor subcategory
G-CSFn/N
Controln/N
RR (random)95% CI
RR (random) 95% CI
01 placebo studies Gough100 4/20 0/20 Kastenbauer118 0/17 2/20
02 standard care studies de Lalla119 7/20 7/20
9.00 (0.52 to 156.91)0.23 (0.01 to 4.55)
1.00 (0.43 to 2.33)
0.001 0.01 0.1 1 10 100 1000
Favours control Favours G-CSF
FIGURE 4 Forest plot of GCSF versus placebo or standard care for ulcer healing
Given that one study by Yonem and colleagues120
did not report ulcer healing outcomes and thepotential methodological and clinicalheterogeneity, we decided not to combine thehealing results in a meta-analysis. A similarapproach was used for the amputation results asone study (Kastenbauer and colleagues118) did notreport amputation rates.
SummaryThere is no reliable evidence that G-CSF isassociated with reduced amputation rates orincreased ulcer healing but the trials are too small(total of 147 participants) to exclude the possibilitythat there is a clinically important effect. A cost study121 of one of the trials100 suggestedlower treatment costs associated with G-CSF butthe authors stated that this finding should betreated with caution as it was based on aretrospective analysis of 28 patients from the 40 inthe original trial, and the two groups receiveddifferent concurrent treatments such as surgerypost-randomisation.
Effectiveness of topical interventionsFive eligible studies compared different topicalpreparations105,122–125
Description of the studiesApelqvist and colleagues (1996)122,126
An open RCT by Apelqvist and colleagues wasconducted in Sweden with 41 outpatients (withWagner grade 1 or 2 diabetic foot ulcer) over a 12-week period.122,126 The study comparedtopically applied cadexomer iodine ointment(Iodosorb) with a standard topical treatmentconsisting of gentamicin (Garamycin),streptodornase/streptokinase (Varidase) or dry
saline gauze (Mesalt). The authors describedcadexomer iodine ointment as a highly fluid-absorbing, antibacterial agent. All patients wereoffered oral antibiotics (ciprofloxacin,cephalosporin, metronidazole, clindamycin) ifnecessary, along with saline dressing, a paraffingauze and special footwear where appropriate.Outcomes are given on 35 patients as no data arepresented on five patients from the cadexomeriodine group and one from the standard caregroup. There was no statistically significantdifference in the number of patients who requiredsurgical intervention in the standard treatment[(5/18 28%)] or the chlorhexidine group [3/1718%)] (RR for surgery 0.64, 95% CI 0.19 to 2.07).There was no statistically significant differencebetween the proportions of patients whose ulcerwas completely healed, 2/18 (11%) in standardcare and 5/17 (29%) in cadexomer iodine (RR2.65, 95% CI 0.68 to 10.89). In addition, there wasno statistically significant difference in theoutcome of ‘wound area reduction of at least 50%or improvement in Wagner grade’ between the twogroups [12/17 (71%) in Iodosorb and 13/18 (72%)in standard care; RR 0.98, 95% CI 0.64 to 1.49].No adverse events were documented. Six patientswithdrew from the study owing to violation ofinclusion criteria, hospitalisation, non-adherenceto treatment and insufficient data on resource use.
Since there were no significant differences inclinical effectiveness between the two study groups,a cost-minimisation analysis was performed by thesame authors using the 1993 exchange rate for theSwedish Kroner (SEK).122,126 The analysis focusedupon resource use in terms of dressing changes,drug prescription, materials consumption andtime involved. Costs were estimated for dressing
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Review: G-CSF – DFUComparison: 02 G-CSF versus placebo or standard careOutcome: 01 Amputation
Studyor subcategory
G-CSFn/N
Controln/N
RR (random)95% CI
RR (random) 95% CI
01 placebo studies Gough100 4/20 0/20
02 standard care studies de Lalla119 3/20 9/20 Yonem120 2/15 3/15
0.20 (0.01 to 3.92)
0.33 (0.11 to 1.05)0.67 (0.13 to 3.44)
0.001 0.01 0.1 1 10 100 1000
Favours controlFavours G-CSF
FIGURE 5 Forest plot of G-CSF versus placebo or standard care for amputation
materials, drugs, staff, transport and othersrelating to secondary complications. There were ahigher (mean) number of dressing changes perweek in the standard care group (9.9, range3.12–13.9) compared with the cadexomer iodinegroup (4.7, range 3.2–6.9). The authors did notprovide sufficient data for the CIs for thedifference in the number of dressings changes perweek to be calculated. More dressings wereperformed by nurses and auxiliary nurses, ratherthan patient or spouse, in the standard caregroup. The authors reported the time for eachdressing change, 13 minutes (range 8–24) forcadexomer iodine, 11 minutes (range 5–23) forstandard care, and the mean number of weeks oftreatment needed, 10 (range 1–12) in cadexomeriodine, 11 (range 5–12) for standard care. Theystated that these were similar between the twogroups, although statistical significance was notreported. Mean staff costs were reported assignificantly higher in the standard care group(884 SEK, range 315–1492) than the cadexomeriodine group (380 SEK, range 96–570) (authorsstate p < 0.001), but insufficient data wereprovided to calculate CIs for the difference. Meanweekly transport costs were reported assignificantly higher in the standard care group(243 SEK, range 76–341) than the cadexomeriodine group (100 SEK, range 29–156) (authorsstate p < 0.001), but insufficient data wereprovided to calculate CIs for the difference. As thestaff costs and transport costs were both higher inthe standard care group, the mean total weeklycosts were also higher. Costs of materials anddrugs were lower in the standard care group (294 SEK, range 37–981) compared with thecadexomer iodine group (423 SEK, range166–1113). The authors state that this differenceis not statistically significant but insufficient datawere provided to allow calculation of the CIs forthe difference. Following a synthesis of costs andbenefits, the weekly cost per patient healed washigher in the standard care group (12,790 SEK)than the cadexomer iodine group (3070 SEK).The authors state that this difference is notstatistically significant but insufficient data wereprovided to allow calculation of the CIs for thedifference. Sensitivity analysis was carried out totest whether the findings were affected byvariations in assumptions about travel distanceand costs, the number of home-based dressingchanges, different staff categories beingresponsible for care, adherence to regimen andadverse reactions relating to treatment. Reducingthe costs of staff travel (from 10 to 5 km) reducedthe cost of standard care by 31% and ofcadexomer iodine treatment by 20%. Changing
the grade of staff changing the dressing so that anauxiliary performed all reduced the cost ofstandard care by 9% and of cadexomer iodinetreatment by 7%.
Assuming that a patient or their carer performed50% of dressing changes, rather than a paidhealth professional, reduced the cost of standardcare by 40% and of cadexomer iodine treatmentby 27%.
Assuming that the dressings were changed as perphysician’s instructions at all times (e.g. daily)meant that the cost of standard care reduced to1914 SEK and that of cadexomer iodine to 836SEK. When the sensitivity analysis included onepatient in the cadexomer iodine group who hadexperienced an adverse event and had beenhospitalised, then the cost of cadexomer iodineincreased to 1040 SEK and standard care costswere lower, at 903 SEK. Hence the economicanalysis is sensitive to inclusion or exclusion of thepatient with an adverse event.
Using the matrix of cost-effectiveness,87,89 and theauthors findings that Iodosorb was less costly thanstandard care, then we find that Iodosorb ispreferred, appearing in cell H of the cost-effectiveness matrix in Box 1, but this should beinterpreted with caution as the costs are sensitiveto the inclusion of costs of adverse events, andtherefore Iodosorb may be more expensive and nomore effective (cell B of the matrix in Box 1) thanstandard care.
Marchina and Renzi (1997)123
Marchina and Renzi compared an antiseptic spray(content not described) with a 2% eosin and 0.3%chloroxylenol spray in 40 people, of whom 21 hadDFUs, over 15 days.123 Data were reported for theDFU group. Ulcers were dressed with gauze andchanged 2–3 times per day. No otherantimicrobial agents, analgesics or anti-inflammatory agents were used during the study.At 15 days, 82% of the people in theeosin/chloroxylenol group were completely healed,compared with 50% in the antiseptic spray group.The actual number of ulcers healed was not givenfor the two groups and was only available from agraph in the trial report, therefore we cannotcalculate the RR of healing or the CIs. This trialwas too small to detect clinically importantdifference in healing rates.
Markevich and colleagues (2000)105
Markevich and colleagues reported an RCT oflarval therapy versus a hydrogel for DFUs (of
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neuropathic origin) in 140 inpatients.105 Larvaltherapy uses sterile maggots of the green bottle fly(Lucilia sericata) to remove dead tissue withinwounds, and during this process the larvae ingestbacteria, which are destroyed in the larval gut, andare reputed to have an antibacterial effect.Hydrogel dressings rehydrate dead tissue withinwounds and allow the cells within the wound toremove it. The follow-up period was for up to10 days (after three applications of larvaltherapy/hydrogel). Complete healing was reportedin 5/70 (7.1%) patients in the larval therapy groupand 2/70 (2.9%) in the hydrogel group (RR 2.5,95% CI 0.58 to 10.9). The authors also reportoutcomes of ‘at least 50% reduction in area’ and‘granulation tissue covering at least 50% of thewound’, but the clinical relevance of theseoutcomes is not known. For example, it is not clearif halving ulcer area is a reliable interim outcomemeasure for complete healing, or if quickerprogression to a granulated wound bed necessarilyleads to quicker healing.
Rhaiem and colleagues (1998)124
Rhaiem and colleagues studied 80 hospitalisedpatients with cutaneous wounds [of whom 65(81%) had foot wounds].124 Participants wererandomised into three groups: local wound careplus sugar applied into the wound cavity (changeddaily), local wound care plus sugar plus systemicantibiotics, and local wound care plus systemicantibiotics. The method of administration of theantibiotics was not stated (intravenous,intramuscular or oral). All participants receivedstandard care comprising debridement, cleansingand drying.
The authors cited other studies that have usedsugar as a topical antimicrobial and gave detailson the physiological mechanisms to support theirclaim. The study period was not clear and detailswere not given with regard to any treatmentreceived by patients between hospital dischargeand follow-up. This three-arm study of topicalsugar versus systemic antibiotics versus sugar +antibiotics addresses three comparisons:
� systemic antibiotics versus topical sugar � sugar versus standard wound dressing (when
added to systemic antibiotics)� systemic antibiotic versus no treatment (when
added to topical sugar).
There was no statistically significant difference inthe healing rates between systemic antibiotics[16/40 (40%)] and sugar [8/16 (50%)] (RR 1.25,95% CI 0.64 to 2.23).
There was no statistically significant difference inthe healing rates between sugar dressings [11/24(46%)] and standard dressings [16/40 (40%)] whenused in the presence of systemic antibiotics (RR0.87, 95% CI 0.5 to 1.59).
There was no statistically significant difference inthe healing rates between systemic antibiotics[11/24 (46%)] and no antibiotics [8/16 (50%)] whenadded to a local treatment regimen of sugardressings (RR 1.09, 95% CI 0.55 to 2.07).
This study is too small to be able to detect asstatistically significant, clinically importantdifferences.
The usefulness of further data presented onhealing rates was limited, given that it was for all wounds (foot, leg and ‘other wounds’). Adverse effects were not assessed. Some economicanalysis was presented by the authors, whoclaimed that the average cost of treating the studypatients with sugar could be markedly reduced(when compared with hospitalisation) as themajority of care could be home-based, but therewas no concurrent collection of economic data or aformal economic analysis. The authors alsoreported that there was some difficulty in theapplication of sugar.
Vandeputte and Gryson (1996)125
Vandeputte and Gryson compared a hydrogeldressing with dry gauze dressing irrigated withchlorhexidine in an RCT including 29 people withDFUs (setting not stated) over a 3-monthperiod.125 Hydrogel dressings are said to providepressure relieving, moisturising and bacteriostaticproperties. Chlorhexidine is an antimicrobialagent. Systemic antibiotics and topicaltreatments/antiseptics were available to all patientsif required. The necessity for amputation (one ormore toes) was slightly higher in the chlorhexidinegroup [5/14 (36%) versus (1/15 (7%), RR foramputation 5.4, 95% CI 0.98 to 32.7], but thisdifference was not statistically significant.Complete healing data (verified by photographicmeasure) at the end of treatment showed fewerulcers healed in the chlorhexidine, group [5/14(36%)], than the hydrogel group [14/15 (93%)](RR 2.61, 95% CI 1.45 to 5.76). There was a lowerincidence of infection amongst patients in thehydrogel group [1/15 (7%)] than the chlorhexidinegroup [7/14 (50%)] (RR 7.5, 95% CI 1.47 to 44.1).They also reported a reduced requirement forsystemic/local antibiotics/topical treatment [14/14(100%) in chlorhexidine and 1/15 (7%) in thehydrogel group, RR 0.067, 95% CI 0.01 to 0.31].
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Two patients died in the chlorhexidine studygroup during the trial period compared with nonein the hydrogel group. Other adverse events werenot reported.
The trial was sufficiently powered on the completehealing outcome and infection incidence outcometo detect clinically important differences asstatistically significant, but was underpowered todetect other differences in outcomes as statisticallysignificant.
SummaryThe five studies of topical interventions, in whichthere were eight comparisons, found no robustevidence for a statistically significant difference inclinical outcomes associated with any particulartopical antimicrobial. Apelqvist andcolleagues122,126 reported lower treatment costsassociated with cadexomer iodine ointment versusstandard care dressings, but this was not robust tosensitivity analyses. Vandeputte and Gryson125
reported more ulcer healing with a hydrogel thanwith a topical antimicrobial (chlorhexidine ongauze), although it is not clear whether anintention-to-treat analysis was performed, whetherany assessments were blinded and howcomparable the ulcers were at baseline forduration, area and depth.
Effectiveness of other interventionsOne study compared a topical and oralintervention with a standard care regimen.127
Description of the studyDwivedi and colleagues (2000)127
This 5-year clinic-based RCT was conducted on100 people. Dwivedi and colleagues compared atherapy (a decoction of plant extracts) based onAyurvedic principles, administered as both an oraland a topical treatment against standard care – acombination of systemic antibiotics plusmetronidazole, local antiseptics and a peripheralvascular dilator.127 The oral treatment beingevaluated was a water-soluble solid extract of Rubiacordifolia (Manjishtha) and of Withania somnifera(Ashvagandha), each 500 mg, oral, three times perday. Patients were also required to soak theaffected part in a luke-warm water decoction ofthe plants for 30 minutes daily. The authors justifythe potential effectiveness of the Manjishtha plantextract on the basis of its ability to removemicroangiopathic and atherosclerotic changesinside the arteries/capillaries surrounding thewound area, thus facilitating blood supply andsubsequent removal of microbes. The additionalproperties of Ashvagandha, they believe, improve
the immunological status of patients. Patients withnon-healing DFUs of 6–12 months’ duration wereincluded. Both study groups received regularsurgical intervention, e.g. incision or debridement,as required. Some 30% of patients in the standardcare group required surgery, compared with 16%in the active intervention group (Ayurvedicmedicine). The authors do not report the exactnumbers for each group and therefore the CIs andRR cannot be calculated with certainty. However, ifthe data given represent an intention-to-treatanalysis, then the RR of healing with the standardtreatment would be 0.53 (95% CI 0.25 to 1.11).Adverse effects were not reported. This trial wasunderpowered to detect clinically importantoutcomes as statistically significant.
SummaryThere is no reliable evidence of the impact of thiscombination of interventions on non-healingDFUs with respect to the need for amputation.
Overall summaryThe quality of the trials identified was poor andthe sample sizes in the majority of trials wereinsufficient to identify clinically importantdifferences in effectiveness as statisticallysignificant. There was wide variation in theoutcomes reported and the possibility thatunfavourable outcomes were not reported whereasequivocal or positive ones were, cannot beexcluded, as trials rarely specified primaryoutcomes measures a priori.
Twenty-three trials made 19 unique comparisonsbetween interventions. Three comparisons werereplicated: oral ofloxacin versus topical pexigananin two trials, G-CSF growth factor versus placeboin two trials and G-CSF growth factor versusstandard care in two trials, and one trial had threearms, comparing sugar, standard care andantibiotics. None of the trials used a CONSORTchecklist for reporting, but some predate itspublication. Our criticisms of study quality mayreflect poor reporting rather than poor trialdesign, but without sufficient information thereader cannot determine whether sources of biasand error were minimised or not.
There is no strong evidence for recommendingany particular antimicrobial agents for theprevention of amputation, resolution of infectionor ulcer healing. Results suggest that growth factor(G-CSF) was less costly than standard care,cadexomer iodine dressings may be less costly
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than standard care (daily dressings) and A/S wasless costly than A/C. These results are from small,single trials and need replication. Topicalpexiganan cream may be as effective as oralantibiotic treatment with ofloxacin.
Decision analytic modellingThis section of the results describes the structureof the decision analytic model constructed toinvestigate the clinical effectiveness and cost-effectiveness of different diagnostic tests for theidentification of infection in patients with a DFU.The first step in the construction of the model wasto conduct a review of the literature to identify anymodels that described the natural history ofpatients with DFUs, and to identify studies thatcould inform the transitions within a decisionanalytic model. We searched for economic modelsor decision analytic models, i.e. studies in which amathematical structure had been used to representthe health and/or economic outcomes of patientswith a DFU. Table 2 describes the sources used toidentify research. The results of all searches werescrutinised to identify potentially relevant studies.
We report the results of a review of the literatureand then describe the general structure of thenatural history of one DFU model selected for theinvestigation of the potential impact on healthand economic outcomes of using differentdiagnostic tests to identify infection in patientswith DFUs. Next, we describe the initialassumptions regarding the volume of healthcareresources required for the treatment of patientswith DFUs and the way in which the use ofdiagnostic test would influence and/or modify thenatural history, that is, prognosis and treatment ofpatients with DFUs. The information requirementsto inform this new model are then listed. Finally,we discuss the alternatives to using data fromresearch studies as a method of populating thedecision analytic model.
Review of previous models describingthe natural history of diabetic footulcers The literature review of models describing the‘natural history of individuals with diabetic footulcers’ [natural history of disease: the temporalcourse of disease from onset (inception) toresolution] identified five different decisionanalytic models (decision analytic model: theapplication of explicit, quantitative methods thatquantify prognoses, treatment effects and patientvalues in order to analyse a decision under
conditions of uncertainty) investigating a numberof treatment and preventative strategies fordiabetic patients at risk of or who have alreadydeveloped a foot ulcer.15,121,128–130 Among the fivedifferent models identified, there was only onewhich provided a comprehensive description ofthe natural history of patients with diabetic footulcers;130 however, for completeness, a briefdescription of the structure of the identifiedmodels is provided below.
Tennvall and Apelqvist (2001)128
Tennvall and Apelqvist report the findings of amodel that evaluated the cost-effectiveness of twocompeting alternatives for the prevention ofdiabetes-related foot ulcers and amputations.128
The economic evaluation took the form of acost–utility study in which the health benefitsassociated with the two alternative preventivestrategies were measured in terms of quality-adjusted life-years (QALYs). Mean estimates ofcosts and health benefits associated with eachalternative were derived using a decision analyticMarkov model. Transition probabilities for themodel were obtained from a survey of 1677diabetic Swedish patients aged 24 years and over,mean age 66 years. Estimates of the treatmentcosts were retrieved from a previously publishedstudy that reported an analysis of the long-termcosts for foot ulcers in diabetic patients within amultidisciplinary setting.131 Similarly, utilityweights associated with the eight health statesconsidered in this model were based on thefindings of a previously published study in whichthe health-related quality of life (HRQoL) ofpatients with diabetes mellitus and foot ulcers wasinvestigated using the EuroQol questionnaire.132
The main objective in this analysis was to explorethe cost-effectiveness of prevention in four groupsof diabetic patients at different risks of developingfoot ulcers and/or experiencing amputation.Consequently, the description of the naturalhistory of DFUs was mainly focused in thosehealth states more likely to result in amputation.Although a ‘deep foot infection’ health state in thepresence of an open ulcer was included in themodel, no attempt was made to identify footinfections at an earlier stage, the time point atwhich the contribution of formal diagnostic testmay be most valuable.
York Health Economics Consortium (YHEC)(1997)129
YHEC conducted a cost-effectiveness analysis oftissue engineered human dermal replacementcompared to conventional therapy in the treatmentof DFUs in the UK.129 A model-based economic
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evaluation analysis was conducted using a decisionanalytic Markov model. Health benefits weremeasured in terms of ulcer-free weeks. Transitionprobabilities used in the model were derived fromthe results of an RCT of bioengineered humandermal replacement.133 Resource use was estimatedfrom the experience at four major UK NHSdiabetic centres. The unit costs were retrieved froma variety of sources. Although the structure of thismodel did distinguish between health statesaccording to varying degrees of infection, themodel was not described in sufficient detail to beuseful in facilitating the construction of acomprehensive natural history model.
Edmonds and colleagues (1999)121
Edmonds and colleagues report on the results of aretrospective cost analysis of rhG-CSF versusplacebo in the treatment of hospitalised diabeticpatients with infected foot ulcers and extensivefoot cellulitis, of whom 39/40 had an ulcer.121 Adecision tree was constructed to estimate meanexpected costs for both alternatives. Transitionprobabilities and total volume of resource use werederived from a randomised double-blind placebo-controlled study.100 This analysis only consideredthe cost implications associated with the treatmentof diabetic patients with an acute spreading ofinfection, presumably the patient group for whichrhG-CSF is indicated. However, it does notprovide information regarding patients with alesser degree of infection and as such it was notuseful for this project.
Eckman and colleagues (1995)15
Eckman and colleagues report the findings of acost-effectiveness analysis of different alternativesfor the diagnosis and treatment of patients withtype 2 diabetes mellitus, an infected DFU, andsuspected osteomyelitis.15 A Markov statetransition model was constructed to estimate meanlife expectancy and cost. This model consideredthree treatment strategies: (1) a short course ofantibiotics; (2) empirical treatment of osteomyelitiswith a long course of antibiotics; and (3) testingvarious combinations of roentgenography,technetium-99m bone scanning, white blood cellscanning and magnetic resonance imaging. Lifeexpectancy was adjusted for changes in quality oflife. In the base case analysis, quality-adjustedscores were based on expert physicians’judgments. Although this model directly evaluateddifferent diagnosis strategies for infection inpatients with DFUs, there were three main factorsthat prevented us from following this structure inour evaluation. First, a detailed description of themodel structure was not provided in the report.
Second, the study focused only on patients with asevere degree of infection, who were suspected ofsuffering from osteomyelitis. Third, the diagnostictest(s) under evaluation is (are) used to detectosteomyelitis rather than soft tissue infectionassociated with diabetic foot ulcers.
Persson and colleagues (2000)130
Persson and colleagues developed a Markov modelto evaluate the cost-effectiveness of treatingdiabetic lower extremity ulcers with recombinanthuman platelet-derived growth factor (rhPDGF-BB: becaplermin gel, Regranex®) in fourEuropean countries: France, Sweden, Switzerlandand the UK.130 Model results have been reportedin the literature on a single-country basis and alsoin an encompassing multi-country analysis. Thestructure of the model described in this analysiswas not only sufficiently detailed and transparent,but importantly, it provided a comprehensivedescription of the natural history of patients withDFUs. Consequently, it was decided to utilise thismodel as the basic structure for the analysis. Theauthors of the UK analysis were contacted andkindly agreed to provide us with an electroniccopy of their model.134
A model to describe the natural historyof diabetic foot ulcersModel structurePersson and colleagues’ Markov model wasadapted and used to describe the natural historyof DFUs.130 This type of model was used as itallows the simulation of disease prognosisincorporating the complications and reoccurrencesassociated with DFUs over a lifetime. The modeldescribing the natural history of DFUs consistedof nine discrete health states, although in thePersson model there were only six. The states inthe adapted model comprised uninfected ulcer,infected ulcer, healed ulcer, gangrene, gangrenehistory of amputation, healed history ofamputation, uninfected history of amputation,infected history of amputation and death. Thesestates represent what appear to be clinically andeconomically important events in the diseaseprocess being modelled. All of the states aremutually exclusive, since one of the requirementsof a Markov model is that a patient cannot be inmore than one state at a time. By attachingestimates of both resource use and health outcomeconsequence to the states and transitionsthroughout the model and then running themodel for a specified number of cycles, it ispossible to estimate the long-term costs andoutcomes associated with the disease andintervention being modelled.135 Amputation was
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considered to be a treatment that aided healingand as such was not considered a health state.
Transition probabilitiesMovement between the states is determined bytransition probabilities, and takes place after apredetermined length of time known as a cycle.Cycle length should be determined according to thefrequency with which patients are likely to changestates in real life. In this model, patients wereallowed to transit between states at monthly cycles.
In Persson’s natural history of the disease model,some transitions between states were disallowed,for example, a person could not develop an ulcerafter having an amputation (see Figure 6). ThePersson model was based on a patient populationwho were suffering from deep, ischaemia-free,diabetic neuropathic lower extremity ulcers.130
Consequently, it was necessary for the modelstructure to be modified to allow transitions thathad previously been ruled out, thus allowing themodel to reflect the clinical pathways of patientswith different underlying causes for DFUs, such asneuropathy and/or ischaemia. These conditionscover the largest proportion of patients withdiabetic foot ulcers.
The achievable transitions allow the patient tomove from the uninfected state to the healed,infected, gangrene or deceased state; from theinfected state a patient can make the transition tothe uninfected, gangrene, healed history of
amputation, infected history of amputation ordeceased state; and from the gangrene health statea patient can make transitions to the infected,gangrene history of amputation, healed history ofamputation or deceased state; from the healedhistory of amputation state a patient can onlymake the transition to deceased. The deceasedhealth state is an absorbing state from which notransitions can be made. An adaptation of theoriginal model is the transition from uninfected togangrene. Originally disallowed, this transitionwas incorporated into our model to allow for amore diverse study population that includedischaemic patients.
The transition probabilities used in Persson’smodel were derived from a cost of illness studyconducted in the USA. The study samplecomprised 183 US patients with either type-1 ortype-2 diabetes.136 The transition probabilitieswere derived directly from the study data (seeTable 11). Additionally, to ascertain the transitionsthat rely on information about the rates ofsuccessful or unsuccessful amputation, the studydata were augmented by Persson and colleaguesusing estimates based on the literature or expertclinical opinion.137,138 The transition cycles of themodel are monthly and the simulation is run untilall patients are healed or deceased.
Model assumptionsPersson and colleagues made a number of modelassumptions, which were necessary to facilitate
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Uninfectedulcer
Infectedulcer
Healedulcer amp.
Death
Amputationamp.
Healedulcer
Gangrene
Infectedhistory amp.
Gangrenehistory amp.
Uninfectedhistory amp.
FIGURE 6 Natural history of diabetic foot ulcers (Markov model)
completing the natural history model. Theassumptions were made both to simplify themodelling process and to supplement the lack ofavailable evidence to inform a different modellingsolution. First, it was assumed that after receivingan amputation that resulted in healing, it was notpossible for a patient to have a recurrence. Also, itwas assumed that amputation did not increase therisk of mortality and that a gangrene ulcer had thesame mortality rate as an infected ulcer. Finally, itwas assumed that infected ulcers are the cause ofapproximately 80–85% of all ulcer-relatedamputations and that gangrene is the cause of theremaining 15–20%.130
Elicitation of utility valuesIt was expected that the main outcome measure ofthe model would be cost per QALY. Identificationof studies reporting utility and HRQoL scores fordiabetic patients with and without DFUs was partof the main electronic searches for the project.Two suitable studies were identified.
Sullivan and colleagues (2002)139
Sullivan and colleagues elicited patientpreferences using both a rating scale and astandard gamble technique.139 The rating scaletechnique involves a scale from 0.0 to 1.0 whichrepresent the worst and best conceivable healthstates, respectively. The individual is then asked toplace health state descriptions on the scale. Theratings given to each health state descriptionsubsequently represent the individual’s rating scalevalues.
The standard gamble technique involves theindividual being given two options and asked tomake a choice as to which option they prefer. Theoptions are varied slightly and re-administered tothe individual in an attempt to reach the point atwhich the individual is indifferent between thechoices with which they are faced. When this pointhas been reached, it is possible to ascertain theindividual’s standard gamble value for the healthstate selected. The standard gamble technique isconsidered by many health economists to be thegold standard approach to eliciting cardinal healthstate values. This is because the technique isgrounded in expected utility theory, the dominanteconomic theory of risk.140
The patient population comprised adults with type1 and type 2 diabetes aged between 18 and80 years. Patients were excluded if they had anysymptoms of diabetic peripheral neuropathy(DPN) such as numbness, tingling or pain in theirextremities or any history of lower extremitycomplication such as a foot ulcer or anamputation. A total of 52 patients were enrolled inthe study. Patients were given detailed descriptionsof seven health states which fully described thestages of disease severity in DPN. The patientsthen completed the preference assessmentinterview for DPN-related health states. The studyfound that patients’ preferences for health statesdecreased as a function of increasing diseaseseverity in DPN regardless of the methods used tomeasure preferences. The results of the study arepresented in Table 12.
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TABLE 11 Model transition probabilities
Transition Probability Reference
Uninfected to healed 0.0787 136Uninfected to infected 0.0473 136Uninfected to dead 0.004 136Healed to uninfected 0.0393 136Healed to dead 0.004 136Infected to uninfected 0.1397 136Infected to gangrene 0.0075 136 Infected to healed (amputation) 0.045 131, 137Infected to infected (amputation) 0.0037 131, 137Infected to dead 0.0098 136 Gangrene to healed (amputation) 0.3082 131, 137Gangrene to gangrene (amputation) 0.1818 131, 137Gangrene to dead 0.0098 136Healed (amputation) to dead 0.004 136Uninfected to gangrenea
a No information regarding this transition probability was identified in the literature. However, for completeness thistransition was allowed in the model since this is a transition patients with arterial insufficiency can make.
When eliciting values for health states, thepopulation chosen can or cannot suffer from thedisease in question. Arguments against and infavour of either approach are a subject of debatefor many economic experts. For some thepreferred method would be to elicit preferencesfrom patients who are currently experiencing thehealth state; however, others will argue thatindividuals who are not experiencing such healthcondition are more likely to make an objectivevaluation. It is highly likely that Sullivan andcolleagues chose to exclude patients sufferingfrom DPN to allow an adequate recruitmentsample to the study.
Tennvall and Apelqvist (2000)141
Tennvall and Apelqvist (HRQoL) used the EuroQol quality of life questionnaire (EQ-5D),which included a visual analogue scale (VAS).141
The questionnaire was distributed by postal surveyat the end of a 3-year period to type 1 and 2diabetic patients who had been treated for footulcers during the 3-year study period. A total of440 patients participated in the study and weresent questionnaires. The study had a 70%response rate.
The study protocol defined four mutuallyexclusive groups dependent on their foot ulcerand amputation status at the time of thequestionnaire. The four groups were current footulcer with no previous amputation, primaryhealed with no current amputation, maximalminor amputation and maximal majoramputation. The study presents values for both EQ-5D and the VAS; the results of the studyare presented in Table 13. The study findings show that patients under current foot ulcertreatment value their HRQoL lower than thosewho have healed primarily without amputation. Inaddition, quality of life is reduced after majoramputations.
Utility values used in the modelThe health states which patients were asked tovalue in these two studies did not directly matchthose considered in this model. To facilitate theiruse, the differing health states were matchedwhere possible using both the Wagner scale,142
which is a widely used classification tool in theclinical field, and the health state descriptions aspresented by the individual papers (see Table 12).Where necessary, the project team usedassumptions and previous experience to ensurethe best possible match was achieved (seeTable 13).
Given that the standard gamble is considered tobe the ‘gold standard’ approach, it wasdetermined that the scores obtained using thistechnique would be used in the base-case model.Further, the other scores would be used tofacilitate sensitivity analysis in an attempt to assessthe robustness of the model results obtained.
Healthcare resource use requirementsThe perspective adopted for the economic analysisis that of the UK NHS and Personal SocialServices and as such only direct costs are included.Resource utilisation for the UK corresponds tothat reported by Ghatnekar and colleagues.143
Unit costs were derived from a number of sourcesincluding the BNF, NHS 2000 reference costs andpreviously published studies.
The unit costing and resource use used in thebase-case model are presented in Tables 14 and 15.
The prices are expressed in 2000 values. Themodel applies a discount rate of 6% to costs and1.5% to benefits according to NICE guidance foreconomic evaluation analysis.144
Based on Ghatnekar and colleagues’ assumptionsregarding volume of healthcare resources used,
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TABLE 12 Health-related quality of life states
Model health state Tennvall health states141 Sullivan health state139
Healed Primary healed, no amputation Severe neuropathyUninfected Current foot ulcer, no amputation Minor ulcerInfected Severe ulcerGangrene Severe ulcerUninfected (amputation) Severe ulcerInfected (amputation) Maximal major amputation Major amputationHealed (amputation) Maximal minor amputation Minor amputationGangrene (amputation) Maximal major amputation Major amputation
the total monthly recurring and non-recurringcosts per patient for each health state wereestimated to be for the uninfected state £1248.47, for the infected state £1237.44, for the gangrene state £2220.95 and for the healedstate £14.01.
Incorporation of diagnostic test in the modelstructure of the natural history of diabetic footulcersThe use of a diagnostic test can facilitate earlydetection of infection and allow a treatmentpackage to be tailored to meet the requirements ofthe individual patient. Consequently, theincorporation of a diagnostic test to the modelallowed the patients to be split into two groups,those with a positive test result and those with anegative test result, with each group following adifferent treatment pattern.
The two groups then enter into two differenttrajectory paths within the model. Those with apositive test result enter their model in theinfected state (Figure 7a). Transitions through themodel follow the same structure as the naturalhistory model, although the rate at which eachtransition is made will vary. Those patients whohave a negative test result enter their model in theuninfected state and will follow the same structureas the natural history model, (Figure 7b). Although,as with the patients who had a positive test, thetransition probabilities will vary from those in thenatural history model.
Target populationThe identification of the target population, that is,those patients with DFU most likely to benefitfrom the use of diagnostic tests to inform their
treatment, was made based on the findings fromthe systematic reviews conducted within thisproject and consultation with clinical experts.Applying a diagnostic test for infection to allpatients with a DFU irrespective of the conditionof their ulcers might be an inefficient use ofalready scarce UK NHS resources, hence therelevance to identify the groups of patients whoare more likely to benefit. Initially, the researchteam identified clinically infected patients as thetarget population for diagnostic testing. Theliterature was then used to characterise this targetpopulation fully.
The review of the literature found no consensuson a definition of what it means to be clinicallyinfected. Owing to the lack of clarity surroundingan appropriate definition of ‘a clinically infectedulcer’, current clinical procedure, the relevance ofour target population, and data for the model, itwas decided to construct a questionnaire to beadministered to what was deemed a relevantaudience in an attempt first to derive a definitionfor clinically infected foot ulcers from clinicalexperts and to estimate relevant parameters forthe decision model using clinical judgement. Aquestionnaire was designed and personalinterviews conducted at the 13th Conference ofthe European Wound Management Association,Pisa, Italy, 22–24 May 2003. The target audienceat the conference was expert wound careresearchers and clinicians. Personal interviewswere conducted in an attempt to ascertain aconsensual definition of ‘clinical infection’ whichcould help us to characterise fully the populationof interest (see Appendix 7). This in turn wouldlead to clarification of the relevant economicquestion.
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TABLE 13 Health-related quality of life scoresa
Health state Standard gamble Rating scale EQ-5D VASMean (SE) Mean (SE) Mean MeanRange (0.0 –1.0)139 Range (0.0–1.0)139 Range (–0.594 to 1)141 Range (0–100)141
Uninfected 0.76 (0.23) 0.57 (0.16) 0.44 52Healed 0.84 (0.19) 0.70 (0.15) 0.6 63Infected 0.62 (0.30) 0.41 (0.17)Gangrene 0.62 (0.30)a
Uninfected (amputation) 0.62 (0.30)a
Healed (amputation) 0.74 (0.24) 0.45 (0.19) 0.61 64Infected (amputation) 0.61 (0.29) 0.27 (0.19) 0.31 54Gangrene (amputation) 0.62 (0.30)b
a Higher scores indicate better health status.b Assumption.
The results of the interviews revealed that inpractice in the UK any patient showing any signsof an infection would receive a first course ofantibiotics when they first presented to a clinician.The only patients whose treatment would beinformed by diagnostic tests are those who showno signs of infection but whose ulcer is not healingand those in whom a first course of antibiotics was
not successful. These two groups of patients thenbecame our new target populations.
Model information requirementsIn order to operationalise the model, estimates ofall the parameters within it, such as transitionprobabilities, sensitivity of different diagnostictests, among others, and the uncertainty
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TABLE 14 Healthcare resource use requirements associated with the treatment of diabetic foot ulcers (Ghatnekar’s assumptions)143
Quantity Unit cost (£)
Topical treatment per visit (outpatient)� Patients were assumed to require 6 visits per week8-Ply gauze swab 1 0.0338Conforming bandage 0.5 0.435Nursing cost 1 22.00
Infected patients treated as outpatients� 14 days of treatment� After 14 days 20% required hospital treatmentAmoxicillin 1500 mg 0.15Flucloxacillin 2000 mg 0.498
Infected patients treated as inpatient� Treatment continued for 14 daysI.v. Ceftazidime 4000 mg 39.60Metronidazole 1500 mg 10.23
Antibiotics – daily treatment (gangrene)� 14 days of treatment � After 14 days 50% of patients require hospitalisationAnd 50% are treated as outpatients and require metronidazole
Gangrene treatment as outpatients� Treatment continued for 14 daysCiproxacillin 1000 mg 2.84Amoxicillin 1000 mg 0.15Flucloxacillin 2000 mg 0.498Metronidazole (50% require) 1200 mg 0.649
Gangrene treatment as inpatients� 50% require inpatient treatment for 14 daysI.v. Ceftazidime 4000 mg 39.60Metronidazole 1500 mg 10.23
Other outpatient costs (infected and uninfected)Podiatrist visit 4 per month 16.00Diabetologist 1 per month 73.00
Other outpatient costs (gangrene)Surgical consultation 1 per year 89.00
Inpatient careLength of stay 14 daysAmputation Major 7224.00
Minor 3052.00Prostheses 1 NA
Orthopaedic appliances� A percentage of patients are assumed to require orthopaedic appliancesAir cast (30%) 1 100.00Healing shoes (Neoprene) (70%) 1 pair 27.50Custom shoes (30% of healed) 1 pair 375.00Orthopaedic stock shoes (70% of healed) 1 pair 100.00
NA, not available.
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TABLE 15 Clinical and diagnostic tests assumed to be required by diabetic patients with an open foot ulcera
Test Frequency Unit cost Uninfected Infected Gangrene(monthly) (monthly) (monthly)
Blood glucose 4 times/month 1.10 4.40 4.40 4.40X-ray 1 time/year 40.0 3.33 3.33 3.33Full blood count 2 times/year 3.73 0.62 0.62 0.62U + E 1 time/year 4.00 0.33 0.33 0.33Blood culture 1 time/year 8.05 0.67 0.67 0.67Chest X-ray 1 time/year 13.77 1.15 1.15 1.15HbA1c 1 time/3 months 1.10 0.37 0.37 0.37
Diagnostic tests Quantities Unit costs
Wound swabs 1 7.9 (5.61–9.33)Wound biopsy 1 7.9 (5.61–9.33)Wound lavage and analysis of the fluid 1 7.9 (5.61–9.33)
a As testing does not take place in the healed and dead state, no testing costs are incurred for these states.
Amputationamp.
Uninfectedulcer
Healedulcer
Infectedulcer (test +)
Gangrene
Infectedhistory amp.
Uninfectedhistory amp.
Gangrenehistory amp.
Healedulcer amp.
Death(a)
Amputationamp.
Infectedulcer
Healedulcer
Uninfectedulcer (test –)
Gangrene
Infectedhistory amp.
Uninfectedhistory amp.
Gangrenehistory amp.
Healedulcer amp.
Death
(b)
FIGURE 7 Model structure
associated with them are required. The modelinformation requirements are described inTables 16–19. It is worth noting that these datashould be specific to the two groups of patientswith DFUs in which diagnostic tests are routinelyused in the UK, namely:
� Patients with DFUs who do not show anyclinical symptoms of infection but whose ulcer isnot healing.
� Patients with diabetic foot ulcers in whom a firstcourse of antibiotics was not successful.
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TABLE 17 Effectiveness information requirements to run model
Impact on treatment Information required
Wound swabs Expected changes in antibiotic treatment effectiveness (i.e. changes in proportion ofpatients whose infection resolves) due to prompt detection of infection using thistest
Wound biopsy Expected changes in antibiotic treatment effectiveness due to prompt detection ofinfection using this test
Wound lavage and analysis of the Expected changes in antibiotic treatment effectiveness due to prompt detection of fluid infection using this test
TABLE 16 Diagnostic information requirements to run model
Diagnostic test Information required
Wound swabs Sensitivity and specificityWound biopsy Sensitivity and specificityWound lavage and analysis of the fluid Sensitivity and specificity
TABLE 18 Outcome information requirements to run model
Transition probabilities Information required
Uninfected to healed Proportion of patients with an uninfected ulcer who healUninfected to infected Proportion of patients with an uninfected ulcer who are later diagnosed as infectedUninfected to dead Proportion of patients with an uninfected ulcer who dieHealed to uninfected Proportion of healed patients who have an ulcer recurrenceHealed to dead Proportion of healed patients who dieInfected to uninfected Proportion of people diagnosed as infected whose infection resolves after a first
course of antibioticsInfected to gangrene Proportion of people with an infected ulcer who are later diagnosed as having
gangreneInfected to healed (amputation) Proportion of infected people who undergo amputation
Proportion of people with an amputation who healInfected to infected (amputation) Proportion of infected people who undergo amputation
Proportion of people with an amputation who are later diagnosed as infectedwithout having healed
Infected to dead Proportion of infected people who dieGangrene to healed (amputation) Proportion of people with an infected ulcer who are later diagnosed as having
gangreneProportion of people with gangrene who undergo amputationProportion of people with gangrene who heal after amputation
Gangrene to gangrene (amputation) Proportion of people with an infected ulcer who are later diagnosed as havinggangreneProportion of people with gangrene who undergo amputationProportion of people with gangrene whose gangrene reoccurs after amputation
Gangrene to dead Proportion of people with gangrene who dieHealed (amputation) to dead Proportion of people undergoing amputation who heal
Proportion of healed people after amputation who dieUninfected to gangrene Proportion of uninfected people who are later diagnosed with gangrene without a
prior diagnosis of infection
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TABLE 19 Treatment information requirements to run model
(a) Topical treatment per visitCurrent assumptions in the model regarding topical treatment Does this assumption apply to Quantity
target groups in UK?6 visits per week8-Ply gauze swabConforming bandageNursing time
(b) Treatment of infection (outpatients)Current assumptions in the model regarding outpatients’ Does this assumption apply to Daily dosagetreatment of infection target groups in UK?Treatment was to be continued for 14 days. After 14 days. 20% of these patients required hospital treatmentAmoxicillinFlucloxacillin
(c) Treatment of infection (inpatients)Current assumptions in the model regarding inpatients’ Does this assumption apply to Daily dosagetreatment of infection target groups in UK?Treatment was assumed to continue for 14 daysI.v. CeftazidimeMetronidazole
(d) Treatment of gangrene (outpatients)Current assumptions in the model regarding outpatients’ Does this assumption apply to Daily dosagetreatment of gangrene target groups in UK?Treatment continued for 14 days. After 14 days 50% of these patients will require hospitalisation and 50% will be treated as outpatients and require metronidazoleCiproxacillinAmoxicillinFlucloxacillinMetronidazole
(e) Treatment of gangrene (inpatients)Current assumptions in the model regarding inpatients’ Does this assumption apply to Daily dosagetreatment of gangrene target groups in UK?50% require inpatient treatment for 14 daysI.v. CeftazidimeMetronidazole
(f) Other outpatients’ costs (apply to infected and uninfected patients)Current assumptions in the model regarding other outpatients’ Does this assumption apply to Quantityservices target groups in UK?Podiatrist visitDiabetologist
(g) Other outpatient costs (apply to patients with gangrene)Current assumptions in the model regarding other services for Does this assumption apply to Quantitypatients with gangrene target groups in UK?Surgical consultation
(h) Inpatient careCurrent assumptions in the model regarding other services Does this assumption apply to Quantityfor inpatients target groups in UK?Length of stayMajor amputationMinor amputationProstheses
continued
According to the results obtained from thesystematic review of diagnostic studies, there is apaucity of research regarding the use andcontribution of diagnostic tests in themanagement of patients with DFUs. The reviewfound only three diagnostic studies that wereeligible for inclusion and none of them providedinformation about the sensitivity and specificity ofthe diagnostic tests for the two target populationgroups. Equally, the studies reporting on theclinical effectiveness of different antibiotictreatments for infection do not specifically refer tothe effectiveness of such treatments for either ofthe target populations; rather, they refer to arange of patients with an infected foot ulcer/leg.Consequently, the decision analytic modeldescribed above could not be informed for thepopulations of interest. In order to populate themodel, the data requirements outlined inTables 16–19 would be required. The model couldbe adapted to suit any patient population thatmatched the natural history outlined previouslyand for whom the data could be obtained. At thistime no data for our target populations wereavailable. As a result, no estimates of healthbenefits or costs associated with the use ofdiagnostic test of infection in the relevant patientswith diabetic foot ulcers could be made.
Alternative options to populate the decisionanalytic modelGiven the lack of evidence identified in the reviewof the literature to populate the decision analyticmodel described above for the two populations ofinterest, it was necessary to pursue other avenuesthat may facilitate the data requirements. Hencethe research team decided to consult with clinicalexperts to explore the possibility of populating themodel using clinical judgments.
AimsAn interview schedule was designed with the aimof guiding semi-structured interviews with expertclinicians. The interviews sought to identify a
definition of clinical diagnosis of an infected footulcer and the clinical symptoms associated with it.Clinicians were then presented a number ofalternative courses of action to assess/treatindividuals with a DFU who had been clinicallydiagnosed as having an infected ulcer, and thosewith a non-healing but apparently uninfectedulcer. This included asking about the type ofmicrobiological sample taken and its role indetermining therapy. Finally, interviewees wereasked to give their views about a definition ofclinical diagnosis of infection in foot ulcers thathad been identified in the literature.
SampleOne interviewer approached six internationalexperts working with DFUs who were attending aconference on wound management. Theycomprised two podiatrists, one diabetologist, onevascular surgeon, one nurse specialist and onephysician with an interest in chronic wounds.Responses were recorded on an interview schedulerather than being recorded electronically. Replieswere tabulated to identify agreement anddisagreement between respondents.
Results The responses are reported in Appendix 7.
Definition of infection. Four experts reported thatswelling was indicative of infection (the other twocited cellulitis), four used pain as a potentialmarker of infection and four reported discharge orexudate as being important. The primacy of theclinical diagnosis of infection, as opposed to usingbacteriology to diagnose infection, is highlightedby the statement by respondent C: “We don’t useswabs to diagnose infection, the clinical impressionis the diagnosis, swabs simply confirm theorganism”. Other diagnostic clues for infectionincluded redness or erythema (three reports),smell (three reports), cellulitis (two reports), heat(one report), induration (one report), andundermining (one report).
Results
58
TABLE 19 Treatment information requirements to run model (cont’d)
(i) Orthopaedic appliancesCurrent assumptions in the model regarding orthopaedic appliances Does this assumption apply to Quantity
target groups in UK?Percentage of patients who are assumed to require orthopaedic appliancesAir cast (30%)Healing shoes (Neoprene) (70%)Custom shoes (30% of healed)Orthopaedic stock shoes (70% of healed)
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Hea
led
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Empirical or bacteriology-guided therapy after diagnosisof infection. When asked whether a course ofantibiotics would be commenced following aclinical diagnosis of infection (and before a swabresult is available), three experts stated “all ofthem”, one stated “virtually all of them”, onestated “the majority” and one “5–7 out of 10”. Onereason given for delaying antibiotic therapy wasthe potential for osteomyelitis – it was stated by apodiatrist working in a tertiary referral centre thattherapy would await a bone biopsy if osteomyelitiswas suspected. Another factor affecting thedecision to prescribe empirically or to await resultswas the day of the week on which the patient wasseen – as a patient seen in the early part of theweek could be seen again in 24/48 hours to checkon progress, whereas someone seen on a Fridaycould not be reassessed easily, and therefore weremore likely to be given antibiotics.
Sources of information on wound bacteriology. Swabswere the most common type of sample taken foranalysis (4/6 respondents) with a deep tissuebiopsy taken at centre where a bone infection teamwas available and curettage of neuropathic ulcersat one centre. The role of swabbing wassummarised by one respondent who stated thatthey treat the symptoms, not the swab result(respondent A). Practices following uninformativeswabs were variable.
Managing uninfected ulcers For apparentlyuninfected ulcers, the period of time over whichan assessment of ‘non-healing’ was made rangedfrom 3 to 8 weeks, although one expert stated thatthey used the percentage reduction in area byweek 4 as a guide.
Caputo’s definition of clinical infection25 All expertsagreed with Caputo’s definition of infection indiabetic foot ulceration,25 “erythema, indurationand discharge”, but one pointed out that the lackof erythema in a neuropathic ulcer may reflectpathology rather than prove the absence ofinfection. This expert also said that thecharacteristics of the discharge were important –changes in type/amount of discharge wereimportant as waiting for pus were leaving it “toolate”. Only one expert stated that the presence oftwo of the three signs was sufficient, and it is notclear whether the remaining experts required thepresence of all three signs for most ulcers.
Other findings from the interviews. The three medicaldoctors described different empirical regimens forfirst-line treatment, with two of the threementioning metronidazole and two mentioningclindamycin.
Summary The interviewees lacked agreement overall on thediagnostic criteria for clinical infection, theprevalence of infection, the best course of actionregarding treatment, length of treatment before analternative would be tried and the use ofdiagnostic testing.
DiscussionThe variations in clinical practice regarding thetype of bacteriological sample taken and use ofantimicrobial therapy from the questionnaire’sresponses raised concerns regarding theappropriateness of using clinicians’ estimates toinform the decision analytic model. The variationspresented in the clinical estimates were so widelydispersed that it was not possible to obtain acentral estimate and use sensitivity analysis overplausible ranges to address the uncertainty in ourchosen estimate.
It was decided that the degree of variationreflected in the data suggested that it would not bepossible to reach consensus about any of theparameters of interest based on the informationfrom the interviews with the clinicians. At thispoint, it was decided that the decision analyticmodel could not be populated.
After considering the response of the interviewees,and looking at the literature available, we wereable to revise the clinical pathway initial proposed(Figure 1) to reflect the actual pathways thatclinicians took. This is summarised in Figure 8. Inbrief, it indicates that antimicrobial analysis fordetermining the choice of antibiotics to be usedfor an episode of infection is reserved for patientsin whom there are no frank signs or symptoms ofinfection, but whose ulcer is non-healing. Forpeople with an ulcer infection, a sample may betaken but, as antibiotic therapy is commencedimmediately, then the choice of antibiotics is notinformed by the results. The results frombacteriological analyses were consulted, accordingto our interviewees, only if the infection was notresolving or the ulcer was not healing.
Results
60
Diagnostic studiesLimitations of the researchWhat is the diagnostic performance of clinicalexamination in the identification of infection inDFU?One study was identified that addressed the aboveresearch question.90 The overall sample size wassmall (n = 36), which meant that some sensitivity,specificity and predictive values were estimated at100% (likely to be inflated) and therefore that acorrection factor of 0.5 was required to calculatesome LRs. The derived estimates are likely to havewide CIs, indicating a large degree of uncertaintyaround the central estimates. The use of a largersample size would have increased the precision ofthe estimates.
The sample was heterogeneous with respect towound type. It is possible that different woundtypes present differently with respect to differentclinical signs and symptoms of infection and thatthe usefulness of individual signs and symptomsmay vary according to wound aetiology. This wasreflected in the slightly different profile ofsensitivity values seen in venous leg ulcers whencompared with the overall sample. Of particularinterest is the higher sensitivity for purulentexudate as compared with the overall sample ofwounds of mixed aetiologies (67% versus 18%).However, it may be argued that a sensitivity of67% is still not high enough to be clinically useful,and it would be necessary to consider the clinicaland economic consequences of failing to identifyone-third of wound infections. Another potentialreason for the difference between estimatedoutcomes across different wound types is randomerror (chance). Since there were only two patientswith DFUs and seven patients with venous legulcers, it is difficult to infer from the findings ofthis small study in a way that is useful to theresearch questions posed for this project. It islikely that all patients with a chronic wound arelikely to be subject to clinical examination of thelesion in clinical practice. However, owing to thestrict inclusion criteria in terms of the baselinehaematological status of patients in three out ofthe four study centres, this study is likely to haveexcluded some patients for whom the index testwould be relevant. It is difficult, therefore, to
generalise the results of this study to a populationseen in clinical practice. Another consideration isthat this study estimated diagnostic outcomes for arange of individual clinical signs or symptoms. Itmay be the case that, in reality, clinicians tend todefine infection based on clusters of signs andsymptoms rather than relying on any oneindividually, as described by the expertrespondents in Appendix 7.
The assessment of inter-rater reliability of theindividual checklist items resulted in � statisticsranging from 0.53 to 1.00. The authors providedmore detail about this assessment in a separatepaper.145 The following can be deduced with theassistance of guidelines for interpreting� statistics:146,147 very good agreement(� = 0.81–1.00) was attained for the symptom ofincreasing pain, and signs of oedema, delayedhealing and wound breakdown; there was goodagreement (� = 0.61–0.80) for erythema, purulentexudate, serous exudate, discoloration and friablegranulation; moderate agreement (�= 0.41–0.60)for heat and foul odour; and no agreement betterthan chance was found for pocketing of the woundbase. In terms of percentage agreement, the study authors made use of recommendationssuggesting that an agreement of at least 70% isnecessary, at least 80% is adequate and at least90% is good.145,148,149 Four of the checklist items had agreement values <70%: heat(occurrence agreement 44%); discoloration (non-occurrence agreement 65%); foul odour(occurrence agreement 50%); and pocketing of thewound base (occurrence agreement 0%). All exceptpocketing of the wound base, which did not occurin the sample, had favourable alternativeagreement values in terms of total percentageagreement, occurrence percentage agreement,non-occurrence percentage agreement and/or �statistics.145
Two clinical indicators (increasing pain and wound breakdown) may be useful individually for identifying infection in chronic wounds, andboth showed good inter-rater reliability. However,these findings should be viewed with cautionowing to the small size of the study and theheterogeneity of the study group with regard towound type.
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Chapter 5
Discussion
When interpreting outcomes from diagnosticevaluations, it is important to recognise possiblesources of bias that may impact on the derivedestimates. It was unclear from the paper whetherresults for each patient for the index test wereinterpreted without knowledge of the associatedresult of the reference test, and vice versa. Ifinterpretation was not blind, bias could arise as aresult of non-independent assessment of indexand reference tests, which is thought usually toresult in overestimation of the accuracy of theindex test (test review bias).150 The longer time lagbetween tests for one of the study sites could havemeant that some wounds changed their infectionstatus during the interim period, leading todisease progression bias.
What is the diagnostic performance of specimenacquisition techniques in the identification ofinfection in DFU?Findings suggested a limited usefulness for thewound swab in detecting infection in chronicwounds.91 However, it should be noted that thereare several limitations to this study. The overallgroup size is small and it is heterogeneous withregard to wound type. It is possible that the testcould perform differently in different woundtypes, therefore the estimates reported for theoverall sample should be interpreted with caution.It is not clear whether participants had to havewound infection suspected from clinical signs andsymptoms in order to be recruited. If not, then theusefulness of taking a swab for all wounds may bequestionable, and may not reflect procedures inclinical practice. However, patients had to havewounds present for at least 6 months, and it maybe that the study authors considered that delayedhealing indicated the presence of wound infection.It is possible that the inflammatory response, andtherefore the usual presentation of clinical signsand symptoms of wound infection, may bereduced in people with DFUs, owing to reducedskin vasodilation and/or neuropathy.24,60 Somesources suggest that the presence of bacteria inwounds may delay healing.151 However, thecurrently available evidence on the link betweenpresence of pathogens and wound healing is bothsparse and inconsistent.48,151
The estimates of diagnostic accuracy gleaned fromthis study may have been influenced by test review bias.
There was difficulty in identifying a universallyaccepted reference standard in this field ofresearch. This problem has been observed in otherclinical areas and it has been asserted that ‘gold
standards providing full certainty are rare’.152
Tissue biopsy was employed as the referencestandard for the two studies described above.90,91
Other sources also suggest that tissue biopsy is areliable reference standard.153,154 Given that thedifficulty lies in deriving a standard as close aspossible to the theoretical reference standard,152 itseems likely that researchers will continue toregard tissue biopsy as the optimum referencestandard for evaluations of diagnostic accuracy. Instudies where a reference standard has not beendefined and justified, the evaluation should beregarded as assessing the agreement betweendiagnostic tests as opposed to accuracy. TheNational Coordinating Centre for ResearchMethodology (NCCRM) has recently proposed amethodological research project to review methodsin diagnostic evaluations when there is noreference standard, which may eventually provideguidance for conducting systematic reviews of thistype.155
What is the diagnostic performance of differentlaboratory analysis techniques in theidentification of infection in DFU?Findings, again from a single study, suggest thatsemi-quantitative analysis may be a usefulalternative to quantitative analysis, particularly forsettings where the equipment and materialsnecessary for the latter are not available.92 Thestudy group was heterogeneous in terms of woundtype, and the impact of the use of differenttechniques of laboratory analysis of swabs in DFUsis unclear. It is not known whether analysis resultsvary across samples from different wound typeswhen bacterial loads are similar. Owing to theapparent dearth of research in this important area,it is difficult to say whether the use of aquantitative analysis of wound swab is anacceptable reference standard. Test review bias anddisease progression bias may have had an impacton the derived estimates, therefore the findingsfrom this study should be viewed with caution,particularly when inferring to a particular woundtype.
Reporting issuesIn recent years, several initiatives have beendeveloped to help improve the standard ofreporting of biomedical research. Initially theConsolidated Standards of Reporting Trials(CONSORT) statement was issued with the aim ofimproving the reporting of randomised controlledtrials.156 Later, the Quality of Reporting of Meta-Analyses (QUOROM) statement was introduced, asimilar tool to the assist reporting of systematicreviews and meta-analyses.157 More recently, the
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Standards for Reporting of Diagnostic Accuracy(STARD) initiative has been described to improvethe quality of reporting of studies of diagnosticaccuracy and therefore help readers to judge theinternal and external validity of an evaluation.158
The STARD initiative includes the use of achecklist developed by a project steeringcommittee who used literature searches and aconsensus procedure to develop the range ofconstituent items. The checklist covers thefollowing: ease of identification of the article as astudy of diagnostic accuracy; description ofresearch questions; methods used for participantselection, test execution and statistical analysis;results in terms of participant characteristics, timeinterval between tests, distribution of diseaseseverity, diagnostic outcomes and adverse effects;and discussion of the clinical applicability of studyfindings. With respect to the three studiesincluded in this review, the following were themost important problems with regard to quality ofreporting. None of the studies reported whetherresults of the index test were interpreted withoutknowledge of the results of the reference test, andvice versa. Only one reported test reliability anddescribed the number, training and expertise ofthe people performing and interpreting the indextest, but no description for the reference test,90,145
and only one considered the possible impact ofadverse effects of the tests in terms of the clinicalconsequences of false negative and false positiveresults.92 Two studies did not state the methodsused for selecting participants.90,92 None of thestudies stated whether treatment was delivered tothe wound between administration of tests, and inone study the time interval between tests was notstated.92 In two studies, no information wasprovided about when the study was done orrecruitment dates.90,91 Although there are clearlysome improvements that could have been made tothe reporting of all three studies, it is important toacknowledge that all three studies fulfilled manyof the items on the 25-item STARD checklist.158
Other systematic reviewsNo existing systematic reviews addressing thethree diagnostic research questions were identifiedfrom this project. As far as we can ascertain, thisproject is the first attempt at combining data fromstudies of clinical examination and microbiologicalsampling in DFUs. Two systematic reviews wereidentified in a related area, not within the scope ofthis project, the diagnosis of osteomyelitis.159,160
The earlier review evaluated the diagnosticaccuracy of technetium bone scanning fordetecting lower extremity osteomyelitis in patientswith diabetes, neuropathy or vasculopathy.159 The
more recent review assessed the diagnosticperformance of a variety of methods (includingimaging techniques, probe to bone and bonebiopsy) to identify osteomyelitis in patients with aDFU.160
Novel techniquesNo evaluations meeting the inclusion criteria wereidentified for the two novel techniques of woundinfection detection, the electronic nose/tongue andPCR. Should these techniques eventually prove tobe of value for management of infection in DFUs,they could potentially modify clinicians’ decision-making processes, owing to reducing the waitingtime for test results.
Recommendations from clinicalguidelines on DFUsA review of clinical guidelines on management ofdiabetic foot disease shows varyingrecommendations to inform clinicians about thebest ways of identifying infection in DFUs. Somesources recommend the use of clinicalexamination only, and suggest that cultures are oflimited value.76,78 Other documents suggest thatthere are problems with clinical examinationowing to the absence of many of the classical signsand symptoms of systematic or local infection indiabetic patients.79 However, swabs should only beused following debridement or curettage of theulcer bed.77,79 One recommendation is tocommence antibiotic therapy according to clinicalsigns and symptoms, then modify treatmentaccording to culture results.161
The uncertainty reflected by these varyingrecommendations perhaps reflects the paucity ofrelevant data, and supports our finding of threeeligible studies representing the true extent of theavailable evidence. Several other relevant clinicalguidelines do not contain any information aboutdiagnosis of infection in DFU, which again maycorrespond to the dearth of researchevidence.162–164
Adverse effects of diagnostic testsAs identified above with reference to the STARDchecklist,158 only one of the included studiesreported on possible adverse effects of the tests interms of the impact of false negative and falsepositive results.92 None of the studies investigatedthe possible psychological effects of false negativeand false positive results (e.g. anxiety) or theimpact of pain or discomfort associated withundergoing the tests. Even in the case of clinicalassessment of the wound, the patient may berequired to assume an uncomfortable position
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while the examination takes place. In addition, theacquisition of microbiological samples using tissuebiopsy or swab may be painful. Some swabbingtechniques require that sufficient pressure isapplied to the wound in order to express tissuefluid.91,92
A further related concern is whether the woundflora may be altered through the use of differentacquisition techniques, such as applying pressureto the wound surface using a swab. It is possiblethat transient and resident bacterial populationscould be differentially sampled using gentle oraggressive swabbing techniques. As far as we couldascertain, this aspect of microbiological samplinghas not been evaluated.
Effectiveness studiesLimitations of the research What impact does microbiological analysis haveon therapy?We did not find any studies evaluating the impactof microbiological analysis on the treatment ofinfection, pain, exudate, healing, HRQoL or thedevelopment of complications. It is possible thatin industrialised countries the availability ofmicrobiological testing means that this is routinelydone, and the opportunity to conduct a trial maybe minimal. In interviews with experts to informthe review (Appendix 7), it was stated that aculture and sensitivity result from a swab or biopsywould be necessary to adjust therapy if theempirically chosen therapy was inappropriate or ifthe infection failed to resolve. If there is noclinical improvement over a period of a few days,then the swab or biopsy results are consulted toguide the choice of antibiotic. It is not clear howuseful the results from a microbiological sampleare at this point. As the sample has been drawnfrom the wound prior to the commencement ofantibiotic therapy, the wound flora may havechanged. However, without rapid microbiologicalanalysis techniques the initial swab may be theonly source of information on the cause ofinfection, even if it is imperfect.
What are the effects of treatments on clinicaleffectiveness and cost-effectiveness?Our second effectiveness question addressed theclinical and cost-effectiveness of techniques fortreating infection in DFUs. Outcomes of interestwere infection resolution, amputation, healing andthe transfer of drug-resistant organisms to staffand other patients. Overall, the strength of theevidence to guide the selection of antimicrobial
agents for the treatment of diabetic foot ulcers ispoor. This is due to the poor quality of many ofthe trials and the lack of replication of mostcomparisons.
PopulationWhile the review aimed to summarise the effect ofinterventions for treating infection, it becameapparent that studies reported the ulcercharacteristics in a number of ways. Somedescribed infections associated with foot ulcers asulcer infection, some as soft tissue infection andothers as cellulitis. A number of trials includedmixed populations, either people with diabetesand ulcers or soft tissue infection but noulceration, or people with infected wounds, someof whom had diabetes and foot ulcers. Weincluded trials in which data for infected DFUswere available separately, or where at least 80% ofa population of people with infected wounds hadfoot ulcers and diabetes. A few studies evaluatedthe impact of antimicrobial agents in themanagement of apparently uninfected DFUs andthese were also included as the clinical diagnosisof ‘infected/uninfected’ may not be straightforwardin people with diabetes owing to suppression ofthe normal immunological response to infection.165
Some authors believe that a non-healing wound,even if apparently uninfected, may be delayed inhealing due to a ‘critical colonisation’ of thewound bed by a high bacterial load.166 Wetherefore decided to include all trials where anantimicrobial intervention was used, as this wouldreduce any chance of excluding studies in peoplewith delayed wound healing due to bacterial load.
Defining antimicrobial agents was straightforwardfor antibiotics, but not for other agents which actby direct ingestion of bacteria (larvae), or reducingosmotic potential for bacterial proliferation(sugar), as a number of different agents potentiallyredress the host–bacterial balance.167 We decidedto include an agent if it was a recognisedantimicrobial (antibiotics and antiseptics, forexample) or if the authors of the study stated whatantimicrobial action the agent possessed. Agentswere included in the review regardless of theirmode of administration or their current licensingstatus. With this definition in use we also includeda growth factor which increases neutrophil activity,and which is used in infected ulcers alongsidesystemic antibiotics.
Comparisons madeThe comparisons in the trials tended to be of twoactive interventions. Notable exceptions were thetrial comparing oral antibiotics with a placebo
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tablet in 44 people with ‘uncomplicated’neuropathic foot ulcers (ulcer grade up to 2A),74
and the four growth factors trials, in whichplacebo or standard care alone were thecomparators.100,118–120 For people with a clinicaldiagnosis of established severe wound/footinfection, it is unlikely that a placebo or standardcare controlled trial could be performed asclinicians are convinced of the need to instituteimmediate antibiotic therapy (see Appendix 7)and delay, for example to culture the causativeorganisms, or a placebo treatment could threatenthe limb. It may be more feasible to conduct a trialcomparing antimicrobial agents againstplacebo/standard care alone in people without asevere infection. This would help inform whetherthere is a net benefit associated with antibiotictreatment in this group. Such studies, however,rely upon clinicians having access to reliabletechnologies to distinguish between people withsevere or non-severe infections. Interviews withclinicians indicated that decisions to treatempirically or adopt a watchful waiting approachalso depended on factors such as their confidencein the patient returning if the ulcer deteriorated,and the proximity to the weekend, whenimmediate access to the foot clinic is not possible(Appendix 7).
Study qualityWe assessed the quality of each trial and presentedthe Jadad scores for each characteristic separatelyas simple addition of the scores may bemisleading. Overall – the quality was poor –median score for double-blinding was 0 (i.e. trialwas not described as double-blind); median scorefor randomisation was 1 (i.e. trial was simplydescribed as randomised with no details aboutmethods used to achieve randomisation); medianscore for withdrawals was 1 (i.e. number ofwithdrawals was reported by groups and reason).Allocation concealment was scored as adequate,unclear or inadequate and the mode was ‘unclear’.Two trials described inadequate methods ofallocation.106,122 Two trials described adequatemethods of concealing the allocation from theperson randomising the participant into thetrial.100,101 Two trials allowed patients to selecttheir own treatment.110–112
From the information available, the trial thatscored the highest in terms of quality was anevaluation of subcutaneous growth factors,100 as itdescribed adequate randomisation procedures,allocation concealment, appropriate methods fordouble-blinding, and reported withdrawals bygroup and reason.
One study of systemic antibiotics, by Peterson andcolleagues,101 described allocation concealment,appropriate randomisation, described themselvesas double-blinded (but did not report how this wasachieved), and reported withdrawals by group andreason.
These two studies reported attempts to minimisebias but were too small to allow robust conclusionsto be drawn, hence we did not give themadditional weight in the narrative review.
Statistical powerMost trials (20/23) did not report a calculation,a priori, of the sample size required to be able todetect clinically important difference in outcomesas statistically significant. This means that theyhad a very high risk of concluding that there wasno difference in the effectiveness of thecomparator regimens when in reality there wasinsufficient power to be able to determine whetherthere was a difference or not (a Type II error). Forexample, Chantelau and colleagues concludedthat there was no benefit to the addition ofantibiotics for uncomplicated neuropathic ulcers,but the trial was too small (n = 44) to allow one toexclude a clinically important benefit.74
Baseline comparabilityA large, well-organised RCT with adequaterandomisation should distribute people with poorprognosis for healing/resolution of infectionequally between the treatment groups. It isdesirable, however, to present the characteristics ofthe people in the trial both to allow readers toassess the similarity of the trial participants totheir patient population and to provide these databy treatment groups to see if there were importantimbalances in baseline risk at the outset. In amodest-sized trial, this can happen purely bychance, and visual inspection of the results allowsone to see if there are imbalances. In addition, itcan point one to problems with the randomisationprocedure, for example if the people with moresevere disease tended to be allocated to onegroup, then one might investigate whether therandomisation schedule was subverted byclinicians trying to ensure that people with severedisease received the (in their opinion) ‘better’intervention. Margolis and colleagues undertookan analysis of the risk factor for healing diabeticneuropathic ulcers in 20 weeks and found that therisk factors for non-healing were increasedduration of ulceration, increased area of ulcerationand being Caucasian.168 The above characteristicsshould be reported as baseline characteristics intrials to allow one to determine if the samples
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were comparable at the outset for known factors.Any imbalances in the distribution of risk factorscan then be accounted for in an adjusted analysis.
No trials reported ulcer duration, ulcer area atbaseline and ethnicity by treatment groups. Fivetrials reported ulcer area,74,105,114,119 two trialsreported ulcer duration,75,100 and four trialsreported ethnicity.108,109,114 Other trials reportedbaseline characteristics such as duration ofdiabetes, arterial blood supply (reported as a ratioof ankle and brachial systolic blood pressure toankle brachial pressure to index, or ABPI), orWagner grade. These may inform external validitybut not be as important for determiningprognosis.
OutcomesOwing to the large number of different outcomesreported, it was considered inappropriate tosynthesise results. In addition, the definitions ofthe outcomes used, such as ‘clinical cure ofinfection’, were not specified. There appears to belittle agreement on what is the key outcomemeasure for assessing the effectiveness of anantimicrobial in the management of DFUs. Itcould be resolution of infection, healing of theulcer, prevention of amputation (all amputationsor only major amputations) or maintenance ofHRQoL. The relationship between resolution ofinfection, ulcer healing and the need foramputation is not completely understood so wecannot be confident that an intervention whichleads to quicker resolution of infection wouldnecessarily lead also to quicker healing and hencereduce the need for amputation. In designingclinical studies, there is a need to trade off theneed for an efficient use of trial resources and thedesire to have a lengthy follow-up period in orderto capture sufficient events of interest. However,for an outcome such as major amputation this maybe prohibitively expensive, hence commonerevents such as ‘resolution of infection’, healing orminor amputations may also be reported. A minoramputation may be considered as an outcome initself or as a part of the therapeutic armoury –removal of an ulcerated toe, for example, maylead to dramatic improvement in a patient’squality of life, compared with, for example,sustained non-weight bearing while the ulcer healsconservatively.
It is possible that an intervention could acceleratethe rate at which the infection appears ‘resolved’,but delay healing and increase the risk of majoramputation, for example, by keeping the ulceropen for longer. Having sufficient follow-up to
allow reporting all these outcomes would increaseour knowledge about the relationship betweeninfection, healing and amputation and increaseour confidence in the relevance of the trials thatonly reported resolution of infection or healing.
It is also possible that an intervention could leadto a higher healing rate but lead to reducedHRQoL in patients – for example, having dailyinjections of growth factors, or dressing changesmay be unacceptable for some patients owing totheir effect on their normal activities. No trialsreported the impact of these interventions onHRQoL.
Furthermore, an intervention might delay healingminimally compared with a comparator but reducethe chances of microbial resistance developing,e.g. MRSA, and therefore be desirable from asocietal perspective. It is not clear how these twoperspectives, the individual and the societal,should be weighed against each other.
A number of trials reported both ‘eradication ofpathogens’ and ‘clinical cure’ data. It may beinteresting to investigate the relationship betweenthese two outcomes and eventualhealing/amputation. If it were established thatthere was a known relationship between clinicalcure and amputation or healing outcomes, thentrials could be powered on this outcome and havefollow-up for the length of time needed to captureclinical resolution of infection. Only group-leveldata were available to us and therefore we couldnot do this. If clinical cure and eradication ofpathogens were congruent, then it may be possibleto reduce the number of bacteriology swabsrequested in clinical trials. If they are not inagreement, it would be interesting to see whetherthe false positive and false negative rate is relatedto the diabetes, due to sampling error or otherreasons.
There is some suggestion that people withdiabetes do not exhibit the same response toinfection as those without diabetes owing tochanges in the immune system, hence classicalsigns of clinical resolution of infection may not bea reliable indication for cure or for trial outcomemeasures.165
Applicability of the resultsThe majority of trials (17/23) had more men thanwomen taking part, in two trials there were nodata on the gender of participants, in one trialonly one woman was included101 and in threetrials there were no women participating.75,110–112
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Margolis and colleagues did not find any differencein prognosis for healing of neuropathic ulcers withgender,168 but qualitative studies suggest that menand women adjust to life with a diabetic foot ulcerdifferently,169 and this may affect thegeneralisability of the results from these trials.
The majority of these trials reported that theyincluded people with neuropathic ulceration (n = 12),44,74,105,107,110–112,114,118,122,124,125 orspecified a minimum arterial blood supply (n = 4).100,106,109,119 Four trials43,75,108,123 did notprovide information on the proportion of peoplewith neuropathic, ischaemic or neuroischaemiculceration. Within trials where ulcer aetiologies areprovided, it is also important that the degree ofneuropathy or ischaemia is described so that therelevance of the findings to other patient groupscan be ascertained.
The patient characteristics may also affect theeffectiveness of the intervention. A trial ofantibiotics in people with neuropathic ulcerationmay not be applicable to patients in whom arterialsupply is limited, as the delivery of thisintervention relies upon sufficient arterial supplyto allow the antibiotics to penetrate the tissues at atherapeutic concentration.
The majority of studies were conducted oninpatients and only one study described outpatienttreatment of infected diabetic foot infection.75 Theother trials of antimicrobial agents in outpatientsincluded people without frank ulcer infection.
Trade-offs between the benefits, harmsand costs of the interventionAdministering antimicrobial agents may haveharms in addition to any anticipated benefits.From an individual perspective, the use ofantibiotics can lead to adverse effects rangingfrom relatively common stomach upsets/diarrhoeato rare and potentially fatal reactions.
From a community perspective, the administrationof antibiotics to people with DFUs needs to beweighed against the increasing use of antibioticsand the association to the spread of resistance toantibiotics, for example MRSA. The generalprinciple for reducing the spread of resistance isthat broad-spectrum antibiotics should be avoidedand therapy should be based on culture results.While clinical guidelines reinforce the approach ofprescribing antibiotics according to bacteriologyresults, they also mention the need for empiricaltherapy in limb-threatening infection. Waiting forlaboratory results is not always possible owing to
the potential consequences of delay for theinfection, such as amputation. Reserving antibiotictreatment for people with suspected severe ulcerinfection might help limit the growth of resistantorganisms. Developments in rapid diagnosis ofinfecting organisms, such as PCR or near-patienttesting techniques, may permit rapid diagnosis ofbacterial colonisation/infection, but we knownothing about their usefulness in wounds. Ifuseful, this may help reduce the use of broad-spectrum antibiotics, but if the most infections aretruly polymicrobial then they may still require abroad-spectrum antibiotic and therefore rapidassessment may change the therapeutic regimenin a proportion of patients.
In addition, the majority of the trials of antibioticsused a combination of two agents. It is not clearwhether using multiple agents is of added benefitover single agents in the patient group. Multipleagents might lead to net benefit if, for example,two narrower spectrum agents could be used tocover the most common pathogens (Staphylococcusaureus, Streptococcus spp., Pseudomonas aeruginosaand the anaerobes), but using more than one drugalso puts the patient at risk of more than one setof adverse events/reactions.
In some cases the intervention regimen was verycomplex, involving combinations of intravenous,oral and intramuscular therapies, e.g. in thestudies of Seidel and colleagues.110–112 In somecases there were a number of additional antibioticswhich could be added to the regimen underevaluation, as required, and the lack of objectivecriteria for the use of adjuvant therapies meansthat one cannot be confident that any differencein outcomes is due to the antibiotic under test.109
Costs of these treatments vary. The costs ofantimicrobial agents range from $1.44 to $104 perday,170 but the cost of the antimicrobial agents isusually minimal compared with the costs ofdelivering care such as hospitalisation and nurse’svisits or the costs of interventions such asamputation.
A number of expensive interventions such asgrowth factors and sterile medical larval therapyare relatively new and therefore there may be areduction in costs if more providers come on-stream, e.g. larval therapy costs around £55 perdose (only a few doses are usually needed).171
Growth factors such as G-CSF (filgrastim) cost£540 for 7 days.121 It is not clear if improvementsin the technology to produce these would lead to areduction in costs or whether licensing restrictions
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mean that these costs would be maintained. Twostudies had economic analyses alongside aneffectiveness trial and two additional studiesreported costs.121,124 Further cost-effectivenessstudies need to be run in parallel to effectivenesstrials in order to inform decision-makers of thecosts and benefits of the intervention on offer. Anexpensive intervention may be cost-effective if itreduces the time to healing, the rate ofamputation or the number of days inhospital/clinician visits.
One important advance in reducing the costs oftreatment of established infections could be inmoving the setting of care from hospital toprimary care. Until recently, all the antibioticsrecommended for use in the treatment of limb-threatening infections were administeredintravenously and therefore the patient washospitalised. The development of oral antibioticssuitable for this population might lead to morepeople being treated at home, thus reducing coststo the health service. Hospitalisation not onlyallows antibiotics to be administered intravenously,but also permits close monitoring of diabeticcontrol and ensuring that the patient remainsnon-weight bearing. Outpatient treatmenttherefore may not always be as effective or cost-effective if, for example, it is associated with slowerhealing or requires a different configuration ofservices to ensure close monitoring of progress. Inaddition, people with limb-threatening infectionmay be so unwell that hospitalisation is required.
Strengths and weaknesses of thereviewStrengths of the reviewThe review strengths include the extensiveelectronic search strategies developed to retrievecontrolled trials regardless of publication status,date or language of publication, and theexamination of bibliographies of systematic andnon-systematic reviews and all included studies toidentify additional citations. The wide-rangingsteering group, in terms of professionalbackground and geography, also may haveincreased our chances of identifying unpublished,ongoing or unindexed studies in the area.
Decisions to include or exclude studies were madeby two researchers independently and thenresolved by discussion. We have also set out thereasons for the exclusion of 20 diagnostic studies,140 effectiveness studies and 24 economic studiesin Appendix 6. Data extraction and quality
assessment were done by one person and checkedby a second. These steps sought to reduce error orbias in the review process.
We enlisted a large group of collaborators to peerreview the review protocol, with input from expertsin many disciplines and two people withexperience of diabetic foot ulceration. Thesteering group for the project also represents arange of disciplines and supported the reviewersthroughout.
Weaknesses of the review Weaknesses of the review process included beingunable to undertake handsearching of conferenceproceedings beyond those listed in Table 2(six conferences). Research into the treatment ofDFU infection is presented at conferencesorganised by vascular surgical societies, woundcare societies, diabetologists, podiatrists, clinicalmicrobiologists and experts in infection control.We were able to access only a small proportion ofconference proceedings from these cognate areasthrough our collaborators and may have missedabstracts from other conferences. However, theelectronic databases HELMIS and SIGLE alsoindex some conference proceedings and thereforeour searches will probably have reached otherrelevant conferences.
There may have been research conducted into theeffect of antimicrobial agents with funding fromcommercial concerns and these may not be in thepublic domain. Given the tendency for selectivereporting of research with ‘positive’ findings(publication bias), then it is possible that there areadditional studies published in abstract format orin journals which are unindexed by the databasesthat we used, or indeed not published at all. Whatwe know about publication bias leads us to suggestthat if we have missed other studies, then thesewould tend to be small studies with ‘negative’ orequivocal results.172
Our search for studies to answer the questionabout the effect of microbiological analysis wasconfined to RCTs or CCTs, and it is possible that controlled before and after studies could have been reported in this area. Locatingcontrolled before and after studies is notstraightforward, as the search filters to identifythem from electronic databases are less welldeveloped than for, for example, RCTs. Ourbibliography checking and contact with a largeexpert panel who were not aware of any suchstudies suggest that few, if any, controlled beforeand after studies exist.
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Integration of this review withprevious workWe identified two previous systematic reviews ofintervention for diabetic foot ulceration98,99 andone of the authors led a previous systematic reviewin this area. The reviews by Mason andcolleagues99 and Kaltenthaler and colleagues98
included evaluation of systemic and topicalantimicrobial agents within their scope. Ourprevious review (by O’Meara and colleagues48)evaluated the impact of antimicrobial agents in thehealing of DFUs. In the current review we decidedto include studies if they reported any of thefollowing objective outcomes of interest:
� mortality� ulcer recurrence� incidence/type of amputation� number/duration hospital admissions for DFU
problems� incidence of osteomyelitis� bacterial profile of ulcer� pain� acquisition of resistant organisms� proportion of ulcers healing� relationship between ulcer healing and
bacteriology� time to complete healing� change in mobility� change in ulcer area� change in level of dependence/independence� healing rate� impact on HRQoL� change in ulcer depth or volume.
This is in contrast to the earlier review in whichonly studies which reported wound area/volume,time to healing, healing rate or proportion ofhealed outcomes were included, as we hoped thatwe would identify high-quality data on the effectof these interventions on outcomes that guideclinicians, such as resolution of infection, and toinvestigate the relationship between bacteriologyand healing. We found no such research.
Decision analytic modelWe were unable to identify data on the transitionprobabilities for our two populations of interest.These were people in whom a first course ofantibiotics had failed, and people with apparentlyuninfected ulcers being offered antimicrobialtherapy (presumably as the clinician suspects thatlack of progress towards ulcer healing is due to ahigh bacterial load). None of the existing models
provided transition probabilities for these twogroups as they were designed to evaluate theimpact of therapeutic interventions in either newlyinfected or uninfected populations. No trialsstated that they recruited people for whom a firstcourse of antibiotics had failed. A few trialsinvolved people with apparently clinicallyuninfected ulcers, but these trials did not reportclear criteria for the definition of recalcitrantulceration.
We identified in interviews with six experts thatpeople with clinically infected ulcers are almostinvariably treated with antibiotics without waitingfor the results of microbiological analysis andtherefore the results of a diagnostic test do notinform their therapy, unless they fail to respond.Similarly, patients whose ulcers appear uninfectedand are healing are not considered to requireantimicrobial therapy and are not subjected tomicrobiological analysis. The performance ofdiagnostic tests (following clinical assessment) isunlikely to inform the management of thesepatients unless they fail to heal. Trials ofantibiotics for clinically infected ulcers confirmedthat treatment was decided empirically rather thanafter receiving the results of a microbiological test.Our experts confirmed that this was due to thedanger of waiting for microbiological results andthe high risk of progressive infection which couldresult in amputation. Diagnostic tests appear to beused to guide therapy when a clinical assessmenthas indicated that the ulcer, although apparentlyuninfected, is failing to heal (determined by arange of criteria).
A number of substitute strategies were proposed inan attempt to inform the decision analytic model.The review of the literature indicated thatinformation regarding the populations of interestmight have been collected as part of some studies,and there may have been subgroups within thesestudies which could have provided data on the‘hard to heal’ ulcers. Although direct contact withthe principal investigators of studies reporting on‘hard to heal’ DFUs was considered as an option,we decided not to pursue this avenue as there wassufficient variation in the characterisation of a‘hard to heal’ DFU (from our clinician interviews)to suggest that not much would be gained if accessto the primary data was granted.
It is possible that non-comparative studies, such ascase series, may have described these populationsin sufficient detail to ascertain if individualsbelonged to either of the two target groups and toprovide some transition probabilities, but we were
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unable to search for case series within the staff andtime constraints of this project.
It can be argued that the existing evidenceprovided in the literature indirectly providesinformation about the two groups of patients thatwere identified as the target populations. Forexample, the probability of having an ulcer clear ofinfection after a second course of antibiotics mightbe a function of the probability of having an ulcerclear of infection after a first course of antibiotics
and the effectiveness associated with specificantibiotics in patients with an infected foot ulcer.This can be described as a network of evidence, i.e.information about the parameters of interest couldbe constructed as functions of estimates reported inthe literature. Statistical methods for synthesisingevidence could be used to estimate indirectly therequired parameters for the decision analyticmodel.173 However, the human resources and thetime required to conduct this type of analysis wereoutside the scope of this project.
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Implications for clinical practiceThe available evidence is too weak to draw reliableimplications for practice. This means that, interms of diagnosis, we do not know how to identifyinfection reliably by clinical assessment, whichpatients need formal diagnostic testing forinfection, whether empirical treatment withantibiotics (before the results of diagnostic testsare available) leads to better outcomes and whatthe optimal methods of diagnostic testing are.With respect to treatment, we do not knowwhether treatment with systematic or localantibiotics leads to better outcomes, or whetherany particular agent is more effective. Limitedevidence suggests that both G-CSF and cadexomeriodine dressings are less expensive than ‘standardcare’, that A/S is a less costly treatment than I/C,and that an unlicensed cream (pexiganan) may beas effective as oral ofloxacin.
Implications for researchQuestions to be answered1. What characteristics of infection in people with
DFU influence healing and amputationoutcomes?
2. Does diagnosis of infection-producing bacteriaprior to treatment offer any benefit overempirical therapy?
3. If detecting infection-producing bacteria offersclinical benefit, then what are the most effectiveand cost-effective methods for detectinginfection, for example clinical assessment, woundswabbing or wound biopsy and microbiologicalanalysis, or novel techniques such as electronicnose/tongue, and PCR analysis?
4. What are the relative effectiveness and cost-effectiveness of antimicrobial interventions forDFU infection, for example combinations ofbroad-spectrum antibiotics, larval therapy,growth factors and topical agents/dressings?
Nature of the research� Research needs to have adequate sample sizes
and robust methods to minimise bias.� Future research should attempt to use ‘real-life’
methods as far as possible in order to improvethe clinical applicability of findings.
� Outcomes should include pain, quality of lifeand acceptability associated with diagnosticprocedures and interventions.
� Economic evaluations of diagnosis andantimicrobial agents should be undertaken,where possible, alongside primary studies. Theseshould be undertaken using appropriate methodsas determined by experts in health economics.
� Future research should include sufficient detailsof the quality of sample acquisition, laboratoryprocedures, concurrent therapies and outcomeassessment.
� Attention should be paid to the potential forthe development of resistant organismsassociated with the use of long-term, broad-spectrum antibiotics and the balance of societaland individual benefit.
� Future trials should report the baselinecharacteristics of both patients and theirwounds by study group and analysis shouldattempt to adjust for any imbalances inprognostic factors present at baseline.
Future trials need to be reported using CONSORTguidelines, and evaluations of diagnostic accuracyusing STARD guidelines.
Information regarding the following is required topopulate the decision analytic model:
� Incidence of DFU patients who have failed toheal after a first course of antibiotics and thosewho do not show any clinical symptoms ofinfection but whose ulcer is not healing (targetpopulation).
� Natural history of the target population.� Diabetic foot ulcer recurrences in target
population.� Healthcare resource use of target population in
the UK.� Quality of life scores for the target population.� Diagnostic performance of clinical assessments
and investigations in the target population.� Effects of different strategies or interventions
for the management of DFU infection in thetarget population.
A register including both patient- and ulcer-levelcharacteristics and foot ulcer and systemictreatments and outcomes may provide information
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Chapter 6
Conclusions
to populate the decision analytic model and serveto suggest fruitful areas of study in diagnosis,prognosis and therapeutics, in addition toproviding feedback on quality of care, but it is
unclear whether it would be simple to collect dataon these elements in a diabetic foot register or toextend data collection in existing general diabetesregisters.
Conclusions
72
We would like to thank Dr Stephen Brealey(University of York) for help with the ROC
analysis and the expert advisory panel (seeAppendix 2) for advice and feedback throughout.
Contribution of the authorsE Andrea Nelson (Reader, health research)conceived the study, contributed to the protocoldevelopment, search strategy development andstudy selection. She carried out data extractionand methodological appraisal for some diagnosticstudies, all clinical effectiveness studies andeconomic evaluations and data analysis for theeffectiveness studies. She wrote the results sectionfor effectiveness studies and economic evaluationsand commented on all other sections. She was theoverall supervisor and is the guarantor for theproject. Susan O’Meara (Research Fellow,systematic reviews) contributed to the protocoldevelopment, search strategy development, studyselection for all sections of the project andupdating/maintenance of the bibliographicdatabase. She carried out data extraction andmethodological appraisal for all diagnostic studiesand some of the clinical effectiveness studies andeconomic evaluations and data analysis for thediagnostic studies. She wrote the followingsections: introduction, methods, results fordiagnostic studies and discussion. She read andoffered comments on the other sections. DawnCraig (Research Fellow, health economics) andCynthia Iglesias (Research Fellow, healtheconomics) performed the systematic review ofeconomic models and quality of life studies. Theywere also responsible for the construction of thedecision analytic model and the preparation of themanuscript describing the economic component of
the DASIDU project. C Iglesias (Research Fellow)reviewed the economic and utility evidence andworked on the draft of the economic section of thereport. Su Golder (Information Officer, literaturesearching) devised search strategies, carried outliterature searches and wrote part of themethodology and Appendix 1. Jane Dalton(Reviewer, systematic reviews) undertookhandsearching, assessed papers for inclusion andcontacted authors. She carried out data extractionand quality assessment of papers, data analysis anddrafting report section for effectiveness results. Shealso commented on the final version of the report.Karl Claxton (Senior Lecturer, health economics)provided expert advice on the construction of thedecision analytic model and commented onprevious versions of the economic section of thisreport. Sally Bell-Syer (Research Fellow, systematicreviews) contributed to the protocol developmentand search strategy development. She read andoffered comments on all sections of the report.Edward Jude (Consultant Physician, diabetes care)contributed to the analysis of clinical data andcommented on the draft report. ChristopherDowson (Professor, microbiology) contributed tothe protocol development, analysis andinterpretation of microbiological sections of thereport, and read and commented on the draftreport. Roger Gadsby (Senior Clinical Lecturer,primary care) contributed to the protocoldevelopment, interpretation of outcome data, andcommented on the draft report. Paul O’Hare(Honorary Senior Lecturer, medicine) contributedto the protocol and commented on the draft report.Janet Powell (Visiting Professor, vascular surgery)contributed to the development of the protocol,and the interpretation of the clinical data, and alsocommented on the final draft report.
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282. Nichols RL, Smith JW, Gentry LO, Gezon J,Campbell T, Sokol P, et al. Multicenter,randomized study comparing levofloxacin andciprofloxacin for uncomplicated skin and skinstructure infections. South Med J 1997;90:1193–200.
283. Ohsawa S, Inamori Y, Fukuda K, Hirotuji M.Lower limb amputation for diabetic foot. ArchOrthop Trauma Surg 2001;121:186–90.
284. Parish LC, Jungkind DL. Systemic antimicrobialtherapy for skin and skin structure infections:comparison of fleroxacin and ceftazidime. Am JMed 1993;94(Suppl 3A):166S–73S.
285. Parish LC, Aten EM. Treatment of skin and skinstructure infections: a comparative study ofAugmentin and cefaclor. Cutis 1984;34:567–70.
286. Parish LC, Cocchetto DM, Werner K, Jungkind DL,Witkowski J. Cefuroxime axetil in the treatment ofcutaneous infections. Int J Dermatol 1987;26:389–93.
287. Partsch H, Jochmann W, Mostbeck A, Hirschl M.Nuclear medical investigations on tissueconcentration and hemodynamic effects ofretrograde intravenous pressure infusions. WienMed Wochenschr 1993;143:172–6.
288. Pepe C, Rozza A, Veronesi G. The evaluation byvideo capillaroscopy of the efficacy of a Ginkgobiloba extract with L-arginine and magnesium inthe treatment of trophic lesions in patients withstage-IV chronic obliterating arteriopathy. MinervaCardioangiol 1999;47:223–30.
289. Perez-Ruvalcaba JA, Quintero-Perez NP, Morales-Reyes JJ, Huitron-Ramirez JA, Rodriguez-Chagollan JJ, Rodriguez-Noriega E.Double-blind comparison of ciprofloxacin withcefoxatime in the treatment of skin and skinstructure infections. Am J Med 1987;82(Suppl 4A):242–6.
290. Peters EJ, Lavery LA, Armstrong DG, Fleischli JG.Electric stimulation as an adjunct to heal diabeticfoot ulcers: a randomized clinical trial. Arch PhysMed Rehabil 2001;82:721–5.
291. Pien F. Double-blind comparative study of twodosage regimens of cefaclor and
amoxicillin–clavulanic acid in the outpatienttreatment of soft tissue infections. Antimicrob AgentsChemoth 1983;24:856–9.
292. Pinzur MS. Amputation level selection in thediabetic foot. Clin Orthop Relat Res 1993;296:68–70.
293. Pinzur MS, Slovenkai MP, Trepman E. Guidelinesfor diabetic foot care. The Diabetes Committee ofthe American Orthopaedic Foot and Ankle Society.Foot Ankle Int 1999;20:695–702.
294. Pitkin D, Sheikh W, Wilson S. Comparison of theactivity of meropenem with that of other agents inthe treatment of intraabdominal, obstetric/gynecologic, and skin and soft tissue infections.Clinical Infect Dis 1995;20(Suppl 2):S372–5.
295. Powers RD. Open trial of oral fleroxacin versusamoxicillin/clavulanate in the treatment ofinfections of skin and soft tissue. Am J Med1993;94(Suppl 3A):155–8.
296. Real JT, Valls M, Ascaso P, Basanta ML, Viguer AA,Ascaso JF, et al. Risk factors associated tohospitalization in diabetic patients with foot ulcers.Medicina Clinica 2001;117:64–4.
297. Rice B, Kalker AJ, Schindler JV, Dixon RM. Effectof biofeedback-assisted relaxation training on footulcer healing. J Am Podiatr Med Assoc 2001;91:132–41.
298. Rittenhouse T. The management of lower-extremity ulcers with zinc–saline wet dressingsversus normal saline wet dressings. Adv Ther1996;13:88–94.
299. Saltzman CL, Pedowitz WJ. Diabetic footinfections. Instr Course Lect 1999;48:317–20.
300. Sauerwein RW, Netten PM, Koopmans PP.Antibiotic therapy in diabetic foot ulcers. NedTijdschr Geneeskd 1994;138:557–60.
301. Schwegler B, Boni T, Furrer J, Spinas GA,Lehmann R. Management of the diabetic foot.Ther Umsch 2002;59:435–42.
302. Seewald M. Microbiological aspects in thediagnosis and treatment of the diabetic foot.Diabetes Stoffwechsel 1999;8(Suppl 5):16–20.
303. Segev S, Rosen N, Pitlik SD, Block C, RubinsteinE. Pefloxacin versus ceftazidime in therapy of softtissue infections in compromised patients.J Antimicrob Chemother 1990;26(Suppl B):193–8.
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306. Sesin GP, Paszko A, O’Keefe E. Oral clindamycinand ciprofloxacin therapy for diabetic footinfections. Pharmacotherapy 1990;10:154–6.
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References
86
Clinical effectiveness searchstrategiesInternal CRD administration databasesThe Database of Abstracts of Reviews ofEffectiveness (DARE) and the Health TechnologyAssessment (HTA) Database (searched: 12 November 2002)The Database of Abstracts of Reviews ofEffectiveness (DARE) and Health TechnologyAssessment (HTA) Database were searched via theNHS CRD’s internal administration databases.This provides more detailed and more up-to-dateversions of the databases than those on theCochrane Library or the Internet and includesadditional records to those in the public databases.The same search strategy was used for bothdatabases;
1. S (neuroisch?emic or isch?emic or diabetic orneuropathic)(3w)(foot or feet or ulcer$)
2. S (pedal or plantar or foot or feet orheel)(3w)(ulcer$ or septic or wound$)
3. S (foot or feet)(6w)diabet$4. S deep foot infection$5. S (crural or leg)(5w)ulcer$6. S (venous or stasis or varicos*)(5w)(leg or
ulcer$)7. S (lower extremit$ or lower limb$)(5w)(ulcer$
or wound$)8. S s1 or s2 or s3 or s4 or s5 or s6 or s7
This identified 154 DARE records and 20 HTArecords.
Internet databases(Allied And Complementary Medicine) AMED(1985–2002 November) (searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. exp Acetic Acid/2. (acetic acid$ or acetate$ or acetamide$ or
acetoxyacetylaminofluorene$ orhydroxyacetylaminofluorene$ orallylisopropylacetamide$).ti,ab.
3. (idoacetamide$ or idoacetate$ or piracetam$or thioacetamide$ or gadolinium$ ortechnetium$ or dichoroacetate$ orfluoroacetate$ or iodoacetate$).ti,ab.
4. (foscarnet$ or thioglycolate$ or aceticanhydride$).ti,ab.
5. ((aminooxyacetic or edetic or egtazic oriodoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic or trichloroaceticor trifluoroacetic) adj acid$).ti,ab.
6. (therapeutic fungicide$ or antifungal agent$or antifungals).ti,ab.
7. (benzoate$ or butenafine$ or chlorquinaldol$or cyclosporine$ or dichlorophen$ orfluconazole$ or flucytosine$ or glycyrrhizicacid$ or hexetidine$ or itraconazole$ ormonensin$ or nifuratel$ orpentamidine$).ti,ab.
8. (co-amoxiclav$ or sodium benzoate$ orthimerosal$ or thiram$ or thymol$ ortolnaftate$ or tomatine$ or triacetin$ ortrimetrexate$).ti,ab.
9. (amoroldine$ or benzoic acid$ orclotrimazole$ or econazole$ or ketoconazole$or miconazole$ or nystatin$ or Salicylic acid$or sulconazole$ or terbinafine$ ortioconazole$ or undecenoate$).ti,ab.
10. (antiviral$ or anti viral$ or idoxuridine$).ti,ab.11. (acetylcysteine$ or acyclovir$ or amantadine$
or aphidicolin$ or aprotinin$ or brefeldin orbromodeoxyuridine$ or cytarabine$ ordeoxyglucose$ or dextran sulfate$).ti,ab.
12. (dideoxyadenosine$ or dideoxynucleoside$ ordihematoporphyrin ether$ or ditiocarb$ orfilipin$ or floxuridine$ or ganciclovir$ orinosine pranobex or interferon alfa$ orinterferon type$ or interferon beta orinterferon gamma or interferons).ti,ab.
13. (methisazone$ or phosphonoacetic acid$ orpoly a-u or poly i-c or pyran copolymer$ orribavirin$ or rimantadine$ or streptovaricin$or tenuazonic acid$ or tilorone$ ortrifluridine$ or tunicamycin$ orvidarabine$).ti,ab.
14. (bacitracin$ or povidone iodine$ orbetaisodona$ or polyvinylpyrrolidone iodine$or betadine$ or disadine$ or isodine$ or pvp-ior pharmadine$).ti,ab.
15. (cetyltrimethylammonium or cetrimide$ orcetrimonium).ti,ab.
16. (chlorate$ or cisplatin or hydrochloric acid$ orchloride$ or hypochlorous acid$ orhypochlorite$ or perchloric acid$ orruthenium red$).ti,ab.
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Appendix 1
Search strategies
17. exp "Eosine Yellowish-(YS)"/18. (eusol or phenoxyethanol$ or dextranomer$
or framycetin sulphate$ or mandelic acid$ ortetrabromofluorescein$ or eosin or eosine orchlortetracycline$ or chloroxylenolsolution$).ti,ab.
19. (edinburgh adj university adj solution adj2lime).ti,ab.
20. (cyclandelate$ or vanilmandelic acid$).ti,ab.21. hexachloroph#ne$.ti,ab.22. (triclosan$ or polymyxin$ or
polynoxylin$).ti,ab.23. (silver adj2 dressing$).ti,ab.24. (gentian violet or crystal violet or methyl violet
or methylrosaniline chloride$ orhexamethylpararosanine chloride$).ti,ab.
25. (potassium permanganate$ or permanganicacid$ or potassium salt$).ti,ab.
26. (mupirocin$ or pseudomonic acid$ orbactroban$).ti,ab.
27. (neomycin$ or fradiomycin$ or neamin$).ti,ab.28. (benzyol peroxide$ or benzyol superoxide$ or
diphenylglyoxal superoxide$ orpanoxyl$).ti,ab.
29. exp Hydrogen Peroxide/30. (hydrogen peroxide$ or hydroperoxide$ or
oxydol$ or perhydrol$ or superoxol$ ordiphenylglyoxal superoxide$ orpanoxyl$).ti,ab.
31. (fucithalmic$ or fusidate$ or fusidin$ orstanicide$).ti,ab.
32. (liposome$ adj hydrogel$).ti,ab.33. (fusidic acid$ or inadine$ or betadine$).ti,ab.34. (cadexomer iodine$ or chlorhexidine$ or
novalsan$ or sebidin$ or tubulicid$).ti,ab.35. exp Larva/36. (maggot$ or larva or larvae or larval).ti,ab.37. exp Complementary Therapies/38. (plant extract$ or aromatherap$ or marigold
extract$ or calendula officinalis or tagetespatula or rubia cordifolia or manjishtha orwithania somnifera or ashvagandha).ti,ab.
39. exp Plant Extracts/40. exp Plants, Medicinal/41. (phytotherapy or cascara$ or curare$ or
chinese herb$ or guaiac$ or ipecac$ orpodophyll$ or psyllium$ or senna extract$ ortragacanth$ or turpentine$).ti,ab.
42. exp oils, volatile/ or exp plant oils/43. exp Sucrose/44. exp HONEY/45. (essential oil$ or plant oil$ or tea tree or
lavender or chamomile or camomile orrosemary).ti,ab.
46. (sucrose or sugar paste$ or granulatedsugar).ti,ab.
47. exp Propolis/
48. (propolis or honey or beebread$ or bee bread$or bee glue$).ti,ab.
49. exp Antiviral Agents/50. (disinfect$ or antisept$ or anti-sept$ or
antiviral$ or anti-viral$).ti,ab.51. ((neuroisch?emic or isch?emic or diabetic or
neuropathic) adj3 (foot or feet or ulcer$)).ti,ab.52. ((pedal or plantar or foot or feet or heel) adj3
(ulcer$ or septic or wound$)).ti,ab.53. ((foot or feet) adj6 diabet$).ti,ab.54. deep foot infection$.ti,ab.55. exp Foot Ulcer/56. or/51-5557. Leg Ulcer/58. Varicose Ulcer/59. ((crural or leg) adj5 ulcer$).ti,ab.60. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).ti,ab.61. ((venous or stasis or leg) adj5 wound$).ti.62. ((lower extremit$ or lower limb$) adj5 (ulcer$
or wound$)).ti,ab.63. or/57-6264. 56 or 6365. (penicillin$ or amdinocillin$ or amox#cillin$
or ampicillin$ or azlocillin$).ti,ab.66. (carbenicillin$ or carfecillin$ or cloxacillin$ or
dicloxacillin$ or floxacillin$ or flucloxacillin$or methicillin$ or mazlocillin$ or nafcillin$ oroxacillin$ or penicillanic acid$).ti,ab.
67. (penicillic acid$ or phenoxymethylpenicillin$or piperacillin$ or pivampicillin$ orsulbencillin$ or talampicillin$ or sultamicillin$or ticarcillin$ or ticercillin$).ti,ab.
68. (cefaclor$ or cefadroxil$ or cefalexin$ orcefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).ti,ab.
69. (cefradine$ or ceftazidime$ or ceftizoxime$ orceftriaxone$ or cefuroxime$).ti,ab.
70. (cefonicid$ or cefmenoxine$ or cefoperazone$or cefotiam$ or cefsulodin$ or cephacetrile$or cephalexin$ or cephaloglycin$ orcephaloridine or cephalosporanic acid$ orcephalothin$ or cephapirin$ orcephradine$).ti,ab.
71. (beta lactam$ or aztreonam$ or cilastin$ orimipenem$ or meropenem$ or sulbactam$ ortazobactam$).ti,ab.
72. (caprolactam$ or clavulan$ ormoxalactam$).ti,ab.
73. (Aminoglycoside$ or anthracycline$ oraclarubicin$ or daunorubicin$ or carubicin$ ordoxorubicin$ or epirubicin$ or idarubicin$ ornogalamycin$ or menogaril$ orplicamycin$).ti,ab.
74. (gentamicin$ or neomycin$ or netilmicin$ ortobramycin$).ti,ab.
Appendix 1
88
75. (amphotericin$ or antimycin$ or candicidin$or roxithromycin$ or josamycin$ orleucomycin$ or kitasamycin$ or lucensomycin$or maytansine$ or mepartricin$ ormiocamycin$).ti,ab.
76. (natamycin$ or oleandomycin$ ortroleandomycin$ or oligomycin$ orrutamycin$ or sirolimus$ or tacrolimus$ ortylosin$ or propiolactone$ or spironolactone$or venturicidin$ or zearalenone$ orzeranol$).ti,ab.
77. (azithromycin$ or clarithromycin$ orerythromycin$ or spiramycin$).ti,ab.
78. (moxifloxacin$ or quinolone$ orciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).ti,ab.
79. (fleroxacin$ or enoxacin$ or norfloxacin$ orpefloxacin$ or nalidixic acid$ or nedocromil$or oxolinic acid$ or quinpirole$ or quipazine$or saquinavir$).ti,ab.
80. (dmso or sulfoxide$ or sulphoxide$ orsulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ orsulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).ti,ab.
81. (benzolamide$ or bumetanide$ orchloramine$ or chlorthalidone$ or clopamide$ or dichlorphenamide$ orethoxzolamide$ or indapamide$ or mafenide$or mefruside$ or metolazone$ or prodenecid$or sulfanilamide$ or sulphanilamide$ orfurosemide$ or sulfacetamide$ orsulphacetamide$).ti,ab.
82. (sulfachlorpyridazine$ or sulfadimethoxine$or sulfadoxine$ or sulfaguanidine$ orsulfamerazine$ or sulfameter$ orsulfamethazine$ or sulfamethoxypyridazine$or sulphachlorpyridazine$ orsulphadimethoxine$ or sulphadoxine$ orsulphaguanidine$ or sulphamerazine$ orsulphameter$ or sulphamethazine$ orsulphamethoxypyridazine$).ti,ab.
83. (sulfamonomethoxine$ or sulfamoxole$ orsulfaphenazole$ or sulfapyridine$ orsulfaquinoxaline$ or sulfathiazole$ orsulfamethizole$ or sulfisomidine$ orsulfisoxazole$ or sulfasalazine$ orsumatriptan$ or xipamide$ or thioamide$ orthioacetamide$ or sulphamonomethoxine$ orsulphamoxole$ or sulphaphenazole$ orsulphapyridine$ or sulphaquinoxaline$ orsulphathiazole$ or sulphamethizole$ orsulphisomidine$ or sulphisoxazole$ orsulphasalazine$).ti,ab.
84. (tetracycline$ or demeclocycline$ ordoxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).ti,ab.
85. (chlortetracycline$ or methacycline$ orrolitetracycline$).ti,ab.
86. (cloranfenicol$ or chloramphenicol$).ti,ab.87. (thiamphenicol$ or kloramfenikol$ or
levomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ or detreomycin$ or ophthochlor$ orsyntomycin$).ti,ab.
88. (clindamycin$ or dalacin c or cleocin$ orchlo?lincocin$).ti,ab.
89. (linezolid$ or trivazol$ or vagilen$ or clont$ ordanizol$ or fagyl$ or ginefavir$ or metrogel$or metrodzhil$ or satric$ or trichazol$ ortrichopol$).ti,ab.
90. (granulocyte colony stimulating factor or gcsfor ozone).ti,ab.
91. (fusidate$ adj (sodium or silver)).ti,ab.92. (antibiotic$ or antimicrobial$).ti,ab.93. (griseofulvin or synercid or dalfopristin or
quinupristin).ti,ab.94. exp Complementary medicine/95. exp antiinfective agents/96. or/1-5097. or/65-9598. 64 and (96 or 97)
This identified 49 records.
British Nursing Index (BNI) (1994–2002 August)(searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. (clinical trial$ or random$ or placebo$ orcontrol or controls or controlled).mp.
2. (single blind$ or double blind$ or trebl$blind$ or tripl$ blind$).mp.
3. (meta-analys$ or meta analys$ or comparisongroup or standard treatment$ or systematicreview$).mp.
4. (acetic acid$ or acetate$ or acetamide$ oracetoxyacetylaminofluorene$ orhydroxyacetylaminofluorene$ orallylisopropylacetamide$).mp.
5. (idoacetamide$ or idoacetate$ or piracetam$or thioacetamide$ or gadolinium$ ortechnetium$ or dichoroacetate$ orfluoroacetate$ or iodoacetate$).mp.
6. (foscarnet$ or thioglycolate$ or aceticanhydride$).mp.
7. ((aminooxyacetic or edetic or egtazic oriodoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic or trichloroaceticor trifluoroacetic) adj acid$).mp.
8. (therapeutic fungicide$ or antifungal agent$or antifungals).mp.
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9. (benzoate$ or butenafine$ or chlorquinaldol$or cyclosporine$ or dichlorophen$ orfluconazole$ or flucytosine$ or glycyrrhizicacid$ or hexetidine$ or itraconazole$ ormonensin$ or nifuratel$ or pentamidine$).mp.
10. (co-amoxiclav$ or sodium benzoate$ orthimerosal$ or thiram$ or thymol$ ortolnaftate$ or tomatine$ or triacetin$ ortrimetrexate$).mp.
11. (amoroldine$ or benzoic acid$ orclotrimazole$ or econazole$ or ketoconazole$or miconazole$ or nystatin$ or Salicylic acid$or sulconazole$ or terbinafine$ ortioconazole$ or undecenoate$).mp.
12. (antiviral$ or anti viral$ or idoxuridine$).mp.13. (acetylcysteine$ or acyclovir$ or
amantadine$ or aphidicolin$ or aprotinin$ orbrefeldin or bromodeoxyuridine$ orcytarabine$ or deoxyglucose$ or dextransulfate$).mp.
14. (dideoxyadenosine$ or dideoxynucleoside$ ordihematoporphyrin ether$ or ditiocarb$ orfilipin$ or floxuridine$ or ganciclovir$ orinosine pranobex or interferon alfa$ orinterferon type$ or interferon beta orinterferon gamma or interferons).mp.
15. (methisazone$ or phosphonoacetic acid$ orpoly a-u or poly i-c or pyran copolymer$ orribavirin$ or rimantadine$ or streptovaricin$or tenuazonic acid$ or tilorone$ ortrifluridine$ or tunicamycin$ orvidarabine$).mp.
16. (bacitracin$ or povidone iodine$ orbetaisodona$ or polyvinylpyrrolidone iodine$or betadine$ or disadine$ or isodine$ or pvp-ior pharmadine$).mp.
17. (cetyltrimethylammonium or cetrimide$ orcetrimonium).mp.
18. (chlorate$ or cisplatin or hydrochloric acid$ orchloride$ or hypochlorous acid$ orhypochlorite$ or perchloric acid$ orruthenium red$).mp.
19. (eusol or phenoxyethanol$ or dextranomer$or framycetin sulphate$ or mandelic acid$ ortetrabromofluorescein$ or eosin or eosine orchlortetracycline$ or chloroxylenolsolution$).mp.
20. (edinburgh adj university adj solution adj2lime).mp.
21. (cyclandelate$ or vanilmandelic acid$).mp.22. hexachloroph#ne$.mp.23. (triclosan$ or polymyxin$ or
polynoxylin$).mp.24. (silver adj2 dressing$).mp.25. (gentian violet or crystal violet or methyl violet
or methylrosaniline chloride$ orhexamethylpararosanine chloride$).mp.
26. (potassium permanganate$ or permanganicacid$ or potassium salt$).mp.
27. (mupirocin$ or pseudomonic acid$ orbactroban$).mp.
28. (neomycin$ or fradiomycin$ or neamin$).mp.29. (benzyol peroxide$ or benzyol superoxide$ or
diphenylglyoxal superoxide$ or panoxyl$).mp.30. (hydrogen peroxide$ or hydroperoxide$ or
oxydol$ or perhydrol$ or superoxol$ ordiphenylglyoxal superoxide$ or panoxyl$).mp.
31. (fucithalmic$ or fusidate$ or fusidin$ orstanicide$).mp.
32. (liposome$ adj hydrogel$).mp.33. (fusidic acid$ or inadine$ or betadine$).mp.34. (cadexomer iodine$ or chlorhexidine$ or
novalsan$ or sebidin$ or tubulicid$).mp.35. exp Larva/36. (maggot$ or larva or larvae or larval).mp.37. exp alternative medicine/38. (plant extract$ or aromatherap$ or marigold
extract$ or calendula officinalis or tagetespatula or rubia cordifolia or manjishtha orwithania somnifera or ashvagandha).mp.
39. (phytotherapy or cascara$ or curare$ orchinese herb$ or guaiac$ or ipecac$ orpodophyll$ or psyllium$ or senna extract$ ortragacanth$ or turpentine$).mp.
40. (essential oil$ or plant oil$ or tea tree orlavender or chamomile or camomile orrosemary).mp.
41. (sucrose or sugar paste$ or granulatedsugar).mp.
42. (propolis or honey or beebread$ or bee bread$or bee glue$).mp.
43. (disinfect$ or antisept$ or anti-sept$ orantiviral$ or anti-viral$).mp.
44. ((neuroisch?emic or isch?emic or diabetic orneuropathic) adj3 (foot or feet or ulcer$)).mp.
45. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).mp.
46. ((foot or feet) adj6 diabet$).mp.47. deep foot infection$.mp.48. Leg Ulcer/49. ((crural or leg) adj5 ulcer$).mp.50. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).mp.51. ((venous or stasis or leg) adj5 wound$).mp.52. ((lower extremit$ or lower limb$) adj5 (ulcer$
or wound$)).mp.53. (penicillin$ or amdinocillin$ or amox#cillin$
or ampicillin$ or azlocillin$).mp.54. (carbenicillin$ or carfecillin$ or cloxacillin$ or
dicloxacillin$ or floxacillin$ or flucloxacillin$or methicillin$ or mazlocillin$ or nafcillin$ oroxacillin$ or penicillanic acid$).mp.
55. (penicillic acid$ or phenoxymethylpenicillin$or piperacillin$ or pivampicillin$ or
Appendix 1
90
sulbencillin$ or talampicillin$ or sultamicillin$or ticarcillin$ or ticercillin$).mp.
56. (cefaclor$ or cefadroxil$ or cefalexin$ orcefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).mp.
57. (cefradine$ or ceftazidime$ or ceftizoxime$ orceftriaxone$ or cefuroxime$).mp.
58. (cefonicid$ or cefmenoxine$ or cefoperazone$or cefotiam$ or cefsulodin$ or cephacetrile$or cephalexin$ or cephaloglycin$ orcephaloridine or cephalosporanic acid$ orcephalothin$ or cephapirin$ orcephradine$).mp.
59. (beta lactam$ or aztreonam$ or cilastin$ orimipenem$ or meropenem$ or sulbactam$ ortazobactam$).mp.
60. (caprolactam$ or clavulan$ ormoxalactam$).mp.
61. (Aminoglycoside$ or anthracycline$ oraclarubicin$ or daunorubicin$ or carubicin$ ordoxorubicin$ or epirubicin$ or idarubicin$ ornogalamycin$ or menogaril$ orplicamycin$).mp.
62. (gentamicin$ or neomycin$ or netilmicin$ ortobramycin$).mp.
63. exp Macrolide/64. (amphotericin$ or antimycin$ or candicidin or
roxithromycin$ or josamycin$ or leucomycin$or kitasamycin$ or lucensomycin$ ormaytansine$ or mepartricin$ ormiocamycin$).mp.
65. (natamycin$ or oleandomycin$ ortroleandomycin$ or oligomycin$ orrutamycin$ or sirolimus$ or tacrolimus$ ortylosin$ or propiolactone$ or spironolactone$or venturicidin$ or zearalenone$ orzeranol$).mp.
66. (azithromycin$ or clarithromycin$ orerythromycin$ or spiramycin$).mp.
67. (moxifloxacin$ or quinolone$ orciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).mp.
68. (fleroxacin$ or enoxacin$ or norfloxacin$ orpefloxacin$ or nalidixic acid$ or nedocromil$or oxolinic acid$ or quinpirole$ or quipazine$or saquinavir$).mp.
69. (dmso or sulfoxide$ or sulphoxide$ orsulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ orsulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).mp.
70. (benzolamide$ or bumetanide$ orchloramine$ or chlorthalidone$ or clopamide$
or dichlorphenamide$ or ethoxzolamide$ orindapamide$ or mafenide$ or mefruside$ ormetolazone$ or prodenecid$ or sulfanilamide$or sulphanilamide$ or furosemide$ orsulfacetamide$ or sulphacetamide$).mp.
71. (sulfachlorpyridazine$ or sulfadimethoxine$or sulfadoxine$ or sulfaguanidine$ orsulfamerazine$ or sulfameter$ orsulfamethazine$ or sulfamethoxypyridazine$or sulphachlorpyridazine$ orsulphadimethoxine$ or sulphadoxine$ orsulphaguanidine$ or sulphamerazine$ orsulphameter$ or sulphamethazine$ orsulphamethoxypyridazine$).mp.
72. (sulfamonomethoxine$ or sulfamoxole$ orsulfaphenazole$ or sulfapyridine$ orsulfaquinoxaline$ or sulfathiazole$ orsulfamethizole$ or sulfisomidine$ orsulfisoxazole$ or sulfasalazine$ orsumatriptan$ or xipamide$ or thioamide$ orthioacetamide$ or sulphamonomethoxine$ orsulphamoxole$ or sulphaphenazole$ orsulphapyridine$ or sulphaquinoxaline$ orsulphathiazole$ or sulphamethizole$ orsulphisomidine$ or sulphisoxazole$ orsulphasalazine$).mp.
73. (tetracycline$ or demeclocycline$ ordoxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).mp.
74. (chlortetracycline$ or methacycline$ orrolitetracycline$).mp.
75. (cloranfenicol$ or chloramphenicol$).mp.76. (thiamphenicol$ or kloramfenikol$ or
levomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ or detreomycin$or ophthochlor$ or syntomycin$).mp.
77. (clindamycin$ or dalacin c or cleocin$ orchlo?lincocin$).mp.
78. (linezolid$ or trivazol$ or vagilen$ or clont$ ordanizol$ or fagyl$ or ginefavir$ or metrogel$or metrodzhil$ or satric$ or trichazol$ ortrichopol$).mp.
79. (granulocyte colony stimulating factor or gcsfor ozone).mp.
80. (fusidate$ adj (sodium or silver)).mp.81. (antibiotic$ or antimicrobial$).mp.82. (griseofulvin or synercid or dalfopristin or
quinupristin).mp.83. exp microbiology/84. exp Drug Therapy/85. or/4-4386. (or/4-43) or (or/53-84)87. or/44-5288. or/1-389. (87 and 86) or (87 and 88)
This identified 67 records.
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CINAHL (1982–2002 October, week 4) (searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. exp clinical trials/ or random assignment/ orplacebos/ or meta analysis/ or exp prospectivestudies/
2. systematic review/ or comparative studies/ orclinical trial.pt. or review.pt. or systematicreview.pt.
3. (clinical adj trial$).ti,ab.4. ((singl$ or doubl$ or trebl$ or tripl$) adj
blind$).ti,ab.5. (control or controls or controlled or
controlling or metaanalys$).ti,ab.6. (meta adj analys$).ti,ab.7. (random$ or prospective$ or (comparison
adj group$) or (standard adjtreatment$)).ti,ab.
8. (placebo$ or (systematic adj review$)).ti,ab.9. or/1-8
10. exp Acetic Acid/11. (acetic acid$ or acetate$ or acetamide$ or
acetoxyacetylaminofluorene$ orhydroxyacetylaminofluorene$ orallylisopropylacetamide$).ti,ab.
12. (idoacetamide$ or idoacetate$ or piracetam$or thioacetamide$ or gadolinium$ ortechnetium$ or dichoroacetate$ orfluoroacetate$ or iodoacetate$).ti,ab.
13. (foscarnet$ or thioglycolate$ or aceticanhydride$).ti,ab.
14. ((aminooxyacetic or edetic or egtazic oriodoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic ortrichloroacetic or trifluoroacetic) adjacid$).ti,ab.
15. (therapeutic fungicide$ or antifungal agent$or antifungals).ti,ab.
16. (benzoate$ or butenafine$ or chlorquinaldol$or cyclosporine$ or dichlorophen$ orfluconazole$ or flucytosine$ or glycyrrhizicacid$ or hexetidine$ or itraconazole$ ormonensin$ or nifuratel$ orpentamidine$).ti,ab.
17. (co-amoxiclav$ or sodium benzoate$ orthimerosal$ or thiram$ or thymol$ ortolnaftate$ or tomatine$ or triacetin$ ortrimetrexate$).ti,ab.
18. (amoroldine$ or benzoic acid$ orclotrimazole$ or econazole$ or ketoconazole$or miconazole$ or nystatin$ or Salicylic acid$or sulconazole$ or terbinafine$ ortioconazole$ or undecenoate$).ti,ab.
19. (antiviral$ or anti viral$ oridoxuridine$).ti,ab.
20. (acetylcysteine$ or acyclovir$ or amantadine$or aphidicolin$ or aprotinin$ or brefeldin or
bromodeoxyuridine$ or cytarabine$ ordeoxyglucose$ or dextran sulfate$).ti,ab.
21. (dideoxyadenosine$ or dideoxynucleoside$or dihematoporphyrin ether$ or ditiocarb$or filipin$ or floxuridine$ or ganciclovir$ orinosine pranobex or interferon alfa$ orinterferon type$ or interferon beta orinterferon gamma or interferons).ti,ab.
22. (methisazone$ or phosphonoacetic acid$ orpoly a-u or poly i-c or pyran copolymer$ orribavirin$ or rimantadine$ or streptovaricin$or tenuazonic acid$ or tilorone$ ortrifluridine$ or tunicamycin$ orvidarabine$).ti,ab.
23. exp BACITRACIN/24. (bacitracin$ or povidone iodine$ or
betaisodona$ or polyvinylpyrrolidone iodine$or betadine$ or disadine$ or isodine$ or pvp-i or pharmadine$).ti,ab.
25. (cetyltrimethylammonium or cetrimide$ orcetrimonium).ti,ab.
26. exp Chloride Compounds/27. (chlorate$ or cisplatin or hydrochloric acid$
or chloride$ or hypochlorous acid$ orhypochlorite$ or perchloric acid$ orruthenium red$).ti,ab.
28. (eusol or phenoxyethanol$ or dextranomer$or framycetin sulphate$ or mandelic acid$ ortetrabromofluorescein$ or eosin or eosine orchlortetracycline$ or chloroxylenolsolution$).ti,ab.
29. (edinburgh adj university adj solution adj2lime).ti,ab.
30. (cyclandelate$ or vanilmandelic acid$).ti,ab.31. hexachloroph#ne$.ti,ab.32. (triclosan$ or polymyxin$ or
polynoxylin$).ti,ab.33. (silver adj2 dressing$).ti,ab.34. (gentian violet or crystal violet or methyl
violet or methylrosaniline chloride$ orhexamethylpararosanine chloride$).ti,ab.
35. (potassium permanganate$ or permanganicacid$ or potassium salt$).ti,ab.
36. exp Mupirocin/37. (mupirocin$ or pseudomonic acid$ or
bactroban$).ti,ab.38. exp Neomycin/39. (neomycin$ or fradiomycin$ or
neamin$).ti,ab.40. (benzyol peroxide$ or benzyol superoxide$
or diphenylglyoxal superoxide$ orpanoxyl$).ti,ab.
41. exp Hydrogen Peroxide/42. (hydrogen peroxide$ or hydroperoxide$ or
oxydol$ or perhydrol$ or superoxol$ ordiphenylglyoxal superoxide$ orpanoxyl$).ti,ab.
Appendix 1
92
43. (fucithalmic$ or fusidate$ or fusidin$ orstanicide$).ti,ab.
44. (liposome$ adj hydrogel$).ti,ab.45. (fusidic acid$ or inadine$ or betadine$).ti,ab.46. (cadexomer iodine$ or chlorhexidine$ or
novalsan$ or sebidin$ or tubulicid$).ti,ab.47. exp Larva/48. (maggot$ or larva or larvae or larval).ti,ab.49. exp alternative Therapies/50. (plant extract$ or aromatherap$ or
marigold extract$ or calendula officinalis ortagetes patula or rubia cordifolia ormanjishtha or withania somnifera orashvagandha).ti,ab.
51. exp Plant Extracts/52. exp Plants, Medicinal/53. (phytotherapy or cascara$ or curare$ or
chinese herb$ or guaiac$ or ipecac$ orpodophyll$ or psyllium$ or senna extract$ ortragacanth$ or turpentine$).ti,ab.
54. exp plant oils/55. exp Sucrose/56. exp HONEY/57. (essential oil$ or plant oil$ or tea tree or
lavender or chamomile or camomile orrosemary).ti,ab.
58. (sucrose or sugar paste$ or granulatedsugar).ti,ab.
59. (propolis or honey or beebread$ or beebread$ or bee glue$).ti,ab.
60. exp Anti-Infective Agents/61. (disinfect$ or antisept$ or anti-sept$ or
antiviral$ or anti-viral$).ti,ab.62. ((neuroisch?emic or isch?emic or diabetic or
neuropathic) adj3 (foot or feet orulcer$)).ti,ab.
63. ((pedal or plantar or foot or feet or heel)adj3 (ulcer$ or septic or wound$)).ti,ab.
64. ((foot or feet) adj6 diabet$).ti,ab.65. deep foot infection$.ti,ab.66. exp Foot Ulcer/67. or/62-6668. Leg Ulcer/69. venous Ulcer/70. ((crural or leg) adj5 ulcer$).ti,ab.71. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).ti,ab.72. ((venous or stasis or leg) adj5 wound$).ti.73. ((lower extremit$ or lower limb$) adj5 (ulcer$
or wound$)).ti,ab.74. or/68-7375. 67 or 7476. (penicillin$ or amdinocillin$ or amox#cillin$
or ampicillin$ or azlocillin$).ti,ab.77. (carbenicillin$ or carfecillin$ or cloxacillin$
or dicloxacillin$ or floxacillin$ orflucloxacillin$ or methicillin$ or mazlocillin$
or nafcillin$ or oxacillin$ or penicillanicacid$).ti,ab.
78. (penicillic acid$ or phenoxymethylpenicillin$or piperacillin$ or pivampicillin$ orsulbencillin$ or talampicillin$ orsultamicillin$ or ticarcillin$ orticercillin$).ti,ab.
79. (cefaclor$ or cefadroxil$ or cefalexin$ orcefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).ti,ab.
80. (cefradine$ or ceftazidime$ or ceftizoxime$or ceftriaxone$ or cefuroxime$).ti,ab.
81. (cefonicid$ or cefmenoxine$ orcefoperazone$ or cefotiam$ or cefsulodin$ orcephacetrile$ or cephalexin$ orcephaloglycin$ or cephaloridine orcephalosporanic acid$ or cephalothin$ orcephapirin$ or cephradine$).ti,ab.
82. (beta lactam$ or aztreonam$ or cilastin$ orimipenem$ or meropenem$ or sulbactam$ ortazobactam$).ti,ab.
83. (caprolactam$ or clavulan$ ormoxalactam$).ti,ab.
84. exp Aminoglycosides/85. (Aminoglycoside$ or anthracycline$ or
aclarubicin$ or daunorubicin$ or carubicin$or doxorubicin$ or epirubicin$ oridarubicin$ or nogalamycin$ or menogaril$or plicamycin$).ti,ab.
86. (gentamicin$ or neomycin$ or netilmicin$ ortobramycin$).ti,ab.
87. (amphotericin$ or antimycin$ or candicidin$or roxithromycin$ or josamycin$ orleucomycin$ or kitasamycin$ orlucensomycin$ or maytansine$ ormepartricin$ or miocamycin$).ti,ab.
88. (natamycin$ or oleandomycin$ ortroleandomycin$ or oligomycin$ orrutamycin$ or sirolimus$ or tacrolimus$ ortylosin$ or propiolactone$ or spironolactone$or venturicidin$ or zearalenone$ orzeranol$).ti,ab.
89. (azithromycin$ or clarithromycin$ orerythromycin$ or spiramycin$).ti,ab.
90. (moxifloxacin$ or quinolone$ orciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).ti,ab.
91. (fleroxacin$ or enoxacin$ or norfloxacin$ orpefloxacin$ or nalidixic acid$ or nedocromil$or oxolinic acid$ or quinpirole$ orquipazine$ or saquinavir$).ti,ab.
92. exp Trimethoprim/93. (dmso or sulfoxide$ or sulphoxide$ or
sulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ or
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sulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).ti,ab.
94. (benzolamide$ or bumetanide$ orchloramine$ or chlorthalidone$ orclopamide$ or dichlorphenamide$ orethoxzolamide$ or indapamide$ ormafenide$ or mefruside$ or metolazone$ orprodenecid$ or sulfanilamide$ orsulphanilamide$ or furosemide$ orsulfacetamide$ or sulphacetamide$).ti,ab.
95. (sulfachlorpyridazine$ or sulfadimethoxine$or sulfadoxine$ or sulfaguanidine$ orsulfamerazine$ or sulfameter$ orsulfamethazine$ or sulfamethoxypyridazine$or sulphachlorpyridazine$ orsulphadimethoxine$ or sulphadoxine$ orsulphaguanidine$ or sulphamerazine$ orsulphameter$ or sulphamethazine$ orsulphamethoxypyridazine$).ti,ab.
96. (sulfamonomethoxine$ or sulfamoxole$ orsulfaphenazole$ or sulfapyridine$ orsulfaquinoxaline$ or sulfathiazole$ orsulfamethizole$ or sulfisomidine$ orsulfisoxazole$ or sulfasalazine$ orsumatriptan$ or xipamide$ or thioamide$ orthioacetamide$ or sulphamonomethoxine$or sulphamoxole$ or sulphaphenazole$ orsulphapyridine$ or sulphaquinoxaline$ orsulphathiazole$ or sulphamethizole$ orsulphisomidine$ or sulphisoxazole$ orsulphasalazine$).ti,ab.
97. (tetracycline$ or demeclocycline$ ordoxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).ti,ab.
98. (chlortetracycline$ or methacycline$ orrolitetracycline$).ti,ab.
99. (cloranfenicol$ or chloramphenicol$).ti,ab.100. (thiamphenicol$ or kloramfenikol$ or
levomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ ordetreomycin$ or ophthochlor$ orsyntomycin$).ti,ab.
101. (clindamycin$ or dalacin c or cleocin$ orchlo?lincocin$).ti,ab.
102. exp Metronidazole/103. (linezolid$ or trivazol$ or vagilen$ or clont$
or danizol$ or fagyl$ or ginefavir$ ormetrogel$ or metrodzhil$ or satric$ ortrichazol$ or trichopol$).ti,ab.
104. (fusidate$ adj (sodium or silver)).ti,ab.105. (antibiotic$ or antimicrobial$).ti,ab.106. (griseofulvin or synercid or dalfopristin or
quinupristin).ti,ab.107. (granulocyte colony stimulating factor or gcsf
or ozone).ti,ab.
108. or/10-61109. or/76-107110. 108 or 109111. 75 and 110 and 9
This identified 72 records.
The Cochrane Database of Systematic Reviews(CDSR) and the Cochrane Controlled TrialsRegister (CCTR) [Searched: 12 November 2002via the Cochrane Library (2002, Issue 4)]
#1. (neuroischemic near foot) #2. (neuroischaemic near foot) #3. (neuroischemic near feet) #4. (neuroischaemic near feet) #5. (neuroischemic near ulcer*) #6. (neuroischaemic near ulcer*) #7. (ischemic near foot) #8. (ischemic near feet) #9. (ischemic near ulcer*)
#10. (ischaemic near foot) #11. (ischaemic near feet) #12. (ischaemic near ulcer*) #13. (diabetic near foot) #14. (diabetic near feet) #15. (diabetic near ulcer*) #16. (neuropathic near foot) #17. (neuropathic near feet)#18. (neuropathic near ulcer*) #19. (pedal near ulcer*) #20. (pedal near septic) #21. (pedal near wound*) #22. (plantar near ulcer*) #23. (plantar near septic) #24. (plantar near wound*) #25. (foot near ulcer*) #26. (foot near septic) #27. (foot near wound*) #28. (feet near ulcer*) #29. (feet near septic) #30. (feet near wound*) #31. (heel near ulcer*) #32. (heel near septic) #33. (heel near wound*) #34. (foot near diabet*) #35. (feet near diabet*) #36. (deep next foot next infection*) #37. (crural near ulcer*) #38. (leg near ulcer*) #39. (venous near leg) #40. (venous near ulcer*) #41. (stasis near leg) #42. (stasis near ulcer*) #43. (varicos* near leg) #44. (varicos* near ulcer*) #45. ((lower next extremit*) near ulcer*) #46. ((lower next extremit*) near wound*)
Appendix 1
94
#47. ((lower next limb*) near ulcer*) #48. ((lower next limb*) near wound*) #49. (#1 or #2 or #3 or #4 or #5 or #6 or #7
or #8 or #9 or #10 or #11 or #12 or #13or #14 or #15 or #16 or #17 or #18 or#19 or #20 or #21 or #22 or #23 or #24or #25 or #26 or #27 or #28 or #29 or#30 or #31 or #32 or #33 or #34 or #35or #36 or #37 or #38 or #39 or #40 or#41 or #42 or #43 or #44 or #45 or #46or #47 or #48)
#50. LEG ULCER explode all trees (MeSH) #51. (#49 or #50) #52. ACETIC ACID explode all trees (MeSH)#53. ((acetic next acid*) or acetate* or
acetamide* or acetoxyacetyaminofluorene*or hydrooxyacetylaminofluorene* orallylisopropylacetamide*)
#54. (idoacetamide* or idoacetate* orpiracetam* or thioacetamide* orgalolinium* or technetium* ordichoroacetate* or fluoroacetate* oridoacetate*)
#55. (foscarnet* or thioglycolate* or (acetic nextanhydride*))
#56. (aminooxyacetic or edetic or egtazic oridoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic ortrichloroacetic or trifluoroacetic)
#57. ((therapeutic next fungicide*) or (antifungalnext agent*) or antifungal*)
#58. (benzoate* or butenafine* orchlorquinaldol* or cyclosporine ordichlorophen* or fluconazole* orflucytosine* or (glycyrrhizic next acid*) orhexetidine* or itraconazole* or monensin*or nifuratel* or pentamidine*)
#59. (co-amoxiclav* or (sodium next benzoate*)or thimerosal* or thiram* or thymol* ortolnaftate* or tomatine* or triacetin* ortrimetrexate*)
#60. (amoroldine* or (benzoic next acid*) orclotrimazole* or econazole* orketoconazole* or miconazole* or nystatin*or (salicyclic next acid*) or sulconazole* orterbinafine* or tioconazole* orundecenoate*)
#61. (antiviral* or (anti next viral*) oridoxuridine*)
#62. (acetylcysteine* or acyclovir* or amantadine*or aphidicolin* or aprotinin* or brefeldin orbromodeoxyuridine* or cytarabine* ordeoxyglucose* or (dextran next sulfate*))
#63. (dideoxyadenosine* or dideoxynucleoside*or (dihematoporphyrin next ether*) orditiocarb* or filipin* or floxuridine* organciclovir* or (inosine next pranobex) or
(interferon next alfa*) or (interferon nexttype*) or (interferon next beta) or(interferon next gamma) or interferons)
#64. (methisazone* or (phosphonoacetic nextacid*) or (poly next a-u) or (poly next i-c) or(pyran next copolymer*) or ribavirin* orrimantadine* or streptovaricin* or(tenuazonic next acid*) or tilorone* ortrifluridine* or tunicamycin* or vidarabine*)
#65. (bacitracin* or (povidone next iodine*) orbetaisodona* or (polyvinylpyrrolidone nextiodine*) or betadine* or disadine* orisodine* or pvp-i or pharmadine*)
#66. (cetyltrimethylammonium or cetrimide* orcetrimonium)
#67. (chlorate* or cisplatin or (hydrochloric next acid*) or chloride* or (hypochlorousnext acid*) or hypochlorite* or (perchloricnext acid*) or (ruthenium next red*))
#68. (eusol or phenoxyethanol* ordextranomer* or (framycetin nextsulphate*) or (mandelic next acid*) ortetrabromofluorescein* or eosin or eosineor chlortetracycline* or (chloroxylenol nextsolution*))
#69. (edinburgh next adj next university next adjnext solution next adj2 next lime)
#70. (cyclandelate* or (vanilmandelic nextacid*))
#71. hexachloroph* #72. (triclosan* or polymyxin* or polynoxylin*) #73. (silver near dressing*) #74. ((gentian next violet) or (crystal next violet)
or (methyl next violet) or (methylrosanilinenext chloride*) or (hexamethylpararosaninenext chloride*))
#75. ((potassium next permanganate*) or(permanganic next acid*) or (potassiumnext salt*)) 36
#76. (mupirocin* or (pseudomonic next acid*)or bactroban*)
#77. (neomycin* or fradiomycin* or neamin*) #78. ((benzyol next peroxide*) or (benzyol next
superoxide*) or (diphenylglyoxal nextsuperoxide*) or panoxyl*)
#79. ((hydrogen next peroxide*) orhydroperoxide* or oxydol* or perhydrol*or superoxol* or (diphenylglyoxal nextsuperoxide*) or panoxyl*)
#80. (fucithalmic* or fusidate* or fusidin* orstanicide*)
#81. (liposome* near hydrogel*) #82. ((fusidic next acid*) or inadine* or
betadine*) #83. ((cadexomer next iodine*) or
chlorhexidine* or novalsan* or sebidin* ortubulicid*)
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#84. (maggot* or larva or larvae or larval) #85. ((plant next extract*) or aromatherap* or
(marigold next extract*) or (calendula nextofficinalis) or (tagetes next patula) or (rubianext cordifolia) or manjishtha or (withanianext somnifera) or ashvagandha)
#86. (phytotherapy or cascara* or curare* or(chinese next herb*) or guaiac* or ipecac* or podophyll* or psyllium* or(senna next extract*) or tragacanth* orturpentine*)
#87. ((essential next oil*) or (plant next oil*) or(tea next tree) or lavender or chamomile orcamomile or rosemary)
#88. (sucrose or (sugar next paste*) or(granulated next sugar))
#89. (propolis or honey or beebread* or (beenext bread*) or (bee next glue*))
#90. (disinfect* or antisept* or anti-sept* orantiviral* or anti-viral*)
#91. (penicillin* or amdinocillin* or amox* orampicillin* or azlocillin*)
#92. (carbenicillin* or carfecillin* or cloxacillin*or dicloxacillin* or floxacillin* orflucloxacillin* or methicillin* ormazlocillin* or nafcillin* or oxacillin* or(penicillanic next acid*))
#93. ((penicillic next acid*) orphenoxymethylpenicillin* or piperacillin*or pivampicillin* or sulbencillin* ortalampicillin* or sultamicillin* orticarcillin* or ticercillin*)
#94. (cefaclor* or cefadroxil* or cefalexin* orcefazolin* or cefamandole* or cefixime* orcefotaxime* or cefoxitin* or cefpirome* orcefpodoxime* or cefprozil*)
#95. (cefradine* or ceftazidime* or ceftizoxime*or ceftriaxone* or cefuroxime*)
#96. (cefonicid* or cefmenoxine* orcefoperazone* or cefotiam* or cefsulodin*or cephacetrile* or cephalexin* orcephaloglycin* or cephaloridine or(cephalosporanic next acid*) orcephalothin* or cephapirin* orcephradine*)
#97. ((beta next lactam*) or aztreonam* orcilastin* or imipenem* or meropenem* orsulbactam* or tazobactam*)
#98. (caprolactam* or clavulan* ormoxalactam*)
#99. (aminoglycoside* or anthracycline* oraclarubicin* or daunorubicin* or carubicin*or doxorubicin* or epirubicin* oridarubicin* or nogalamycin* or menogaril*or plicamycin*)
#100. (gentamicin* or neomycin* or netilmicin*or tobramycin*)
#101. (amphotericin* or antimycin* orcandicidin* or roxithromycin* orjosamycin* or leucomycin* or kitasamycin*or lucensomycin* or maytansine* ormepartricin* or miocamycin*)
#102. (natamycin* or oleandomycin* ortroleandomycin* or oligomycin* orrutamycin* or sirolimus* or tacrolimus* ortylosin* or propiolactone* orspironolactone* or venturicidin* orzearalenone* or zeranol*)
#103. (azithromycin* or clarithromycin* orerythromycin* or spiramycin*)
#104. (moxifloxacin* or quinolone* orciprofloxacin* or clinafloxacin* orfluoroquinolone* or levofloxacin* orofloxacin*)
#105. (fleroxacin* or enoxacin* or norfloxacin*or pefloxacin* or (nalidixic next acid*) ornedocromil* or (oxolinic next acid*) orquinpirole* or quipazine* or saquinavir*)
#106. (dmso or sulfoxide* or sulphoxide* orsulfonamide* or sulphonamide* ortrimethoprim* or sulfamethoxazole* orsulphamethoxazole* or co-trimoxazole* orsulfadiazine* or sulphadiazine* orsulfametopyrazine* or sulfalene* orsulphametopyrazine* or sulphalene*) 2593
#107. (benzolamide* or bumetanide* orchloramine* or chlorthalidone* orclopamide* or dichlorphenamide* orethoxzolamide* or indapamide* ormafenide* or mefruside* or metolazone* orprodenecid* or sulfanilamide* orsulphanilamide* or furosemide* orsulfacetamide* or sulphacetamide*) 2041
#108. (sulfachlorpyridazine* or sulfadimethoxine*or sulfadoxine* or sulfaguanidine* orsulfamerazine* or sulfameter* orsulfamethazine* orsulfamethoxypyridazine* orsulphachlorpyridazine* orsulphadimethoxine* or sulphadoxine* orsulphaguanidine* or sulphamerazine* orsulphameter* or sulphamethazine* orsulphamethoxypyridazine*) 290
#109. (sulfamonomethoxine* or sulfamoxole* orsulfaphenazole* or sulfapyridine* orsulfaquinoxaline* or sulfathiazole* orsulfamethizole* or sulfisomidine* orsulfisoxazole* or sulfasalazine* orsumatriptan* or xipamide* or thioamide*)892
#110. (thioacetamide* or sulphamonomethoxine*or sulphamoxole* or sulphaphenazole* orsulphapyridine* or sulphaquinoxaline* orsulphathiazole* or sulphamethizole* or
Appendix 1
96
sulphisomidine* or sulphisoxazole* orsulphasalazine*) 222
#111. (tetracycline* or demeclocycline* ordoxycycline* or lymecycline* orminocycline* or oxytetracycline*) 1988
#112. (chlortetracycline* or methacycline* orrolitetracycline*) 77
#113. (cloranfenicol* or chloramphenicol*) 402 #114. (thiamphenicol* or kloramfenikol* or
levomycetin* or chlornitromycin* orchlorocid* or chloromycetin* ordetreomycin* or ophthochlor* orsyntomycin*) 53
#115. ((clindamycin* or (dalacin next c) orcleocin* or (chlo next lincocin*)) orchlolincocin*) 796
#116. (linezolid* or trivazol* or vagilen* or clont*or danizol* or fagyl* or ginefavir* ormetrogel* or metrodzhil* or satric* ortrichazol* or trichopol*) 19
#117. ((granulocyte next colony next stimulatingnext factor) or gcsf or ozone) 892
#118. (griseofulvin or synercid or dalfopristin orquinupristin) 139
#119. (antibiotic* or antimicrobial*)#120. (fusidate* near sodium) #121. (fusidate* near silver) #122. ANTI-INFECTIVE AGENTS explode all
trees (MeSH) #123. BACITRACIN explode all trees (MeSH) #124. CHLORIDES explode all trees (MeSH) #125. MUPIROCIN explode all trees (MeSH) #126. HYDROGEN PEROXIDE explode all trees
(MeSH) #127. LARVA explode all trees (MeSH) #128. COMPLEMENTARY THERAPIES explode
all trees (MeSH) #129. PLANT OILS explode all trees (MeSH) #130. PLANT EXTRACTS explode all trees
(MeSH) #131. SUCROSE explode all trees (MeSH) #132. HONEY explode all trees (MeSH) #133. aminoglycosides #134. TRIMETHOPRIM explode all trees
(MeSH) #135. METRONIDAZOLE explode all trees
(MeSH) #136. (#52 or #53 or #54 or #55 or #56 or #57
or #58 or #59 or #60 or #61 or #62 or#63 or #64 or #65 or #66 or #67 or #68or #69 or #70 or #71 or #72 or #73 or#74 or #75 or #76 or #77 or #78 or #79or #80 or #81 or #82 or #83 or #84 or#85 or #86 or #87 or #88 or #89 or #90or #91 or #92 or #93 or #94 or #95 or#96 or #97 or #98 or #99 or #100 or#101 or #102 or #103 or #104 or #105 or
#106 or #107 or #108 or #109 or #110 or #111 or #112 or #113 or #114 or #115 or #116 or #117 or #118 or #119 or #120 or #121 or #122 or #123 or #124 or #125 or #126 or #127 or #128 or #129 or #130 or #131 or #132 or #133or #134 or #135)
#137. #51 and #136
This identified 35 reviews in the CDSR (of which12 were protocols) and 176 potential trials inCCTR.
EMBASE (1980–2002 week 44) (searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. exp clinical trial/2. Single Blind Procedure/3. double Blind Procedure/4. placebo/5. meta-analysis/6. randomization/7. randomized-controlled-trial/8. controlled-study/9. exp evidence-based-medicine/
10. exp comparative-study/11. (clinical trial$ or random$ or placebo$ or
control or controls or controlled).ti,ab.12. (single blind$ or double blind$ or trebl$
blind$ or tripl$ blind$).ti,ab.13. (meta-analys$ or meta analys$ or comparison
group or standard treatment$ or systematicreview$).ti,ab.
14. or/1-1315. exp animal/16. exp human/17. nonhuman/18. 15 not (15 and 16)19. 17 not (17 and 16)20. 14 not (18 or 19)21. exp Acetic Acid/22. (acetic acid$ or acetate$ or acetamide$ or
acetoxyacetylaminofluorene$ orhydroxyacetylaminofluorene$ orallylisopropylacetamide$).ti,ab.
23. (idoacetamide$ or idoacetate$ or piracetam$or thioacetamide$ or gadolinium$ ortechnetium$ or dichoroacetate$ orfluoroacetate$ or iodoacetate$).ti,ab.
24. (foscarnet$ or thioglycolate$ or aceticanhydride$).ti,ab.
25. ((aminooxyacetic or edetic or egtazic oriodoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic ortrichloroacetic or trifluoroacetic) adjacid$).ti,ab.
26. exp ANTIFUNGAL AGENTS/
Health Technology Assessment 2006; Vol. 10: No. 12
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© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
27. (therapeutic fungicide$ or antifungal agent$or antifungals).ti,ab.
28. (benzoate$ or butenafine$ or chlorquinaldol$or cyclosporine$ or dichlorophen$ orfluconazole$ or flucytosine$ or glycyrrhizicacid$ or hexetidine$ or itraconazole$ ormonensin$ or nifuratel$ orpentamidine$).ti,ab.
29. (co-amoxiclav$ or sodium benzoate$ orthimerosal$ or thiram$ or thymol$ ortolnaftate$ or tomatine$ or triacetin$ ortrimetrexate$).ti,ab.
30. (amoroldine$ or benzoic acid$ orclotrimazole$ or econazole$ or ketoconazole$or miconazole$ or nystatin$ or Salicylic acid$or sulconazole$ or terbinafine$ ortioconazole$ or undecenoate$).ti,ab.
31. (antiviral$ or anti viral$ oridoxuridine$).ti,ab.
32. (acetylcysteine$ or acyclovir$ or amantadine$or aphidicolin$ or aprotinin$ or brefeldin orbromodeoxyuridine$ or cytarabine$ ordeoxyglucose$ or dextran sulfate$).ti,ab.
33. (dideoxyadenosine$ or dideoxynucleoside$or dihematoporphyrin ether$ or ditiocarb$or filipin$ or floxuridine$ or ganciclovir$ orinosine pranobex or interferon alfa$ orinterferon type$ or interferon beta orinterferon gamma or interferons).ti,ab.
34. (methisazone$ or phosphonoacetic acid$ orpoly a-u or poly i-c or pyran copolymer$ orribavirin$ or rimantadine$ or streptovaricin$or tenuazonic acid$ or tilorone$ ortrifluridine$ or tunicamycin$ orvidarabine$).ti,ab.
35. exp BACITRACIN/36. exp Povidone-Iodine/37. (bacitracin$ or povidone iodine$ or
betaisodona$ or polyvinylpyrrolidone iodine$or betadine$ or disadine$ or isodine$ or pvp-i or pharmadine$).ti,ab.
38. exp Cetrimide/39. (cetyltrimethylammonium or cetrimide$ or
cetrimonium).ti,ab.40. exp Chlorine Derivative/41. (chlorate$ or cisplatin or hydrochloric acid$
or chloride$ or hypochlorous acid$ orhypochlorite$ or perchloric acid$ orruthenium red$).ti,ab.
42. exp Eosin/43. (eusol or phenoxyethanol$ or dextranomer$
or framycetin sulphate$ or mandelic acid$ ortetrabromofluorescein$ or eosin or eosine orchlortetracycline$ or chloroxylenolsolution$).ti,ab.
44. (edinburgh adj university adj solution adj2lime).ti,ab.
45. exp Framycetin/46. exp Mandelic Acid derivative/47. (cyclandelate$ or vanilmandelic acid$).ti,ab.48. exp Hexachlorophene/49. hexachloroph#ne$.ti,ab.50. exp Triclosan/51. exp Polymyxin/52. (triclosan$ or polymyxin$ or
polynoxylin$).ti,ab.53. (silver adj2 dressing$).ti,ab.54. exp crystal Violet/55. (gentian violet or crystal violet or methyl
violet or methylrosaniline chloride$ orhexamethylpararosanine chloride$).ti,ab.
56. exp Permanganate Potassium/57. (potassium permanganate$ or permanganic
acid$ or potassium salt$).ti,ab.58. exp pseudomonic acid/59. (mupirocin$ or pseudomonic acid$ or
bactroban$).ti,ab.60. exp Neomycin/61. (neomycin$ or fradiomycin$ or
neamin$).ti,ab.62. exp Benzoyl Peroxide/63. (benzyol peroxide$ or benzyol superoxide$
or diphenylglyoxal superoxide$ orpanoxyl$).ti,ab.
64. exp Hydrogen Peroxide/65. (hydrogen peroxide$ or hydroperoxide$ or
oxydol$ or perhydrol$ or superoxol$ ordiphenylglyoxal superoxide$ orpanoxyl$).ti,ab.
66. (fucithalmic$ or fusidate$ or fusidin$ orstanicide$).ti,ab.
67. (liposome$ adj hydrogel$).ti,ab.68. (fusidic acid$ or inadine$ or betadine$).ti,ab.69. exp Chlorhexidine/70. (cadexomer iodine$ or chlorhexidine$ or
novalsan$ or sebidin$ or tubulicid$).ti,ab.71. exp Larva/72. (maggot$ or larva or larvae or larval).ti,ab.73. exp alternative medicine/74. (plant extract$ or aromatherap$ or
marigold extract$ or calendula officinalis ortagetes patula or rubia cordifolia ormanjishtha or withania somnifera orashvagandha).ti,ab.
75. exp Plant Extract/76. exp Medicinal Plant/77. (phytotherapy or cascara$ or curare$ or
chinese herb$ or guaiac$ or ipecac$ orpodophyll$ or psyllium$ or senna extract$ ortragacanth$ or turpentine$).ti,ab.
78. exp essential oil/ or exp vegetable oil/79. exp Sucrose/80. exp HONEY/81. (essential oil$ or plant oil$ or tea tree or
Appendix 1
98
lavender or chamomile or camomile orrosemary).ti,ab.
82. (sucrose or sugar paste$ or granulatedsugar).ti,ab.
83. exp Propolis/84. (propolis or honey or beebread$ or bee
bread$ or bee glue$).ti,ab.85. exp Disinfectant Agent/86. exp Anti-Infective Agent/87. exp Antivirus Agent/88. (disinfect$ or antisept$ or anti-sept$ or
antiviral$ or anti-viral$).ti,ab.89. ((neuroisch?emic or isch?emic or diabetic or
neuropathic) adj3 (foot or feet orulcer$)).ti,ab.
90. ((pedal or plantar or foot or feet or heel)adj3 (ulcer$ or septic or wound$)).ti,ab.
91. ((foot or feet) adj6 diabet$).ti,ab.92. deep foot infection$.ti,ab.93. exp Foot Ulcer/94. or/89-9395. Leg Ulcer/96. leg varicosis/97. ((crural or leg) adj5 ulcer$).ti,ab.98. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).ti,ab.99. ((venous or stasis or leg) adj5 wound$).ti.
100. ((lower extremit$ or lower limb$) adj5 (ulcer$or wound$)).ti,ab.
101. or/95-100102. 94 or 101103. exp Penicillin Derivative/104. (penicillin$ or amdinocillin$ or amox#cillin$
or ampicillin$ or azlocillin$).ti,ab.105. (carbenicillin$ or carfecillin$ or cloxacillin$
or dicloxacillin$ or floxacillin$ orflucloxacillin$ or methicillin$ or mazlocillin$or nafcillin$ or oxacillin$ or penicillanicacid$).ti,ab.
106. (penicillic acid$ or phenoxymethylpenicillin$or piperacillin$ or pivampicillin$ orsulbencillin$ or talampicillin$ orsultamicillin$ or ticarcillin$ orticercillin$).ti,ab.
107. exp Cephalosporin Derivative/108. (cefaclor$ or cefadroxil$ or cefalexin$ or
cefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).ti,ab.
109. (cefradine$ or ceftazidime$ or ceftizoxime$or ceftriaxone$ or cefuroxime$).ti,ab.
110. (cefonicid$ or cefmenoxine$ orcefoperazone$ or cefotiam$ or cefsulodin$ orcephacetrile$ or cephalexin$ orcephaloglycin$ or cephaloridine orcephalosporanic acid$ or cephalothin$ orcephapirin$ or cephradine$).ti,ab.
111. exp Lactam/112. (beta lactam$ or aztreonam$ or cilastin$ or
imipenem$ or meropenem$ or sulbactam$ ortazobactam$).ti,ab.
113. (caprolactam$ or clavulan$ ormoxalactam$).ti,ab.
114. exp Aminoglycoside/115. (Aminoglycoside$ or anthracycline$ or
aclarubicin$ or daunorubicin$ or carubicin$or doxorubicin$ or epirubicin$ oridarubicin$ or nogalamycin$ or menogaril$or plicamycin$).ti,ab.
116. (gentamicin$ or neomycin$ or netilmicin$ ortobramycin$).ti,ab.
117. exp Macrolide/118. (amphotericin$ or antimycin$ or candicidin$
or roxithromycin$ or josamycin$ orleucomycin$ or kitasamycin$ orlucensomycin$ or maytansine$ ormepartricin$ or miocamycin$).ti,ab.
119. (natamycin$ or oleandomycin$ ortroleandomycin$ or oligomycin$ orrutamycin$ or sirolimus$ or tacrolimus$ ortylosin$ or propiolactone$ or spironolactone$or venturicidin$ or zearalenone$ orzeranol$).ti,ab.
120. (azithromycin$ or clarithromycin$ orerythromycin$ or spiramycin$).ti,ab.
121. exp Quinolone Derivative/122. (moxifloxacin$ or quinolone$ or
ciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).ti,ab.
123. (fleroxacin$ or enoxacin$ or norfloxacin$ orpefloxacin$ or nalidixic acid$ or nedocromil$or oxolinic acid$ or quinpirole$ orquipazine$ or saquinavir$).ti,ab.
124. exp Sulfonamide/125. exp Trimethoprim/126. (dmso or sulfoxide$ or sulphoxide$ or
sulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ orsulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).ti,ab.
127. (benzolamide$ or bumetanide$ orchloramine$ or chlorthalidone$ orclopamide$ or dichlorphenamide$ orethoxzolamide$ or indapamide$ ormafenide$ or mefruside$ or metolazone$ orprodenecid$ or sulfanilamide$ orsulphanilamide$ or furosemide$ orsulfacetamide$ or sulphacetamide$).ti,ab.
128. (sulfachlorpyridazine$ or sulfadimethoxine$or sulfadoxine$ or sulfaguanidine$ orsulfamerazine$ or sulfameter$ or
Health Technology Assessment 2006; Vol. 10: No. 12
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© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
sulfamethazine$ or sulfamethoxypyridazine$or sulphachlorpyridazine$ orsulphadimethoxine$ or sulphadoxine$ orsulphaguanidine$ or sulphamerazine$ orsulphameter$ or sulphamethazine$ orsulphamethoxypyridazine$).ti,ab.
129. (sulfamonomethoxine$ or sulfamoxole$ orsulfaphenazole$ or sulfapyridine$ orsulfaquinoxaline$ or sulfathiazole$ orsulfamethizole$ or sulfisomidine$ orsulfisoxazole$ or sulfasalazine$ orsumatriptan$ or xipamide$ or thioamide$ orthioacetamide$ or sulphamonomethoxine$or sulphamoxole$ or sulphaphenazole$ orsulphapyridine$ or sulphaquinoxaline$ orsulphathiazole$ or sulphamethizole$ orsulphisomidine$ or sulphisoxazole$ orsulphasalazine$).ti,ab.
130. exp Tetracycline Derivative/131. (tetracycline$ or demeclocycline$ or
doxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).ti,ab.
132. (chlortetracycline$ or methacycline$ orrolitetracycline$).ti,ab.
133. exp Chloramphenicol/134. (cloranfenicol$ or chloramphenicol$).ti,ab.135. (thiamphenicol$ or kloramfenikol$ or
levomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ or detreomycin$or ophthochlor$ or syntomycin$).ti,ab.
136. exp Clindamycin/137. (clindamycin$ or dalacin c or cleocin$ or
chlo?lincocin$).ti,ab.138. exp Metronidazole/139. (linezolid$ or trivazol$ or vagilen$ or clont$
or danizol$ or fagyl$ or ginefavir$ ormetrogel$ or metrodzhil$ or satric$ ortrichazol$ or trichopol$).ti,ab.
140. exp Fusidic Acid/141. (granulocyte colony stimulating factor or gcsf
or ozone).ti,ab.142. (fusidate$ adj (sodium or silver)).ti,ab.143. exp Antibiotic Agent/144. (antibiotic$ or antimicrobial$).ti,ab.145. (griseofulvin or synercid or dalfopristin or
quinupristin).ti,ab.146. or/103-145147. or/21-88148. (146 or 147) and 20 and 102
This identified 449 records.
MEDLINE (1966–2002/10 week 4) andPREMEDLINE (up to 5 November 2002)(searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. exp Acetic Acid/
2. (acetic acid$ or acetate$ or acetamide$ oracetoxyacetylaminofluorene$ orhydroxyacetylaminofluorene$ orallylisopropylacetamide$).ti,ab.
3. (idoacetamide$ or idoacetate$ or piracetam$or thioacetamide$ or gadolinium$ ortechnetium$ or dichoroacetate$ orfluoroacetate$ or iodoacetate$).ti,ab.
4. (foscarnet$ or thioglycolate$ or aceticanhydride$).ti,ab.
5. ((aminooxyacetic or edetic or egtazic oriodoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic ortrichloroacetic or trifluoroacetic) adjacid$).ti,ab.
6. exp ANTIFUNGAL AGENTS/7. (therapeutic fungicide$ or antifungal agent$
or antifungals).ti,ab.8. (benzoate$ or butenafine$ or chlorquinaldol$
or cyclosporine$ or dichlorophen$ orfluconazole$ or flucytosine$ or glycyrrhizicacid$ or hexetidine$ or itraconazole$ ormonensin$ or nifuratel$ orpentamidine$).ti,ab.
9. (co-amoxiclav$ or sodium benzoate$ orthimerosal$ or thiram$ or thymol$ ortolnaftate$ or tomatine$ or triacetin$ ortrimetrexate$).ti,ab.
10. (amoroldine$ or benzoic acid$ orclotrimazole$ or econazole$ or ketoconazole$or miconazole$ or nystatin$ or Salicylic acid$or sulconazole$ or terbinafine$ ortioconazole$ or undecenoate$).ti,ab.
11. (antiviral$ or anti viral$ oridoxuridine$).ti,ab.
12. (acetylcysteine$ or acyclovir$ or amantadine$or aphidicolin$ or aprotinin$ or brefeldin orbromodeoxyuridine$ or cytarabine$ ordeoxyglucose$ or dextran sulfate$).ti,ab.
13. (dideoxyadenosine$ or dideoxynucleoside$or dihematoporphyrin ether$ or ditiocarb$or filipin$ or floxuridine$ or ganciclovir$ orinosine pranobex or interferon alfa$ orinterferon type$ or interferon beta orinterferon gamma or interferons).ti,ab.
14. (methisazone$ or phosphonoacetic acid$ orpoly a-u or poly i-c or pyran copolymer$ orribavirin$ or rimantadine$ or streptovaricin$or tenuazonic acid$ or tilorone$ ortrifluridine$ or tunicamycin$ orvidarabine$).ti,ab.
15. exp BACITRACIN/16. exp Povidone-Iodine/17. (bacitracin$ or povidone iodine$ or
betaisodona$ or polyvinylpyrrolidone iodine$or betadine$ or disadine$ or isodine$ or pvp-i or pharmadine$).ti,ab.
Appendix 1
100
18. exp Cetrimonium Compounds/19. (cetyltrimethylammonium or cetrimide$ or
cetrimonium).ti,ab.20. exp Chlorine Compounds/21. (chlorate$ or cisplatin or hydrochloric acid$
or chloride$ or hypochlorous acid$ orhypochlorite$ or perchloric acid$ orruthenium red$).ti,ab.
22. exp "Eosine Yellowish-(YS)"/23. (eusol or phenoxyethanol$ or dextranomer$
or framycetin sulphate$ or mandelic acid$ ortetrabromofluorescein$ or eosin or eosine orchlortetracycline$ or chloroxylenolsolution$).ti,ab.
24. (edinburgh adj university adj solution adj2lime).ti,ab.
25. exp Framycetin/26. exp Mandelic Acids/27. (cyclandelate$ or vanilmandelic acid$).ti,ab.28. exp Hexachlorophene/29. hexachloroph#ne$.ti,ab.30. exp Triclosan/31. exp Polymyxin/32. (triclosan$ or polymyxin$ or
polynoxylin$).ti,ab.33. (silver adj2 dressing$).ti,ab.34. exp Gentian Violet/35. (gentian violet or crystal violet or methyl
violet or methylrosaniline chloride$ orhexamethylpararosanine chloride$).ti,ab.
36. exp Potassium Permanganate/37. (potassium permanganate$ or permanganic
acid$ or potassium salt$).ti,ab.38. exp Mupirocin/39. (mupirocin$ or pseudomonic acid$ or
bactroban$).ti,ab.40. exp Neomycin/41. (neomycin$ or fradiomycin$ or
neamin$).ti,ab.42. exp Benzoyl Peroxide/43. (benzyol peroxide$ or benzyol superoxide$
or diphenylglyoxal superoxide$ orpanoxyl$).ti,ab.
44. exp Hydrogen Peroxide/45. (hydrogen peroxide$ or hydroperoxide$ or
oxydol$ or perhydrol$ or superoxol$ ordiphenylglyoxal superoxide$ orpanoxyl$).ti,ab.
46. (fucithalmic$ or fusidate$ or fusidin$ orstanicide$).ti,ab.
47. (liposome$ adj hydrogel$).ti,ab.48. (fusidic acid$ or inadine$ or betadine$).ti,ab.49. exp Chlorhexidine/50. (cadexomer iodine$ or chlorhexidine$ or
novalsan$ or sebidin$ or tubulicid$).ti,ab.51. exp Larva/52. (maggot$ or larva or larvae or larval).ti,ab.
53. exp Complementary Therapies/54. (plant extract$ or aromatherap$ or marigold
extract$ or calendula officinalis or tagetespatula or rubia cordifolia or manjishtha orwithania somnifera or ashvagandha).ti,ab.
55. exp Plant Extracts/56. exp Plants, Medicinal/57. (phytotherapy or cascara$ or curare$ or
chinese herb$ or guaiac$ or ipecac$ orpodophyll$ or psyllium$ or senna extract$ ortragacanth$ or turpentine$).ti,ab.
58. exp oils, volatile/ or exp plant oils/59. exp Sucrose/60. exp HONEY/61. (essential oil$ or plant oil$ or tea tree or
lavender or chamomile or camomile orrosemary).ti,ab.
62. (sucrose or sugar paste$ or granulatedsugar).ti,ab.
63. exp Propolis/64. (propolis or honey or beebread$ or bee
bread$ or bee glue$).ti,ab.65. exp Disinfectants/66. exp Anti-Infective Agents, Local/67. exp Antiviral Agents/68. (disinfect$ or antisept$ or anti-sept$ or
antiviral$ or anti-viral$).ti,ab.69. ((neuroisch?emic or isch?emic or diabetic or
neuropathic) adj3 (foot or feet orulcer$)).ti,ab.
70. ((pedal or plantar or foot or feet or heel)adj3 (ulcer$ or septic or wound$)).ti,ab.
71. ((foot or feet) adj6 diabet$).ti,ab.72. deep foot infection$.ti,ab.73. exp Foot Ulcer/74. or/69-7375. Leg Ulcer/76. Varicose Ulcer/77. ((crural or leg) adj5 ulcer$).ti,ab.78. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).ti,ab.79. ((venous or stasis or leg) adj5 wound$).ti,ab80. ((lower extremit$ or lower limb$) adj5 (ulcer$
or wound$)).ti,ab.81. or/75-8082. 74 or 8183. random allocation/ or randomized controlled
trials/84. exp clinical trials/85. single-blind method/ or double-blind
method/ or publication bias/ or meta-analysis/86. comparative study/87. (controlled clinical trial or randomized
controlled trial or review).pt.88. meta-analysis.pt.89. random$.ti,ab.90. ((clinical adj trial$) or control$).ti,ab.
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91. ((standard adj treatment$) or compar$ or(single adj blind$) or (double adjblind$)).ti,ab.
92. (placebo$ or (systematic adj review$)).ti,ab.93. or/83-9294. 82 and 9395. exp Penicillins/96. (penicillin$ or amdinocillin$ or amox#cillin$
or ampicillin$ or azlocillin$).ti,ab.97. (carbenicillin$ or carfecillin$ or cloxacillin$ or
dicloxacillin$ or floxacillin$ or flucloxacillin$or methicillin$ or mazlocillin$ or nafcillin$ oroxacillin$ or penicillanic acid$).ti,ab.
98. (penicillic acid$ or phenoxymethylpenicillin$or piperacillin$ or pivampicillin$ orsulbencillin$ or talampicillin$ orsultamicillin$ or ticarcillin$ orticercillin$).ti,ab.
99. exp Cephalosporins/100. (cefaclor$ or cefadroxil$ or cefalexin$ or
cefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).ti,ab.
101. (cefradine$ or ceftazidime$ or ceftizoxime$or ceftriaxone$ or cefuroxime$).ti,ab.
102. (cefonicid$ or cefmenoxine$ orcefoperazone$ or cefotiam$ or cefsulodin$ orcephacetrile$ or cephalexin$ orcephaloglycin$ or cephaloridine orcephalosporanic acid$ or cephalothin$ orcephapirin$ or cephradine$).ti,ab.
103. exp Lactams/104. (beta lactam$ or aztreonam$ or cilastin$ or
imipenem$ or meropenem$ or sulbactam$ ortazobactam$).ti,ab.
105. (caprolactam$ or clavulan$ ormoxalactam$).ti,ab.
106. exp Aminoglycosides/107. (Aminoglycoside$ or anthracycline$ or
aclarubicin$ or daunorubicin$ or carubicin$or doxorubicin$ or epirubicin$ oridarubicin$ or nogalamycin$ or menogaril$or plicamycin$).ti,ab.
108. (gentamicin$ or neomycin$ or netilmicin$ ortobramycin$).ti,ab.
109. exp Macrolides/110. (amphotericin$ or antimycin$ or candicidin$
or roxithromycin$ or josamycin$ orleucomycin$ or kitasamycin$ orlucensomycin$ or maytansine$ ormepartricin$ or miocamycin$).ti,ab.
111. (natamycin$ or oleandomycin$ ortroleandomycin$ or oligomycin$ orrutamycin$ or sirolimus$ or tacrolimus$ ortylosin$ or propiolactone$ or spironolactone$or venturicidin$ or zearalenone$ orzeranol$).ti,ab.
112. (azithromycin$ or clarithromycin$ orerythromycin$ or spiramycin$).ti,ab.
113. exp Quinolones/114. (moxifloxacin$ or quinolone$ or
ciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).ti,ab.
115. (fleroxacin$ or enoxacin$ or norfloxacin$ orpefloxacin$ or nalidixic acid$ or nedocromil$or oxolinic acid$ or quinpirole$ orquipazine$ or saquinavir$).ti,ab.
116. exp Sulfonamides/117. exp Trimethoprim/118. (dmso or sulfoxide$ or sulphoxide$ or
sulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ orsulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).ti,ab.
119. (benzolamide$ or bumetanide$ orchloramine$ or chlorthalidone$ orclopamide$ or dichlorphenamide$ orethoxzolamide$ or indapamide$ ormafenide$ or mefruside$ or metolazone$ orprodenecid$ or sulfanilamide$ orsulphanilamide$ or furosemide$ orsulfacetamide$ or sulphacetamide$).ti,ab.
120. (sulfachlorpyridazine$ or sulfadimethoxine$or sulfadoxine$ or sulfaguanidine$ orsulfamerazine$ or sulfameter$ orsulfamethazine$ or sulfamethoxypyridazine$or sulphachlorpyridazine$ orsulphadimethoxine$ or sulphadoxine$ orsulphaguanidine$ or sulphamerazine$ orsulphameter$ or sulphamethazine$ orsulphamethoxypyridazine$).ti,ab.
121. (sulfamonomethoxine$ or sulfamoxole$ orsulfaphenazole$ or sulfapyridine$ orsulfaquinoxaline$ or sulfathiazole$ orsulfamethizole$ or sulfisomidine$ orsulfisoxazole$ or sulfasalazine$ orsumatriptan$ or xipamide$ or thioamide$ orthioacetamide$ or sulphamonomethoxine$or sulphamoxole$ or sulphaphenazole$ orsulphapyridine$ or sulphaquinoxaline$ orsulphathiazole$ or sulphamethizole$ orsulphisomidine$ or sulphisoxazole$ orsulphasalazine$).ti,ab.
122. exp Tetracyclines/123. (tetracycline$ or demeclocycline$ or
doxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).ti,ab.
124. (chlortetracycline$ or methacycline$ orrolitetracycline$).ti,ab.
125. exp Chloramphenicol/126. (cloranfenicol$ or chloramphenicol$).ti,ab.
Appendix 1
102
127. (thiamphenicol$ or kloramfenikol$ orlevomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ ordetreomycin$ or ophthochlor$ orsyntomycin$).ti,ab.
128. exp Clindamycin/129. (clindamycin$ or dalacin c or cleocin$ or
chlo?lincocin$).ti,ab.130. exp Metronidazole/131. (linezolid$ or trivazol$ or vagilen$ or clont$
or danizol$ or fagyl$ or ginefavir$ ormetrogel$ or metrodzhil$ or satric$ ortrichazol$ or trichopol$).ti,ab.
132. exp Fusidic Acid/133. (granulocyte colony stimulating factor or gcsf
or ozone).ti,ab.134. (fusidate$ adj (sodium or silver)).ti,ab.135. exp Antibiotics/136. (antibiotic$ or antimicrobial$).ti,ab.137. (griseofulvin or synercid or dalfopristin or
quinupristin).ti,ab.138. or/95-137139. or/1-68140. 94 and (138 or 139)
This identified 590 records.
Controlled-Trials.com (searched 27 November2002)(venous or stasis or varicose or leg or legs or footor feet or heel or pedal or plantar) and (ulcers orulceration or ulcerations or ulcer or wound orwounds or infection or infections or septic ordiabetic or diabetes)
This identified 89 records
Cost-effectiveness searchstrategiesCRD internal administration databases NHS Economic Evaluation Database (NHS EED)(searched 13 November 2002)The NHS Economic Evaluation Database (NHSEED) was searched via the NHS CRD’s internaladministration databases. This provides a moreup-to-date version of the database than theCochrane Library or the Internet and includesadditional records to those in the public database.The search strategy used was as follows:
1. (neuroisch?emic or isch?emic or diabetic orneuropathic)(3W) (foot or feet or ulcer$)
2. (pedal or plantar or foot or feet orheel)(3w)(ulcer$ or septic or wound$)
3. (foot or feet)(6w)diabet$
4. deep foot infection$ 5. 1 or 2 or 3 or 4
This identified 172 records.
CD-ROM resourcesEconLit (1969–2002 October) (searched: 12November 2002 on ARC SilverPlatter)No economic filter was necessary for this database.1. (neuroisch?emic or isch?emic or diabetic or
neuropathic) near3 (foot or feet or ulcer*) 2. (pedal or plantar or foot or feet or heel) near3
(ulcer* or septic or wound*) 3. (foot or feet) near6 diabet* 4. deep foot infection* 5. 1 or 2 or 3 or 4
This identified three records.
Health Economic Evaluation Database (HEED)(Issue: November 2002) (searched: 13 November2002 on stand-alone CD-ROM)(neuroischemic or ischemic or neuroischaemic orischaemic or diabetic or neuropathic) and (foot orfeet or ulcer*) OR(pedal or plantar or foot or feet or heel) and(ulcer* or septic or wound*) OR(foot or feet) and diabet* OR'deep foot infection' within 2 OR 'deep foot infections' within 2
This identified 77 records.
Internet databases(Allied and Complementary Medicine) AMED(1985–2002 November) (searched: 12 November2002 on OvidWeb Gateway athttp://gateway.ovid.com/athens)
1. ((neuroisch?emi$ or isch?emi$ or neuropathic or diabetic) adj3 (foot or feet orulcer$)).ti,ab.
2. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).ti,ab.
3. ((foot or feet) adj6 diabet$).ti,ab.4. deep foot infection$.ti,ab.5. exp Foot Ulcer/6. or/1-57. (cost or costs or costing or costed or
costly).ti,ab.8. (economic$ or pharmacoeconomic$ or price
or prices or pricing).ti,ab.9. decision making/
10. decision analysis.ti,ab.11. decision model$.ti,ab.12. mathematical model$.ti,ab.13. statistical model$.ti,ab.14. markov.ti,ab.
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15. economics/ or "costs and cost analysis"/ or costbenefit analysis/ or cost of illness/
16. or/7-1517. 6 and 16
This identified 15 records.
British Nursing Index (BNI) (1994–2002 August)(searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. ((neuroisch?emi$ or isch?emi$ or neuropathicor diabetic) adj3 (foot or feet or ulcer$)).mp.
2. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).mp.
3. ((foot or feet) adj6 diabet$).mp.4. deep foot infection$.mp.5. exp Foot Ulcer/6. or/1-57. exp health economics/8. (cost or costs or costed or costly or
costing).mp.9. (economic$ or pharmacoeconomic$ or price$
or pricing).mp.10. exp decision making process/11. markov.mp.12. decision analysis.mp.13. decision model$.mp.14. mathematical model$.mp.15. statistical model$.mp.16. or/7-1517. 6 and 16
This identified 23 records.
CINAHL (1982–2002 October, week 4)(searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. exp "Costs and Cost Analysis"/2. economics.sh.3. exp "costs and cost analysis"/4. economic aspects of illness.sh.5. economics, pharmaceutical.sh.6. economic value of life.sh.7. exp "fees and charges"/8. budgets.sh.9. (cost or costs or costed or costly or
costing).ab,ti,hw.10. (economic$ or pharmacoeconomic$ or price$
or pricing).ab,ti,hw.11. or/1-1012. markov.ti,ab.13. Decision Making, Clinical/14. decision analysis.ti,ab.15. decision model$.ti,ab.16. mathematical model$.ti,ab.17. Models, Statistical/18. or/12-17
19. ((neuroisch?emi$ or isch?emi$ or neuropathicor diabetic) adj3 (foot or feet or ulcer$)).ti,ab.
20. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).ti,ab.
21. ((foot or feet) adj6 diabet$).ti,ab.22. deep foot infection$.ti,ab.23. exp Foot Ulcer/24. or/19-2325. 11 or 1826. 24 and 25
This identified 85 records.
EMBASE (1980–2002 week 44) (searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. markov.ti,ab,hw.2. decision analysis.ti,ab.3. decision model$.ti,ab.4. mathematical model$.ti,ab.5. exp Medical Decision Making/6. mathematical model/ or statistical model/ or
stochastic model/7. or/1-68. exp health economics/9. cost/
10. exp health care cost/11. exp economic evaluation/12. (cost or costs or costing or costed or
costly).ti,ab.13. (economic$ or pharmacoeconomic$ or price
or prices or pricing).ti,ab.14. or/8-1315. exp animal/16. exp human/17. nonhuman/18. 15 not (15 and 16)19. 17 not (17 and 16)20. 14 not (18 or 19)21. ((neuroisch?emi$ or isch?emi$ or neuropathic
or diabetic) adj3 (foot or feet or ulcer$)).ti,ab.22. ((pedal or plantar or foot or feet or heel) adj3
(ulcer$ or septic or wound$)).ti,ab.23. ((foot or feet) adj6 diabet$).ti,ab.24. deep foot infection$.ti,ab.25. exp Foot Ulcer/26. or/21-2527. 7 or 2028. 26 and 27
This identified 250 records.
MEDLINE (1966–2002 October. week 5) andPREMEDLINE (up to 11 November 2002)(searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. economics/
Appendix 1
104
2. exp "costs and cost analysis"/3. economic value of life/4. exp economics,hospital/5. economics, medical/6. economics, nursing/7. economics, pharmaceutical/8. (econom$ or cost or costs or costly or costing
or price or prices or pricing orpharmacoeconomic$).ti,ab.
9. (expenditure$ not energy).ti,ab.10. (value adj2 money).ti,ab.11. (budget$ or (quality adj adjusted) or
qaly$).ti,ab.12. or/1-1113. ((metabolic adj cost$) or (energy adj cost$) or
(oxygen adj cost$)).ti,ab.14. letter.pt.15. editorial.pt.16. historical article.pt.17. animal/18. human/19. 17 not (17 and 18)20. (or/13-16) or 1921. 12 not 2022. exp decision support techniques/23. markov.ti,ab,hw.24. exp models, economic/25. decision analysis.ti,ab.26. decision model$.ti,ab.27. mathematical model$.ti,ab.28. or/22-2729. ((neuroisch?emi$ or isch?emi$ or neuropathic
or diabetic) adj3 (foot or feet or ulcer$)).ti,ab.30. ((pedal or plantar or foot or feet or heel) adj3
(ulcer$ or septic or wound$)).ti,ab.31. ((foot or feet) adj6 diabet$).ti,ab.32. deep foot infection$.ti,ab.33. exp Foot Ulcer/34. or/29-3335. 21 or 2836. 34 and 35
This identified 261 records.
Diagnostic searchesInternet databases(Allied And Complementary Medicine) AMED(1985–2002 November) (searched: 23 November2002 on OvidWeb Gateway athttp://gateway.ovid.com/athens)
1. (specificit$ or sensitivit$).ti,ab.2. (false negative$ or false positive$ or true
negative$ or true positive$).ti,ab.3. (positive rate$ or negative rate$).ti,ab.4. screening.ti,ab.
5. accuracy.ti,ab.6. reference value$.ti,ab.7. likelihood ratio$.ti,ab.8. (sroc or srocs or roc or rocs).ti,ab.9. receiver operat$ curve$.ti,ab.
10. receiver operat$ character$.ti,ab.11. diagnosis/ or diagnosis differential/ or
diagnostic errors/ or exp "diagnostictechniques and procedures"/
12. (diagnos$ adj3 (efficac$ or efficien$ oreffectiv$ or accura$ or correct$ or reliable orreliability)).ti,ab.
13. (diagnos$ adj3 (error$ or mistake$ orinaccura$ or incorrect or unreliable)).ti,ab.
14. diagnostic yield$.mp. or misdiagnos$.ti,ab.[mp=abstract, heading words, title]
15. (reproductivity or logistical regression).mp. orlogistical model$.ti,ab. [mp=abstract, headingwords, title]
16. (ability adj2 predict$).ti,ab.17. ((test or tests or testing or standard) adj3
(reliable or reliability or performance)).ti,ab.18. (predictive adj (value$ or standard$ or model$
or factor$)).ti,ab.19. ((reference or index) adj (test or tests or
testing)).ti,ab.20. ((clinical or patient) adj (exam$ or asses$ or
recognition or identif$ or inspection)).ti,ab.21. (specimen$ or swab$ or smear$).ti,ab.22. ((tissue or fluid$ or wound$ or cell or cells)
adj2 sample$).ti,ab.23. (sausage toe or dactylitis).ti,ab.24. (puncture or biopsy or biopsies or needle
aspiration$ or (bone adj2 prob$)).ti,ab.25. exp Specimen Handling/26. exp Microbiology/27. (excis$ or curettage or curetage or curet or
curette or aspirate or yeast or gram stain orgas liquid chromatography).ti,ab.
28. Irrigation/ or exp chromatography/ or yeasts/29. (irrigation or lavage).ti,ab.30. (fluorescen$ adj2 (analys$ or imag$ or
antibod$ or microscopy or probe or probes ortag or tags or marker$ or technique$)).ti,ab.
31. Dyes/32. (fluorogenic substrate$ or fluorochrome$ or
immunofluorescence or ryb or red or yellow orblack).ti,ab.
33. (colo?r$ adj2 (asess$ or code or codes orcoding$ or concept or concepts or estimat$ orclassifi$ or system$ or three)).ti,ab.
34. pseudomonas fluorescen$.ti,ab.35. ((Fluorescen$ or vital) adj5 dye$).ti,ab.36. (electronic adj (sensor$ or nose)).ti,ab.37. (e-nose or e-sensor$ or x-ray$ or mri or nmror
(gallium adj2 citrate)).ti,ab.38. exp diagnosic imaging/
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39. (imaging or scanning or scan or (computedand tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or(magnetic and resonance) or (nuclear andmagnetic)).ti,ab.
40. (tissue adj (culture$ or diagnos$ orantigen$)).ti,ab.
41. microscopy/42. (aerob$ or anaerob$).ti,ab.43. (biological or mycobacter$ or coloni$ or
contaminat$ or bacter$ or antimicrob$ or anti-microb$ or microb$ or osteomyeliti$ orcelluliti$ or infect$).ti,ab.
44. exp BACTERIA/45. (gram adj (negative or positive)).ti,ab.46. (plate culture$ or colony count$).ti,ab.47. (pus or cicatrix or exudate or suppuration or
oozing or discharge or drainage or odo?r ormalodo?r or erythema or redness or warmthor tender$ or pain$ or induration orfluctuance or swelling or swollen or warm orheat).ti,ab.
48. (signs and symptoms).mp.49. abscess/ or Cicatrix/ or Drainage/ or Erythema/
or smell/ or inflammation/50. pain/ or exp neuralgia/ or pain intractable/51. (public health laboratory or phl).ti,ab.52. (molecular adj (screen$ or diagnos$)).ti,ab.53. (polymerase chain reaction adj3
screening).ti,ab.54. exp polymerase chain reaction/55. (primed adj2 situ label$).ti,ab.56. random amplified polymorphic dna.ti,ab.57. reverse transcriptase pcr.ti,ab.58. (pcr or ctpcr or mlst).ti,ab.59. multi locus sequence typing.ti,ab.60. 16 s rdna.ti,ab.61. (fluoresce$ adj4 diagnos$).ti,ab.62. ((near patient or site or onsite or rapid) adj
(test$ or system$ or assessment$ or diagnos$or analysis)).ti,ab.
63. (point adj2 care adj (test$ or system$ orassessment$ or diagnos$ or analysis)).ti,ab.
64. ((neuroisch?emi$ or isch?emi$ or diabetic orneuropathic) adj3 (foot or feet or ulcer$)).ti,ab.
65. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).ti,ab.
66. ((foot or feet) adj6 diabet$).ti,ab.67. deep foot infection$.ti,ab.68. exp Foot Ulcer/69. or/64-6870. Leg Ulcer/71. Varicose Ulcer/72. ((crural or leg) adj5 ulcer$).ti,ab.73. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).ti,ab.
74. ((venous or stasis or leg) adj5 wound$).ti.75. ((lower extremit$ or lower limb$) adj5 (ulcer$
or wound$)).ti,ab.76. or/70-7577. 69 or 7678. or/1-1979. or/20-6380. 77 and 78 and 79
This identified 44 records.
British Nursing Index (BNI) (1994–2002September) (searched: 23 November 2002 onOvidWeb Gateway athttp://gateway.ovid.com/athens)
1. (specificit$ or sensitivit$).mp.2. (false negative$ or false positive$ or true
negative$ or true positive$).mp.3. (positive rate$ or negative rate$).mp.4. screening.mp.5. accuracy.mp.6. reference value$.mp.7. likelihood ratio$.mp.8. (sroc or srocs or roc or rocs).mp.9. receiver operat$ curve$.mp.
10. receiver operat$ character$.mp.11. exp diagnosis/12. (diagnos$ or misdiagnos$).mp.13. (reproductivity or logistical regression or
logistical model$).mp.14. (ability adj2 predict$).mp.15. ((test or tests or testing or standard) adj3
(reliable or reliability or performance)).mp.16. (predictive adj (value$ or standard$ or model$
or factor$)).mp.17. ((reference or index) adj (test or tests or
testing)).mp.18. ((clinical or patient) adj (exam$ or asses$ or
recognition or identif$ or inspection)).mp.19. (specimen$ or swab$ or smear$).mp.20. ((tissue or fluid$ or wound$ or cell or cells)
adj2 sample$).mp.21. (sausage toe or dactylitis).mp.22. (puncture or biopsy or biopsies or needle
aspiration$ or (bone adj2 prob$)).mp.23. exp Microbiology/24. (excis$ or curettage or curetage or curet or
curette or aspirate or yeast or gram stain orgas liquid chromatography).mp.
25. (irrigation or lavage).mp.26. (fluorescen$ adj2 (analys$ or imag$ or
antibod$ or microscopy or probe or probes ortag or tags or marker$ or technique$)).mp.
27. (fluorogenic substrate$ or fluorochrome$ orimmunofluorescence or ryb or red or yellow orblack).mp.
28. (colo?r$ adj2 (asess$ or code or codes or
Appendix 1
106
coding$ or concept or concepts or estimat$ orclassifi$ or system$ or three)).mp.
29. pseudomonas fluorescen$.mp.30. ((Fluorescen$ or vital) adj5 dye$).mp.31. (electronic adj (sensor$ or nose)).mp.32. (e-nose or e-sensor$ or x-ray$ or mri or nmr
or (gallium adj2 citrate)).mp.33. exp imaging/34. (imaging or scanning or scan or (computed
and tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or(magnetic and resonance) or (nuclear andmagnetic)).mp.
35. (tissue adj (culture$ or diagnos$ orantigen$)).mp.
36. (aerob$ or anaerob$).mp.37. (biological or mycobacter$ or coloni$ or
contaminat$ or bacter$ or antimicrob$ or anti-microb$ or microb$ or osteomyeliti$ orcelluliti$ or infect$).mp.
38. exp BACTERIA/39. (gram adj (negative or positive)).mp.40. (plate culture$ or colony count$).mp.41. (pus or cicatrix or exudate or suppuration or
oozing or discharge or drainage or odo?r ormalodo?r or erythema or redness or warmthor tender$ or pain$ or induration orfluctuance or swelling or swollen or warm orheat).mp.
42. (signs and symptoms).mp.43. (public health laboratory or phl).mp.44. (molecular adj (screen$ or diagnos$)).mp.45. (polymerase chain reaction adj3
screening).mp.46. (primed adj2 situ label$).mp.47. random amplified polymorphic dna.mp.48. reverse transcriptase pcr.mp.49. (pcr or ctpcr or mlst).mp.50. multi locus sequence typing.mp.51. 16 s rdna.mp.52. (fluoresce$ adj4 diagnos$).mp.53. ((near patient or site or onsite or rapid) adj
(test$ or system$ or assessment$ or diagnos$or analysis)).mp.
54. (point adj2 care adj (test$ or system$ orassessment$ or diagnos$ or analysis)).mp.
55. ((neuroisch?emi$ or isch?emi$ or diabetic orneuropathic) adj3 (foot or feet or ulcer$)).mp.
56. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).mp.
57. ((foot or feet) adj6 diabet$).mp.58. deep foot infection$.mp.59. Leg Ulcer/60. ((crural or leg) adj5 ulcer$).mp.61. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).mp.
62. ((venous or stasis or leg) adj5 wound$).mp.63. ((lower extremit$ or lower limb$) adj5 (ulcer$
or wound$)).mp.64. or/55-6365. or/1-1766. or/18-5467. 64 and 65 and 66
This identified 54 records.
CINAHL (1982–2002 week 4) (searched: 23November 2002 on OvidWeb Gateway athttp://gateway.ovid.com/athens)
1. exp "Sensitivity and Specificity"/2. False Positive Reactions/3. False Negative Reactions/4. (specificit$ or sensitivit$).ti,ab.5. (false negative$ or false positive$ or true
negative$ or true positive$).ti,ab.6. (positive rate$ or negative rate$).ti,ab.7. screening.ti,ab.8. accuracy.ti,ab.9. reference value$.ti,ab.
10. likelihood ratio$.ti,ab.11. (sroc or srocs or roc or rocs).ti,ab.12. receiver operat$ curve$.ti,ab.13. receiver operat$ character$.ti,ab.14. exp Logistic Regression/15. diagnosis/ or diagnosis, delayed/ or diagnosis,
differential/ or diagnosis, laboratory/ ordiagnostic errors/ or diagnostic tests, routine/or predictive value of tests/
16. (diagnos$ adj3 (efficac$ or efficien$ oreffectiv$ or accura$ or correct$ or reliable orreliability)).ti,ab.
17. (diagnos$ adj3 (error$ or mistake$ orinaccura$ or incorrect or unreliable)).ti,ab.
18. diagnostic yield$.mp. or misdiagnos$.ti,ab.[mp=title, cinahl subject heading, abstract,instrumentation]
19. (reproductivity or logistical regression).mp. orlogistical model$.ti,ab. [mp=title, cinahlsubject heading, abstract, instrumentation]
20. (ability adj2 predict$).ti,ab.21. ((test or tests or testing or standard) adj3
(reliable or reliability or performance)).ti,ab.22. (predictive adj (value$ or standard$ or model$
or factor$)).ti,ab.23. ((reference or index) adj (test or tests or
testing)).ti,ab.24. ((clinical or patient) adj (exam$ or asses$
or recognition or identif$ or inspection)).ti,ab.
25. (specimen$ or swab$ or smear$).ti,ab.26. ((tissue or fluid$ or wound$ or cell or cells)
adj2 sample$).ti,ab.27. (sausage toe or dactylitis).ti,ab.
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28. (puncture or biopsy or biopsies or needleaspiration$ or (bone adj2 prob$)).ti,ab.
29. exp Specimen Handling/30. exp Biopsy/31. exp Microbiological Techniques/32. Curettage/33. (excis$ or curettage or curetage or curet or
curette or aspirate or yeast or gram stain orgas liquid chromatography).ti,ab.
34. exp Irrigation/ or exp chromatography/ oryeasts/
35. (irrigation or lavage).ti,ab.36. (fluorescen$ adj2 (analys$ or imag$ or
antibod$ or microscopy or probe or probes ortag or tags or marker$ or technique$)).ti,ab.
37. exp Fluorescent Antibody Technique/38. exp Fluorescent Dyes/39. (fluorogenic substrate$ or fluorochrome$ or
immunofluorescence or ryb or red or yellow orblack).ti,ab.
40. (colo?r$ adj2 (asess$ or code or codes orcoding$ or concept or concepts or estimat$ orclassifi$ or system$ or three)).ti,ab.
41. pseudomonas fluorescen$.ti,ab.42. ((Fluorescen$ or vital) adj5 dye$).ti,ab.43. (electronic adj (sensor$ or nose)).ti,ab.44. (e-nose or e-sensor$ or x-ray$ or mri or nmr
or (gallium adj2 citrate)).ti,ab.45. exp diagnostic imaging/46. (imaging or scanning or scan or (computed
and tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or(magnetic and resonance) or (nuclear andmagnetic)).ti,ab.
47. (tissue adj (culture$ or diagnos$ orantigen$)).ti,ab.
48. exp Tissue Culture/ or exp microscopy/49. (aerob$ or anaerob$).ti,ab.50. (biological or mycobacter$ or coloni$ or
contaminat$ or bacter$ or antimicrob$ or anti-microb$ or microb$ or osteomyeliti$ orcelluliti$ or infect$).ti,ab.
51. exp BACTERIA/52. (gram adj (negative or positive)).ti,ab.53. (plate culture$ or colony count$).ti,ab.54. (pus or cicatrix or exudate or suppuration or
oozing or discharge or drainage or odo?r ormalodo?r or erythema or redness or warmthor tender$ or pain$ or induration orfluctuance or swelling or swollen or warm orheat).ti,ab.
55. (signs and symptoms).mp.56. abscess/ or cellulitis/ or exp Cicatrix/ or
Drainage/ or exp Erythema/ or Odors/57. pain/ or neuralgia/ or "exudates and
transudates"/
58. (public health laboratory or phl).ti,ab.59. (molecular adj (screen$ or diagnos$)).ti,ab.60. (polymerase chain reaction adj3
screening).ti,ab.61. exp polymerase chain reaction/62. (primed adj2 situ label$).ti,ab.63. random amplified polymorphic dna.ti,ab.64. reverse transcriptase pcr.ti,ab.65. (pcr or ctpcr or mlst).ti,ab.66. multi locus sequence typing.ti,ab.67. 16 s rdna.ti,ab.68. (fluoresce$ adj4 diagnos$).ti,ab.69. ((near patient or site or onsite or rapid) adj
(test$ or system$ or assessment$ or diagnos$or analysis)).ti,ab.
70. (point adj2 care adj (test$ or system$ orassessment$ or diagnos$ or analysis)).ti,ab.
71. ((neuroisch?emi$ or isch?emi$ or diabetic orneuropathic) adj3 (foot or feet or ulcer$)).ti,ab.
72. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).ti,ab.
73. ((foot or feet) adj6 diabet$).ti,ab.74. deep foot infection$.ti,ab.75. exp Foot Ulcer/76. or/71-7577. Leg Ulcer/78. Varicose Ulcer/79. ((crural or leg) adj5 ulcer$).ti,ab.80. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).ti,ab.81. ((venous or stasis or leg) adj5 wound$).ti.82. ((lower extremit$ or lower limb$) adj5 (ulcer$
or wound$)).ti,ab.83. or/77-8284. 76 or 8385. or/1-2386. or/24-7087. 84 and 85 and 86
This identified 68 records.
EMBASE (1980–2002 week 46) (searched: 24November 2002 on OvidWeb Gateway athttp://gateway.ovid.com/athens)
1. "Sensitivity and Specificity"/2. (specificit$ or sensitivit$).ti,ab.3. (false negative$ or false positive$ or true
negative$ or true positive$).ti,ab.4. (positive rate$ or negative rate$).ti,ab.5. screening.ti,ab.6. accuracy.ti,ab.7. reference value$.ti,ab.8. likelihood ratio$.ti,ab.9. (sroc or srocs or roc or rocs).ti,ab.
10. receiver operat$ curve$.ti,ab.11. receiver operat$ character$.ti,ab.12. receiver operating characteristic/ or roc curve/
Appendix 1
108
13. logistic regression analysis/14. diagnos$.ti,ab,hw.15. exp diagnosis/16. misdiagnos$.ti,ab.17. (reproductivity or logistical regression).mp. or
logistical model$.ti,ab. [mp=abstract, headingwords, title]
18. (ability adj2 predict$).ti,ab.19. ((test or tests or testing or standard) adj3
(reliable or reliability or performance)).ti,ab.20. (predictive adj (value$ or standard$ or model$
or factor$)).ti,ab.21. ((reference or index) adj (test or tests or
testing)).ti,ab.22. ((clinical or patient) adj (exam$ or asses$ or
recognition or identif$ or inspection)).ti,ab.23. (specimen$ or swab$ or smear$).ti,ab.24. ((tissue or fluid$ or wound$ or cell or cells)
adj2 sample$).ti,ab.25. (sausage toe or dactylitis).ti,ab.26. (puncture or biopsy or biopsies or needle
aspiration$ or (bone adj2 prob$)).ti,ab.27. biopsy/ or bone biopsy/ or exp biopsy
technique/28. exp microbiological examination/ or exp
"microbiological phenomena and functions"/29. Curettage/30. (excis$ or curettage or curetage or curet or
curette or aspirate or yeast or gram stain orgas liquid chromatography).ti,ab.
31. wound irrigation/ or gas liquidchromatography/ or yeast/
32. (irrigation or lavage).ti,ab.33. (fluorescen$ adj2 (analys$ or imag$ or
antibod$ or microscopy or probe or probes ortag or tags or marker$ or technique$)).ti,ab.
34. Fluorescent Antibody Technique/35. exp Fluorescent Dye/36. (fluorogenic substrate$ or fluorochrome$ or
immunofluorescence or ryb or red or yellow orblack).ti,ab.
37. (colo?r$ adj2 (asess$ or code or codes orcoding$ or concept or concepts or estimat$ orclassifi$ or system$ or three)).ti,ab.
38. Pseudomonas fluorescens/39. pseudomonas fluorescen$.ti,ab.40. ((Fluorescen$ or vital) adj5 dye$).ti,ab.41. (electronic adj (sensor$ or nose)).ti,ab.42. (e-nose or e-sensor$ or x-ray$ or mri or nmr
or (gallium adj2 citrate)).ti,ab.43. tomography/ or exp computer assisted
tomography/ or nuclear magnetic resonanceimaging/ or exp X-Ray/
44. (imaging or scanning or scan or (computedand tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or
(magnetic and resonance) or (nuclear andmagnetic)).ti,ab.
45. (tissue adj (culture$ or diagnos$ orantigen$)).ti,ab.
46. exp Tissue Culture/ or exp microscopy/47. (aerob$ or anaerob$).ti,ab.48. (biological or mycobacter$ or coloni$ or
contaminat$ or bacter$ or antimicrob$ or anti-microb$ or microb$ or osteomyeliti$ orcelluliti$ or infect$).ti,ab.
49. exp BACTERIA/50. (gram adj (negative or positive)).ti,ab.51. (plate culture$ or colony count$).ti,ab.52. (pus or cicatrix or exudate or suppuration or
oozing or discharge or drainage or odo?r ormalodo?r or erythema or redness or warmthor tender$ or pain$ or induration orfluctuance or swelling or swollen or warm orheat).ti,ab.
53. (signs and symptoms).mp.54. abscess/ or cellulitis/ or abscess drainage/ or
wound drainage/ or exp Erythema/ or Odor/55. pain/ or exp bone pain/ or exp leg pain/ or
exp neuralgia/ or exp exudate/ or cyst fluid/56. (public health laboratory or phl).ti,ab.57. (molecular adj (screen$ or diagnos$)).ti,ab.58. (polymerase chain reaction adj3
screening).ti,ab.59. exp polymerase chain reaction/60. (primed adj2 situ label$).ti,ab.61. random amplified polymorphic dna.ti,ab.62. reverse transcriptase pcr.ti,ab.63. (pcr or ctpcr or mlst).ti,ab.64. multi locus sequence typing.ti,ab.65. 16 s rdna.ti,ab.66. (fluoresce$ adj4 diagnos$).ti,ab.67. ((near patient or site or onsite or rapid) adj
(test$ or system$ or assessment$ or diagnos$or analysis)).ti,ab.
68. (point adj2 care adj (test$ or system$ orassessment$ or diagnos$ or analysis)).ti,ab.
69. ((neuroisch?emi$ or isch?emi$ or diabetic orneuropathic) adj3 (foot or feet or ulcer$)).ti,ab.
70. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).ti,ab.
71. ((foot or feet) adj6 diabet$).ti,ab.72. deep foot infection$.ti,ab.73. exp Foot Ulcer/74. or/69-7375. Leg Ulcer/76. leg varicosis/77. ((crural or leg) adj5 ulcer$).ti,ab.78. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).ti,ab.79. ((venous or stasis or leg) adj5 wound$).ti.80. ((lower extremit$ or lower limb$) adj5 (ulcer$
or wound$)).ti,ab.
Health Technology Assessment 2006; Vol. 10: No. 12
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© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
81. or/75-8082. 74 or 8183. or/1-2184. or/22-6885. 82 and 83 and 8486. exp diagnosis/87. diagnos$.mp.88. 86 or 87 or 8389. 88 and 82 and 84
This identified 1549 records.
MEDLINE (1996–2002 October, week 5) andPREMEDLINE (up to 21 November 2002)(searched: 24 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)
1. exp "Sensitivity and Specificity"/2. False Positive Reactions/3. False Negative Reactions/4. (specificit$ or sensitivit$).ti,ab.5. (false negative$ or false positive$ or true
negative$ or true positive$).ti,ab.6. (positive rate$ or negative rate$).ti,ab.7. screening.ti,ab.8. accuracy.ti,ab.9. reference value$.ti,ab.
10. likelihood ratio$.ti,ab.11. (sroc or srocs or roc or rocs).ti,ab.12. receiver operat$ curve$.ti,ab.13. receiver operat$ character$.ti,ab.14. roc-curve/ or logistic-models/ or likelihood-
functions/15. diagnosis/ or exp "diagnostic errors"/ or exp
"diagnostic techniques and procedures"/ or exp"laboratory techniques and procedures"/
16. (diagnos$ adj3 (efficac$ or efficien$ oreffectiv$ or accura$ or correct$ or reliable orreliability)).ti,ab.
17. (diagnos$ adj3 (error$ or mistake$ orinaccura$ or incorrect or unreliable)).ti,ab.
18. diagnostic yield$.mp. or misdiagnos$.ti,ab.[mp=ti, ab, rw, sh]
19. (reproductivity or logistical regression).mp. orlogistical model$.ti,ab. [mp=ti, ab, rw, sh]
20. (ability adj2 predict$).ti,ab.21. ((test or tests or testing or standard) adj3
(reliable or reliability or performance)).ti,ab.22. (predictive adj (value$ or standard$ or model$
or factor$)).ti,ab.23. ((reference or index) adj (test or tests or
testing)).ti,ab.24. ((clinical or patient) adj (exam$ or asses$ or
recognition or identif$ or inspection)).ti,ab.25. (specimen$ or swab$ or smear$).ti,ab.26. ((tissue or fluid$ or wound$ or cell or cells)
adj2 sample$).ti,ab.27. (sausage toe or dactylitis).ti,ab.
28. (puncture or biopsy or biopsies or needleaspiration$ or (bone adj2 prob$)).ti,ab.
29. exp Specimen Handling/30. exp Biopsy/31. exp Microbiological Techniques/32. Curettage/33. (excis$ or curettage or curetage or curet or
curette or aspirate or yeast or gram stain orgas liquid chromatography).ti,ab.
34. exp Irrigation/ or exp chromatography/ oryeasts/
35. (irrigation or lavage).ti,ab.36. (fluorescen$ adj2 (analys$ or imag$ or
antibod$ or microscopy or probe or probes ortag or tags or marker$ or technique$)).ti,ab.
37. exp Fluorescent Antibody Technique/38. exp Fluorescent Dyes/39. (fluorogenic substrate$ or fluorochrome$ or
immunofluorescence or ryb or red or yellow orblack).ti,ab.
40. (colo?r$ adj2 (asess$ or code or codes orcoding$ or concept or concepts or estimat$ orclassifi$ or system$ or three)).ti,ab.
41. exp Pseudomonas fluorescens/42. pseudomonas fluorescen$.ti,ab.43. ((Fluorescen$ or vital) adj5 dye$).ti,ab.44. (electronic adj (sensor$ or nose)).ti,ab.45. (e-nose or e-sensor$ or x-ray$ or mri or nmr
or (gallium adj2 citrate)).ti,ab.46. exp Tomography, X-Ray Computed/ or exp
Magnetic Resonance Imaging/ or exp X-Rays/47. (imaging or scanning or scan or (computed
and tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or(magnetic and resonance) or (nuclear andmagnetic)).ti,ab.
48. (tissue adj (culture$ or diagnos$ orantigen$)).ti,ab.
49. exp Tissue Culture/ or exp microscopy/50. (aerob$ or anaerob$).ti,ab.51. (biological or mycobacter$ or coloni$ or
contaminat$ or bacter$ or antimicrob$ or anti-microb$ or microb$ or osteomyeliti$ orcelluliti$ or infect$).ti,ab.
52. exp BACTERIA/53. (gram adj (negative or positive)).ti,ab.54. (plate culture$ or colony count$).ti,ab.55. (pus or cicatrix or exudate or suppuration or
oozing or discharge or drainage or odo?r ormalodo?r or erythema or redness or warmthor tender$ or pain$ or induration orfluctuance or swelling or swollen or warm orheat).ti,ab.
56. (signs and symptoms).mp.57. suppuration/ or abscess/ or cellulitis/ or
Cicatrix/ or Drainage/ or Erythema/ or Odors/
Appendix 1
110
58. pain/ or neuralgia/ or pain, intractable/ or"exudates and transudates"/ or cyst fluid/
59. (public health laboratory or phl).ti,ab.60. (molecular adj (screen$ or diagnos$)).ti,ab.61. (polymerase chain reaction adj3
screening).ti,ab.62. exp polymerase chain reaction/63. (primed adj2 situ label$).ti,ab.64. random amplified polymorphic dna.ti,ab.65. reverse transcriptase pcr.ti,ab.66. (pcr or ctpcr or mlst).ti,ab.67. multi locus sequence typing.ti,ab.68. 16 s rdna.ti,ab.69. (fluoresce$ adj4 diagnos$).ti,ab.70. ((near patient or site or onsite or rapid) adj
(test$ or system$ or assessment$ or diagnos$or analysis)).ti,ab.
71. (point adj2 care adj (test$ or system$ orassessment$ or diagnos$ or analysis)).ti,ab.
72. ((neuroisch?emi$ or isch?emi$ or diabetic or neuropathic) adj3 (foot or feet orulcer$)).ti,ab.
73. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).ti,ab.
74. ((foot or feet) adj6 diabet$).ti,ab.75. deep foot infection$.ti,ab.76. exp Foot Ulcer/77. or/72-7678. Leg Ulcer/79. Varicose Ulcer/80. ((crural or leg) adj5 ulcer$).ti,ab.81. ((venous or stasis or varicos$) adj5 (leg or
ulcer$)).ti,ab.82. ((venous or stasis or leg) adj5 wound$).ti,ab.83. ((lower extremit$ or lower limb$) adj5 (ulcer$
or wound$)).ti,ab.84. or/78-8385. 77 or 8486. (or/1-23) and (or/24-71) and 85
This identified 1472 records.
Generic searchesInternet resources and databasesSearched: 26 August 2002Those Internet sites that contained only a fewreferences were simply browsed for relevantpapers. Other Internet sites were searched using asearch engine/search form. The search interfacesallowed only very simple searching and in mostinstances a series of keywords were entered andthe results scanned for relevant material. Most webinterfaces do not offer date restriction and none ofthe searches were limited by date. There was someduplication between the results and these were
removed before all potentially relevant recordswere entered into an Endnote Library.
Health Evidence Bulletins Wales no hitshttp://www.uwcm.ac.uk/uwcm/1b/pep
Health Services Technology Assessment Text(HSTAT)no hitshttp://text.nlm.nih.gov/
National Coordinating Centre for HealthTechnology Assessment 1 hithttp://www.hta.nhsweb.nhs.uk
National Guideline Clearinghouseno hitshttp://www.ahcpr.gov/clinic/assess.htm
National Institute for Health and ClinicalExcellence (NICE) (published appraisals)1 hithttp://www.nice.org.uk/nice-web/
Scottish Intercollegiate Guidelines Network(SIGN) Guidelines1 hithttp://www.sign.ac.uk/
Turning Research Into Practice (TRIP) Index110 hitshttp://www.ceres.uwcm.ac.uk/framset.cfm?section=trip
CD-ROM resources Health Management Information Consortium(HMIC) Databases; HELMIS 1984–1998/DH-Data & King’s Fund Database 1983–2002/King’sFund Database 1979–2002 (searched: 9 November 2002 on ARCSilverPlatter)1. (neuroisch?emic or isch?emic or diabetic or
neuropathic) near3 (foot or feet or ulcer*)2. (pedal or plantar or foot or feet or heel) near3
(ulcer* or septic or wound*)3. (foot or feet) near6 diabet*4. deep foot infection*5. (crural or leg) near5 ulcer*6. (venous or stasis or varicos*) near5 (leg or
ulcer*)7. (lower extremit* or lower limb*) near5 (ulcer*
or wound*)8. #1 or #2 or #3 or #4 or #5 or #6 or #7
This identified 189 records.
Health Technology Assessment 2006; Vol. 10: No. 12
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National Research Register (NRR) (2002, Issue 4)(searched: 12 November 2002) The National Research Register (NRR) wassearched using the CD-ROM interface.#1 (neuroisch?emic or isch?emic or diabetic or
neuropathic) near (foot or feet or ulcer*)#2 (pedal or plantar or foot or feet or heel) near
(ulcer* or septic or wound*)#3 (foot or feet) near diabet*#4 deep foot infection*#5 (crural or leg) near ulcer*#6 (venous or stasis or varicos*) near (leg or
ulcer*)#7 (lower extremit* or lower limb*) near (ulcer*
or wound*)#8 #1 or #2 or #3 or #4 or #5 or #6 or #7
This identified 95 records.
SIGLE (1980–2002 June) (searched: 6 November2002 on ARC SilverPlatter)#1 (neuroisch?emic or isch?emic or diabetic or
neuropathic) near3 (foot or feet or ulcer*)#2 (pedal or plantar or foot or feet or heel) near3
(ulcer* or septic or wound*)#3 (foot or feet) near6 diabet*#4 deep foot infection*#5 (crural or leg) near5 ulcer*#6 (venous or stasis or varicos*) near5 (leg or
ulcer*)#7 (lower extremit* or lower limb*) near5 (ulcer*
or wound*)#8 #1 or #2 or #3 or #4 or #5 or #6 or #7
This identified 43 records.
Appendix 1
112
ResultsNumber of records retrieved by search type and database
Database Clinical-effectiveness Cost-effectiveness Diagnostic testing
MEDLINE and PREMEDLINE 590 261 1471EMBASE 449 250 1549CINAHL 72 85 68British Nursing Index (BNI) 67 23 54Allied and Complementary Medicine (AMED) 49 15 44EconLit 0 3HEED 0 77NHS EED admin. 0 172SIGLEa 43CDSR 35CCTR 176DARE admin. 154HTA admin. 20Controlled Trials 89NRRa 95HELMISa 189Total/pre- and post-removal of duplicate citations 2028/1310 886/747 3186/2762
a The search strategy covered all three search types: clinical effectiveness, cost-effectiveness and diagnostic testing.
Members of the expert advisory panelprovided feedback on the draft protocol and
review.
Dr Jan ApelqvistDepartment of Internal Medicine, LundUniversity Hospital, Sweden
Dr David G. ArmstrongDirector of Research and Education, Departmentof Surgery, Podiatry Section, Southern ArizonaVeterans Affairs Medical Center, Tucson, AZ, USA
Professor Andrew BoultonSchool of MedicineUniversity of ManchesterManchester, UK
Dr Phil BowlerWound Care & Prevention Global DevelopmentCentre, ConvaTec, Deeside Industrial Park,Flintshire, UK
Dr Gregory CaputoCenter for Locomotion Studies, Pennsylvania StateDiabetes Foot Clinics, Pennsylvania StateUniversity, University ParkPA, USA
Dr Carol DealeyResearch Fellow, School of Health Sciences,University of Birmingham and University HospitalBirmingham NHS Trust, Research andDevelopment Office, UK.
Ms Jacque DinnesSenior Research Fellow, Wessex Institute forHealth Research and Development, University ofSouthampton, UK
Dr Dawn Dowding Department of Health Sciences/Hull York MedicalSchool, University of York, UK
Ms Madeleine FlanaganAssociate Head of Department, Department ofPost-Registration Nursing, University ofHertfordshire, Hatfield, UK
Mr Brian GilchristHead of Pre-registration Education, FlorenceNightingale School of Nursing and Midwifery,King’s College London, UK
Professor Keith HardingDepartment of Rehabilitation Medicine (WoundHealing), University of Wales College of Medicine,Cardiff, UK
Daniel HigmanConsultant SurgeonWalsgrave HospitalCoventry, UK
Professor Derek L. HuntFaculty of Health Sciences, McMaster University,Hamilton, Ontario, Canada
Ms June JonesResearch Fellow/Clinical Nurse Specialist, Healthand Community Care Research Unit (HaCCRU),University of Liverpool, UK
Dr Khalid S. KhanEducation Resource Centre, Birmingham Women'sHealthcare NHS Trust, UK
Dr Christopher LawrenceNewton House, Crick, near Chepstow, UK
Professor DJ LeaperUniversity Hospital of North Tees, Hardwick,Stockton on Tees, UK
Professor BA LipskyAntibiotic Research Clinic, Veterans’ Affairs PugetSound Health Care System and Department ofMedicine, University of Washington, Seattle, WA,USA
Dr Astrid K PetrichMolecular Microbiologist, Department ofPathology and Molecular Medicine, McMasterUniversity, Hamilton, Ontario, Canada
Professor Terence J RyanWound Healing Institute, Oxford, UK
Health Technology Assessment 2006; Vol. 10: No. 12
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Appendix 2
Expert advisory panel
Dr Joseph B SelkonDepartment of Microbiology, John RadcliffeHospital, Oxford, UK
Ms Jude SmithPodiatrist, Department of Podiatry, Selby and YorkNHS Primary Care Trust, Diabetes Centre, YorkDistrict Hospital, UK
Dr Steve ThomasSurgical Materials Testing Laboratory, Princess ofWales Hospital, Bridgend, UK
Dr Carl ThompsonSenior Research Fellow, Department of HealthSciences, University of York, UK
Dr Marie WestwoodResearch Fellow, NHS Centre for Reviews andDissemination, University of York, UK
Mrs Anne WitherowAltnaglevin Hospital Trust, Londonderry, UK
Mr Peter Jackson (Manchester, UK) and ProfessorKeith Wilson (York, UK) kindly provided a patientperspective.
Appendix 2
114
Health Technology Assessment 2006; Vol. 10: No. 12
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Appendix 3
Data extraction forms
Abbreviations used in the following tables are given in the footnote after the final table.
Appendix 3
116 Que
stio
n 1a
: dia
gnos
is o
f wou
nd in
fect
ion
usin
g cl
inic
al e
xam
inat
ion
(dia
beti
c fo
ot u
lcer
)
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
enti
on d
etai
lsR
esul
tsW
ithd
raw
als
Com
men
ts
Firs
t au
thor
, yea
r,co
untr
y
Stud
y de
sign:
case
–con
trol
, coh
ort,
othe
r?Pr
ospe
ctiv
e or
retr
ospe
ctiv
e?M
etho
d of
pat
ient
sele
ctio
n (e
.g.
cons
ecut
ive,
ran
dom
)
Cal
cula
tion
ofst
atist
ical
pow
er
Out
com
es a
sses
sed
and
met
hods
of d
ata
colle
ctio
n us
ed
Sett
ing
Elig
ibili
ty c
riter
iafo
r in
clus
ion
in t
hest
udy
Prev
alen
ce o
fdi
seas
e in
the
sam
ple
Des
crip
tion
ofst
udy
popu
latio
n –
spec
trum
com
posit
ion
Gen
der
Ethn
icity
Mea
n ±
SD a
ge
Type
of d
iabe
tes
Mea
n ±
SD d
urat
ion
ofdi
abet
es
Trea
ted
with
ora
l ant
i-dia
betic
med
icat
ion/
insu
lin d
epen
dent
Mea
n ±
SD H
bA1 C
Body
wei
ght/
BMI
Evid
ence
of n
euro
path
y, a
ndty
pe
Evid
ence
of i
scha
emia
, deg
ree
and
met
hod
of a
sses
smen
t (e
.g.
toe
pres
sure
, ABP
I, T
CPO
2) o
rot
her
vasc
ular
dise
ase
Pres
ence
of r
etin
opat
hy
Und
erly
ing
fact
ors
such
as
nutr
ition
al s
tatu
s,im
mun
ocom
pete
nce,
cont
inen
ce, m
obili
ty
Mea
n ±
SD u
lcer
are
a
Mea
n ±
SD u
lcer
dep
th
Mea
n ±
SD u
lcer
vol
ume
Mea
n ±
SD u
lcer
dur
atio
n
Num
ber
of u
lcer
epi
sode
s
Gra
de o
f ulc
er (e
.g. W
agne
r)
Prev
ious
am
puta
tion
Pres
ence
of n
ecro
tic t
issue
Pres
ence
of c
allu
s
Bact
erio
logy
Prio
r/cu
rren
t us
e of
antim
icro
bial
age
nts
Inde
x te
stPr
ovid
e de
scrip
tion
ofdi
agno
stic
inde
x te
st, i
.e. g
ive
deta
ils o
f clin
ical
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min
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nm
etho
ds u
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Rep
ort
num
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of p
atie
nts
rece
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g th
e te
st
Refe
renc
e te
stPr
ovid
e de
scrip
tion
ofre
fere
nce
test
use
d. R
epor
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mbe
r of
pat
ient
s re
ceiv
ing
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e te
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xpla
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e se
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the
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nt fr
omth
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g th
e in
dex
test
Stat
e tim
e la
g be
twee
n th
ein
dex
and
refe
renc
e te
sts.
Sta
tew
ho a
dmin
ister
ed t
he t
ests
Stat
istic
al m
etho
ds
Sens
itivi
ty a
nd s
peci
ficity
Like
lihoo
d ra
tios
Dia
gnos
tic o
dds
ratio
Posit
ive
and
nega
tive
pred
ictiv
e va
lues
ROC
ana
lysis
Adv
erse
effe
cts
of t
ests
Hea
lth-r
elat
ed q
ualit
y of
life
Adh
eren
ce w
ith r
egim
en
Num
bers
of
patie
nts
lost
to
follo
w-u
p
Reas
ons
for
loss
to fo
llow
-up
Not
es a
bout
dupl
icat
epu
blic
atio
n
Lim
itatio
ns o
fth
e st
udy
asno
ted
byau
thor
s or
revi
ewer
Stud
ysp
onso
rshi
p
Health Technology Assessment 2006; Vol. 10: No. 12
117
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Que
stio
n 1b
: dia
gnos
is o
f wou
nd in
fect
ion
usin
g cl
inic
al e
xam
inat
ion
(ven
ous
leg
ulce
r)
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
enti
on d
etai
lsR
esul
tsW
ithd
raw
als
Com
men
ts
Firs
t au
thor
, yea
r,co
untr
y
Stud
y de
sign:
case
–con
trol
, coh
ort,
othe
r?Pr
ospe
ctiv
e or
retr
ospe
ctiv
e?M
etho
d of
pat
ient
sele
ctio
n (e
.g.
cons
ecut
ive,
ran
dom
)
Cal
cula
tion
ofst
atist
ical
pow
er
Out
com
es a
sses
sed
and
met
hods
of d
ata
colle
ctio
n us
ed
Sett
ing
Elig
ibili
ty c
riter
iafo
r in
clus
ion
in t
hest
udy
Prev
alen
ce o
fdi
seas
e in
the
sam
ple
Des
crip
tion
ofst
udy
popu
latio
n –
spec
trum
com
posit
ion
Gen
der
Ethn
icity
Mea
n ±
SD a
ge
Body
wei
ght/
BMI
Pres
ence
of c
o-m
orbi
ditie
s, e
.g.
diab
etes
Ass
essm
ent
of v
enou
spa
thol
ogy
(usin
g re
flect
ion
rheo
grap
hy, a
irpl
ethy
smog
raph
y, d
uple
xD
oppl
er u
ltras
ound
)
Und
erly
ing
fact
ors
such
as
nutr
ition
al s
tatu
s,im
mun
ocom
pete
nce,
cont
inen
ce, m
obili
ty
Mea
n ±
SD u
lcer
are
a
Mea
n ±
SD u
lcer
dep
th
Mea
n ±
SD u
lcer
vol
ume
Mea
n ±
SD u
lcer
dur
atio
n
Num
ber
of u
lcer
epi
sode
s
Gra
de o
f ulc
er
Pres
ence
of n
ecro
tic t
issue
Bact
erio
logy
Prio
r/cu
rren
t us
e of
antim
icro
bial
age
nts
Inde
x te
stPr
ovid
e de
scrip
tion
ofdi
agno
stic
inde
x te
st, i
.e. g
ive
deta
ils o
f clin
ical
exa
min
atio
nm
etho
ds u
sed.
Rep
ort
num
ber
of p
atie
nts
rece
ivin
g th
e te
st
Refe
renc
e te
stPr
ovid
e de
scrip
tion
ofre
fere
nce
test
use
d. R
epor
tnu
mbe
r of
pat
ient
s re
ceiv
ing
the
refe
renc
e te
st a
nd e
xpla
inho
w p
atie
nts
wer
e se
lect
ed if
the
num
ber
is di
ffere
nt fr
omth
ose
rece
ivin
g th
e in
dex
test
Stat
e tim
e la
g be
twee
n th
ein
dex
and
refe
renc
e te
sts.
Sta
tew
ho a
dmin
ister
ed t
he t
ests
Stat
istic
al m
etho
ds
Sens
itivi
ty a
nd s
peci
ficity
Like
lihoo
d ra
tios
Dia
gnos
tic o
dds
ratio
Posit
ive
and
nega
tive
pred
ictiv
e va
lues
ROC
ana
lysis
Adv
erse
effe
cts
of t
ests
Hea
lth-r
elat
ed q
ualit
y of
life
Adh
eren
ce w
ith r
egim
en
Num
bers
of
patie
nts
lost
to
follo
w-u
p
Reas
ons
for
loss
to fo
llow
-up
Not
es a
bout
dupl
icat
epu
blic
atio
n
Lim
itatio
ns o
f the
stud
y as
not
ed b
yau
thor
s or
revi
ewer
Stud
y sp
onso
rshi
p
Appendix 3
118 Que
stio
n 2a
: dia
gnos
is –
sam
plin
g m
etho
ds (
diab
etic
foot
ulc
er)
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
enti
on d
etai
lsR
esul
tsW
ithd
raw
als
Com
men
ts
Firs
t au
thor
, yea
r,co
untr
y
Stud
y de
sign:
case
–con
trol
,co
hort
, oth
er?
Pros
pect
ive
orre
tros
pect
ive?
Met
hod
of p
atie
ntse
lect
ion
(e.g
.co
nsec
utiv
e,ra
ndom
)C
alcu
latio
n of
stat
istic
al p
ower
Out
com
es a
sses
sed
and
met
hods
of
data
col
lect
ion
used
Sett
ing
Elig
ibili
ty c
riter
iafo
r in
clus
ion
in t
hest
udy
Prev
alen
ce o
fdi
seas
e in
the
sam
ple
Des
crip
tion
ofst
udy
popu
latio
n –
spec
trum
com
posit
ion
Gen
der
Ethn
icity
Mea
n ±
SD a
ge
Type
of d
iabe
tes
Mea
n ±
SD d
urat
ion
ofdi
abet
es
Trea
ted
with
ora
l ant
i-dia
betic
med
icat
ion/
insu
lin d
epen
dent
Mea
n ±
SD H
bA1 C
Body
wei
ght/
BMI
Evid
ence
of n
euro
path
y, an
d ty
pe
Evid
ence
of i
scha
emia
, deg
ree
and
met
hod
of a
sses
smen
t (e
.g.
toe
pres
sure
, ABP
I, T
CPO
2) o
rot
her
vasc
ular
dise
ase
Pres
ence
of r
etin
opat
hy
Und
erly
ing
fact
ors
such
as
nutr
ition
al s
tatu
s,im
mun
ocom
pete
nce,
cont
inen
ce, m
obili
ty
Mea
n ±
SD u
lcer
are
a
Mea
n ±
SD u
lcer
dep
th
Mea
n ±
SD u
lcer
vol
ume
Mea
n ±
SD u
lcer
dur
atio
n
Num
ber
of u
lcer
epi
sode
s
Gra
de o
f ulc
er (e
.g. W
agne
r)
Prev
ious
am
puta
tion
Pres
ence
of n
ecro
tic t
issue
Pres
ence
of c
allu
s
Bact
erio
logy
Prio
r/cu
rren
t us
e of
antim
icro
bial
age
nts
Inde
x te
stPr
ovid
e de
scrip
tion
of d
iagn
ostic
inde
x te
st, i
.e. g
ive
deta
ils o
fsa
mpl
ing/
spec
imen
col
lect
ion
met
hods
use
d. R
epor
t nu
mbe
r of
patie
nts
rece
ivin
g th
e te
st
Refe
renc
e te
stPr
ovid
e de
scrip
tion
of r
efer
ence
tes
tus
ed. R
epor
t nu
mbe
r of
pat
ient
sre
ceiv
ing
the
refe
renc
e te
st a
ndex
plai
n ho
w p
atie
nts
wer
e se
lect
ed if
the
num
ber
is di
ffere
nt fr
om t
hose
rece
ivin
g th
e in
dex
test
Stat
e cu
t-of
f crit
erio
n us
ed. S
tate
time
lag
betw
een
the
inde
x an
dre
fere
nce
test
s. S
tate
who
adm
inist
ered
the
tes
ts
Repo
rt t
he fo
llow
ing,
if d
ata
avai
labl
efr
om t
he s
tudy
: typ
e of
sam
ple
used
(tiss
ue, a
spira
te, f
luid
, sw
ab) a
nd h
owit
was
tak
en (e
.g. s
wab
bing
met
hod
used
); if
swab
use
d, s
tate
typ
e (e
.g.
char
coal
tip
ped)
; wou
nd t
reat
men
tpr
ior
to s
ampl
ing
(e.g
. cle
ansin
g,de
brid
emen
t); t
rans
port
med
ium
used
; tra
nspo
rtat
ion
of s
ampl
e(t
imin
g an
d m
ode)
; lab
ellin
g of
sam
ple
(clin
ical
det
ail p
rovi
ded)
;ra
nge
of t
estin
g us
ed in
lab.
; whe
ther
spec
ific
assa
ys o
r ge
nera
l cul
ture
met
hods
use
d; m
etho
d of
rep
ortin
gre
sults
(qua
ntita
tive,
sem
i-qu
antit
ativ
e, c
onfir
med
iden
tific
atio
n,an
tibio
gram
); ot
her
inte
rven
tions
perf
orm
ed in
con
junc
tion
with
test
ing;
spe
ed o
f ret
urn
of r
epor
t;sp
eed
of a
ntib
iotic
pre
scrip
tion
Stat
istic
al m
etho
ds
Sens
itivi
ty a
ndsp
ecifi
city
Like
lihoo
d ra
tios
Dia
gnos
tic o
dds
ratio
Posit
ive
and
nega
tive
pred
ictiv
e va
lues
ROC
ana
lysis
Adv
erse
effe
cts
ofte
sts
Hea
lth-r
elat
ed q
ualit
yof
life
Adh
eren
ce w
ithre
gim
en
Num
bers
of
patie
nts
lost
to
follo
w-u
p
Reas
ons
for
loss
to fo
llow
-up
Not
es a
bout
dupl
icat
epu
blic
atio
n
Lim
itatio
ns o
f the
stud
y as
not
ed b
yau
thor
s or
revi
ewer
Stud
y sp
onso
rshi
p
Health Technology Assessment 2006; Vol. 10: No. 12
119
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Que
stio
n 2b
: dia
gnos
is –
sam
plin
g m
etho
ds (
veno
us le
g ul
cer)
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
enti
on d
etai
lsR
esul
tsW
ithd
raw
als
Com
men
ts
Firs
t au
thor
, yea
r,co
untr
y
Stud
y de
sign:
case
–con
trol
,co
hort
, oth
er?
Pros
pect
ive
orre
tros
pect
ive?
Met
hod
of p
atie
ntse
lect
ion
(e.g
.co
nsec
utiv
e,ra
ndom
)
Cal
cula
tion
ofst
atist
ical
pow
er
Out
com
es a
sses
sed
and
met
hods
of
data
col
lect
ion
used
Sett
ing
Elig
ibili
ty c
riter
iafo
r in
clus
ion
in t
hest
udy
Prev
alen
ce o
fdi
seas
e in
the
sam
ple
Des
crip
tion
ofst
udy
popu
latio
n –
spec
trum
com
posit
ion
Gen
der
Ethn
icity
Mea
n ±
SD a
ge
Body
wei
ght/
BMI
Pres
ence
of c
o-m
orbi
ditie
s, e
.g.
diab
etes
Ass
essm
ent
of v
enou
spa
thol
ogy
(usin
g re
flect
ion
rheo
grap
hy, a
irpl
ethy
smog
raph
y, d
uple
xD
oppl
er u
ltras
ound
)
Und
erly
ing
fact
ors
such
as
nutr
ition
al s
tatu
s,im
mun
ocom
pete
nce,
cont
inen
ce, m
obili
ty
Mea
n ±
SD u
lcer
are
a
Mea
n ±
SD u
lcer
dep
th
Mea
n ±
SD u
lcer
vol
ume
Mea
n ±
SD u
lcer
dur
atio
n
Num
ber
of u
lcer
epi
sode
s
Gra
de o
f ulc
er
Pres
ence
of n
ecro
tic t
issue
Bact
erio
logy
Prio
r/cu
rren
t us
e of
antim
icro
bial
age
nts
Inde
x te
stPr
ovid
e de
scrip
tion
of d
iagn
ostic
inde
x te
st, i
.e. g
ive
deta
ils o
fsa
mpl
ing/
spec
imen
col
lect
ion
met
hods
use
d. R
epor
t nu
mbe
r of
patie
nts
rece
ivin
g th
e te
st
Refe
renc
e te
stPr
ovid
e de
scrip
tion
of r
efer
ence
tes
tus
ed. R
epor
t nu
mbe
r of
pat
ient
sre
ceiv
ing
the
refe
renc
e te
st, a
ndex
plai
n ho
w p
atie
nts
wer
e se
lect
ed if
the
num
ber
is di
ffere
nt fr
om t
hose
rece
ivin
g th
e in
dex
test
Stat
e cu
t-of
f crit
erio
n us
ed. S
tate
time
lag
betw
een
the
inde
x an
dre
fere
nce
test
s. S
tate
who
adm
inist
ered
the
tes
ts
Repo
rt t
he fo
llow
ing,
if d
ata
avai
labl
efr
om t
he s
tudy
: typ
e of
sam
ple
used
(tiss
ue, a
spira
te, f
luid
, sw
ab) a
nd h
owit
was
tak
en (e
.g. s
wab
bing
met
hod
used
); if
swab
use
d, s
tate
typ
e (e
.g.
char
coal
tip
ped)
; wou
nd t
reat
men
tpr
ior
to s
ampl
ing
(e.g
. cle
ansin
g,de
brid
emen
t); t
rans
port
med
ium
used
; tra
nspo
rtat
ion
of s
ampl
e(t
imin
g an
d m
ode)
; lab
ellin
g of
sam
ple
(clin
ical
det
ail p
rovi
ded)
;ra
nge
of t
estin
g us
ed in
lab.
; whe
ther
spec
ific
assa
ys o
r ge
nera
l cul
ture
met
hods
use
d; m
etho
d of
rep
ortin
gre
sults
(qua
ntita
tive,
sem
i-qu
antit
ativ
e, c
onfir
med
iden
tific
atio
n,an
tibio
gram
); ot
her
inte
rven
tions
perf
orm
ed in
con
junc
tion
with
test
ing;
spe
ed o
f ret
urn
of r
epor
t;sp
eed
of a
ntib
iotic
pre
scrip
tion
Stat
istic
al m
etho
ds
Sens
itivi
ty a
ndsp
ecifi
city
Like
lihoo
d ra
tios
Dia
gnos
tic o
dds
ratio
Posit
ive
and
nega
tive
pred
ictiv
e va
lues
ROC
ana
lysis
Adv
erse
effe
cts
ofte
sts
Hea
lth-r
elat
ed q
ualit
yof
life
Adh
eren
ce w
ithre
gim
en
Num
bers
of
patie
nts
lost
to
follo
w-u
p
Reas
ons
for
loss
to fo
llow
-up
Not
es a
bout
dupl
icat
epu
blic
atio
n
Lim
itatio
ns o
f the
stud
y as
not
ed b
yau
thor
s or
revi
ewer
Stud
y sp
onso
rshi
p
Appendix 3
120 Que
stio
n 3a
: dia
gnos
is –
labo
rato
ry m
etho
ds (
diab
etic
foot
ulc
er)
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
enti
on d
etai
lsR
esul
tsW
ithd
raw
als
Com
men
ts
Firs
t au
thor
, yea
r,co
untr
y
Stud
y de
sign:
case
–con
trol
,co
hort
, oth
er?
Pros
pect
ive
orre
tros
pect
ive?
Met
hod
of p
atie
ntse
lect
ion
(e.g
.co
nsec
utiv
e,ra
ndom
)
Cal
cula
tion
ofst
atist
ical
pow
er
Out
com
es a
sses
sed
and
met
hods
of
data
col
lect
ion
used
Sett
ing
Elig
ibili
ty c
riter
iafo
r in
clus
ion
inth
e st
udy
Prev
alen
ce o
fdi
seas
e in
the
sam
ple
Des
crip
tion
ofst
udy
popu
latio
n–
spec
trum
com
posit
ion
Gen
der
Ethn
icity
Mea
n ±
SD a
ge
Type
of d
iabe
tes
Mea
n ±
SD d
urat
ion
of d
iabe
tes
Trea
ted
with
ora
l ant
i-dia
betic
med
icat
ion/
insu
lin d
epen
dent
Mea
n ±
SD H
bA1 C
Body
wei
ght/
BMI
Evid
ence
of n
euro
path
y, a
nd t
ype
Evid
ence
of i
scha
emia
, deg
ree
and
met
hod
of a
sses
smen
t (e
.g.
toe
pres
sure
, ABP
I, T
cPO
2), o
rot
her
vasc
ular
dise
ase
Pres
ence
of r
etin
opat
hy
Und
erly
ing
fact
ors
such
as
nutr
ition
al s
tatu
s,im
mun
ocom
pete
nce,
con
tinen
ce,
mob
ility
Mea
n ±
SD u
lcer
are
a
Mea
n ±
SD u
lcer
dep
th
Mea
n ±
SD u
lcer
vol
ume
Mea
n ±
SD u
lcer
dur
atio
n
Num
ber
of u
lcer
epi
sode
s
Gra
de o
f ulc
er (e
.g. W
agne
r)
Prev
ious
am
puta
tion
Pres
ence
of n
ecro
tic t
issue
Pres
ence
of c
allu
s
Bact
erio
logy
Prio
r/cu
rren
t us
e of
ant
imic
robi
alag
ents
Inde
x te
stPr
ovid
e de
scrip
tion
of d
iagn
ostic
inde
xte
st, i
.e.,
give
det
ails
of la
bora
tory
tech
niqu
es u
sed.
Rep
ort
num
ber
ofsa
mpl
es t
este
d
Refe
renc
e te
stPr
ovid
e de
scrip
tion
of r
efer
ence
tes
tus
ed. R
epor
t nu
mbe
r of
sam
ples
tes
ted,
and
expl
ain
how
the
sam
ples
wer
ese
lect
ed if
the
num
ber
is di
ffere
nt fr
omth
ose
test
ed w
ith t
he in
dex
test
Stat
e cu
t-of
f crit
erio
n us
ed. S
tate
tim
ela
g be
twee
n th
e in
dex
and
refe
renc
ete
sts.
Sta
te w
ho a
dmin
ister
ed t
he t
ests
Repo
rt t
he fo
llow
ing,
if d
ata
avai
labl
efr
om t
he s
tudy
: typ
e of
sam
ple
used
(tiss
ue, a
spira
te, f
luid
, sw
ab) a
nd h
ow it
was
tak
en (e
.g. s
wab
bing
met
hod
used
);if
swab
use
d, s
tate
typ
e (e
.g. c
harc
oal
tippe
d); w
ound
tre
atm
ent
prio
r to
sam
plin
g (e
.g. c
lean
sing,
deb
ridem
ent)
;tr
ansp
ort
med
ium
use
d; t
rans
port
atio
nof
sam
ple
(tim
ing
and
mod
e); l
abel
ling
of s
ampl
e (c
linic
al d
etai
l pro
vide
d);
rang
e of
tes
ting
used
in la
b.; w
heth
ersp
ecifi
c as
says
or
gene
ral c
ultu
rem
etho
ds u
sed;
met
hod
of r
epor
ting
resu
lts (q
uant
itativ
e, s
emi-q
uant
itativ
e,co
nfirm
ed id
entif
icat
ion,
ant
ibio
gram
);in
terp
reta
tion
of m
olec
ular
tes
ts a
ndap
prop
riate
ness
of c
ontr
ols
used
;cl
inic
ian’
s re
spon
se t
o la
bora
tory
resu
lts; o
ther
inte
rven
tions
per
form
edin
con
junc
tion
with
tes
ting;
spe
ed o
fre
turn
of r
epor
t; sp
eed
of a
ntib
iotic
pres
crip
tion
Stat
istic
al m
etho
ds
Sens
itivi
ty a
ndsp
ecifi
city
Like
lihoo
d ra
tios
Dia
gnos
tic o
dds
ratio
Posit
ive
and
nega
tive
pred
ictiv
eva
lues
ROC
ana
lysis
Adv
erse
effe
cts
ofte
sts
Hea
lth-r
elat
edqu
ality
of l
ife
Adh
eren
ce w
ithre
gim
en
Num
bers
of
patie
nts
lost
to
follo
w-u
p
Reas
ons
for
loss
to fo
llow
-up
Not
es a
bout
dupl
icat
epu
blic
atio
n
Lim
itatio
ns o
f the
stud
y as
not
ed b
yau
thor
s or
revi
ewer
Stud
y sp
onso
rshi
p
Health Technology Assessment 2006; Vol. 10: No. 12
121
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Que
stio
n 3b
: dia
gnos
is –
labo
rato
ry m
etho
ds (
veno
us le
g ul
cer)
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
enti
on d
etai
lsR
esul
tsW
ithd
raw
als
Com
men
ts
Firs
t au
thor
, yea
r,co
untr
y
Stud
y de
sign:
case
–con
trol
,co
hort
, oth
er?
Pros
pect
ive
orre
tros
pect
ive?
Met
hod
of p
atie
ntse
lect
ion
(e.g
.co
nsec
utiv
e,ra
ndom
)
Cal
cula
tion
ofst
atist
ical
pow
er
Out
com
es a
sses
sed
and
met
hods
of
data
col
lect
ion
used
Sett
ing
Elig
ibili
ty c
riter
iafo
r in
clus
ion
inth
e st
udy
Prev
alen
ce o
fdi
seas
e in
the
sam
ple
Des
crip
tion
ofst
udy
popu
latio
n–
spec
trum
com
posit
ion
Gen
der
Ethn
icity
Mea
n ±
SD a
ge
Body
wei
ght/
BMI
Pres
ence
of c
o-m
orbi
ditie
s, e
.g.
diab
etes
Ass
essm
ent
of v
enou
s pa
thol
ogy
(usin
g re
flect
ion
rheo
grap
hy, a
irpl
ethy
smog
raph
y, d
uple
xD
oppl
er u
ltras
ound
)
Und
erly
ing
fact
ors
such
as
nutr
ition
al s
tatu
s,im
mun
ocom
pete
nce,
con
tinen
ce,
mob
ility
Mea
n ±
SD u
lcer
are
a
Mea
n ±
SD u
lcer
dep
th
Mea
n ±
SD u
lcer
vol
ume
Mea
n ±
SD u
lcer
dur
atio
n
Num
ber
of u
lcer
epi
sode
s
Gra
de o
f ulc
er
Pres
ence
of n
ecro
tic t
issue
Bact
erio
logy
Prio
r/cu
rren
t us
e of
ant
imic
robi
alag
ents
Inde
x te
stPr
ovid
e de
scrip
tion
of d
iagn
ostic
inde
xte
st, i
.e. g
ive
deta
ils o
f lab
orat
ory
tech
niqu
es u
sed.
Rep
ort
num
ber
ofsa
mpl
es t
este
d
Refe
renc
e te
stPr
ovid
e de
scrip
tion
of r
efer
ence
tes
tus
ed. R
epor
t nu
mbe
r of
sam
ples
tes
ted
and
expl
ain
how
the
sam
ples
wer
ese
lect
ed if
the
num
ber
is di
ffere
nt fr
omth
ose
test
ed w
ith t
he in
dex
test
Stat
e cu
t-of
f crit
erio
n us
ed. S
tate
tim
ela
g be
twee
n th
e in
dex
and
refe
renc
ete
sts.
Sta
te w
ho a
dmin
ister
ed t
he t
ests
Repo
rt t
he fo
llow
ing,
if d
ata
avai
labl
efr
om t
he s
tudy
: typ
e of
sam
ple
used
(tiss
ue, a
spira
te, f
luid
, sw
ab) a
nd h
ow it
was
tak
en (e
.g. s
wab
bing
met
hod
used
);if
swab
use
d, s
tate
typ
e (e
.g. c
harc
oal
tippe
d); w
ound
tre
atm
ent
prio
r to
sam
plin
g (e
.g. c
lean
sing,
deb
ridem
ent)
;tr
ansp
ort
med
ium
use
d; t
rans
port
atio
nof
sam
ple
(tim
ing
and
mod
e); l
abel
ling
of s
ampl
e (c
linic
al d
etai
l pro
vide
d);
rang
e of
tes
ting
used
in la
b.; w
heth
ersp
ecifi
c as
says
or
gene
ral c
ultu
rem
etho
ds u
sed;
met
hod
of r
epor
ting
resu
lts (q
uant
itativ
e, s
emi-q
uant
itativ
e,co
nfirm
ed id
entif
icat
ion,
ant
ibio
gram
);in
terp
reta
tion
of m
olec
ular
tes
ts a
ndap
prop
riate
ness
of c
ontr
ols
used
;cl
inic
ian’
s re
spon
se t
o la
bora
tory
resu
lts; o
ther
inte
rven
tions
per
form
edin
con
junc
tion
with
tes
ting;
spe
ed o
fre
turn
of r
epor
t; sp
eed
of a
ntib
iotic
pres
crip
tion
Stat
istic
al m
etho
ds
Sens
itivi
ty a
ndsp
ecifi
city
Like
lihoo
d ra
tios
Dia
gnos
tic o
dds
ratio
Posit
ive
and
nega
tive
pred
ictiv
eva
lues
ROC
ana
lysis
Adv
erse
effe
cts
ofte
sts
Hea
lth-r
elat
edqu
ality
of l
ife
Adh
eren
ce w
ithre
gim
en
Num
bers
of
patie
nts
lost
to
follo
w-u
p
Reas
ons
for
loss
to fo
llow
-up
Not
es a
bout
dupl
icat
epu
blic
atio
n
Lim
itatio
ns o
f the
stud
y as
not
ed b
yau
thor
s or
revi
ewer
Stud
y sp
onso
rshi
p
Appendix 3
122 Que
stio
n 4:
ass
essi
ng im
pact
of m
icro
biol
ogic
al a
naly
sis
on t
hera
py in
dia
beti
c fo
ot u
lcer
s
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
enti
on d
etai
lsR
esul
tsW
ithd
raw
als
Com
men
ts
Firs
t au
thor
, yea
r,co
untr
y
Stud
y de
sign:
RC
Tor
CC
T
Met
hod
ofra
ndom
isatio
n (o
rm
etho
d of
allo
catio
n if
CC
T)
Uni
t of
allo
catio
n
Cal
cula
tion
ofst
atist
ical
pow
er
Out
com
es a
sses
sed
and
met
hods
of
data
col
lect
ion
used
Sett
ing
Popu
latio
n
Incl
usio
n cr
iteria
Excl
usio
n cr
iteria
Gen
der
Ethn
icity
Mea
n ±
SD a
ge
Type
of d
iabe
tes
Mea
n ±
SD d
urat
ion
of d
iabe
tes
Trea
ted
with
ora
l ant
i-dia
betic
med
icat
ion/
insu
lin d
epen
dent
Mea
n ±
SD H
bA1 C
Body
wei
ght/
BMI
Evid
ence
of n
euro
path
y an
d ty
pe
Evid
ence
of i
scha
emia
, deg
ree
and
met
hod
of a
sses
smen
t (e
.g.
toe
pres
sure
, ABP
I, T
CPO
2) o
rot
her
vasc
ular
dise
ase
Pres
ence
of r
etin
opat
hy
Und
erly
ing
fact
ors
such
as
nutr
ition
al s
tatu
s,im
mun
ocom
pete
nce,
con
tinen
ce,
mob
ility
Mea
n ±
SD u
lcer
are
a
Mea
n ±
SD u
lcer
dep
th
Mea
n ±
SD u
lcer
vol
ume
Mea
n ±
SD u
lcer
dur
atio
n
Num
ber
of u
lcer
epi
sode
s
Gra
de o
f ulc
er (e
.g. W
agne
r)
Prev
ious
am
puta
tion
Pres
ence
of n
ecro
tic t
issue
Pres
ence
of c
allu
s
Bact
erio
logy
Prio
r/cu
rren
t us
e of
ant
imic
robi
alag
ents
I1: d
escr
iptio
n of
stra
tegy
‘tre
at w
ithou
tkn
owin
g re
sults
of
mic
robi
olog
ical
ana
lysis
’,gi
ving
nam
es o
fan
tibio
tics
or o
ther
agen
ts p
resc
ribed
, with
dose
, fre
quen
cy a
nddu
ratio
n of
adm
inist
ratio
n. A
lsore
port
des
crip
tion
ofot
her
conc
omita
ntin
terv
entio
ns u
sed
such
as t
opic
al a
pplic
atio
nsan
d/or
dre
ssin
gs. R
epor
tnu
mbe
r of
pat
ient
sre
ceiv
ing
this
stra
tegy
I2: d
escr
iptio
n of
stra
tegy
‘tre
at a
fter
rece
ivin
g re
sults
of
mic
robi
olog
ical
ana
lysis
’,gi
ving
nam
es o
fan
tibio
tics
or o
ther
agen
ts p
resc
ribed
, with
dose
, fre
quen
cy a
nddu
ratio
n of
adm
inist
ratio
n. A
lsore
port
des
crip
tion
ofot
her
conc
omita
ntin
terv
entio
ns u
sed
such
as t
opic
al a
pplic
atio
nsan
d/or
dre
ssin
gs. R
epor
tnu
mbe
r of
pat
ient
sre
ceiv
ing
this
stra
tegy
Stat
e sp
eed
of r
etur
n of
repo
rt a
nd s
peed
of
antib
iotic
pre
scrip
tion
Stat
istic
al m
etho
ds
Mor
talit
y (a
ll)
Mor
talit
y (r
elat
ed t
o am
puta
tion)
Am
puta
tion
(inci
denc
e an
d ty
pe,
e.g.
maj
or/m
inor
)
Inci
denc
e of
ost
eom
yelit
is
Num
ber/
dura
tion
of h
ospi
tal
adm
issio
ns fo
r D
FU p
robl
ems
Prop
ortio
n of
pat
ient
s ac
hiev
ing
com
plet
e he
alin
g
Tim
e to
com
plet
e he
alin
g
Cha
nge
in u
lcer
are
a (a
bsol
ute
orpe
rcen
tage
val
ues)
Rem
aini
ng w
ound
are
a
Hea
ling
rate
(abs
olut
e or
rel
ativ
e)
Cha
nge
in u
lcer
dep
th (a
bsol
ute
or r
elat
ive)
Cha
nge
in u
lcer
vol
ume
(abs
olut
eor
rel
ativ
e)
Recu
rren
ce o
f ulc
er
Pain
(in
patie
nts
with
out
neur
opat
hy)
Bact
eria
l pro
file
Acq
uisit
ion
of r
esist
ant
orga
nism
s
Rela
tions
hip
betw
een
ulce
rhe
alin
g an
d ba
cter
iolo
gy
Cha
nge
in m
obili
ty
Cha
nge
in le
vel o
f dep
ende
nce
Adv
erse
eve
nts
Qua
lity
of li
fe
Adh
eren
ce w
ith t
reat
men
tre
gim
en
Num
bers
of
with
draw
als
per
trea
tmen
t gr
oup
Reas
ons
for
with
draw
al
Not
es a
bout
dupl
icat
epu
blic
atio
n
Lim
itatio
ns o
f the
stud
y as
not
ed b
yau
thor
s or
revi
ewer
Stud
y sp
onso
rshi
p
Health Technology Assessment 2006; Vol. 10: No. 12
123
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Que
stio
n 5a
: ass
essi
ng c
linic
al e
ffect
iven
ess
of t
hera
py in
dia
beti
c fo
ot u
lcer
s
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
enti
on d
etai
lsR
esul
tsW
ithd
raw
als
Com
men
ts
Firs
t au
thor
, yea
r,co
untr
y
Stud
y de
sign:
RC
Tor
CC
T
Met
hod
ofra
ndom
isatio
n (o
rm
etho
d of
allo
catio
n if
CC
T)
Uni
t of
allo
catio
n
Cal
cula
tion
ofst
atist
ical
pow
er
Out
com
es a
sses
sed
and
met
hods
of
data
col
lect
ion
used
Sett
ing
Popu
latio
n
Incl
usio
n cr
iteria
Excl
usio
n cr
iteria
Gen
der
Ethn
icity
Mea
n ±
SD a
ge
Type
of d
iabe
tes
Mea
n ±
SD d
urat
ion
of d
iabe
tes
Trea
ted
with
ora
l ant
i-dia
betic
med
icat
ion/
insu
lin d
epen
dent
Mea
n ±
SD H
bA1 C
Body
wei
ght/
BMI
Evid
ence
of n
euro
path
y an
d ty
pe
Evid
ence
of i
scha
emia
, deg
ree
and
met
hod
of a
sses
smen
t (e
.g.
toe
pres
sure
, ABP
I, T
CPO
2) o
rot
her
vasc
ular
dise
ase
Pres
ence
of r
etin
opat
hy
Und
erly
ing
fact
ors
such
as
nutr
ition
al s
tatu
s,im
mun
ocom
pete
nce,
con
tinen
ce,
mob
ility
Mea
n ±
SD u
lcer
are
a
Mea
n ±
SD u
lcer
dep
th
Mea
n ±
SD u
lcer
vol
ume
Mea
n ±
SD u
lcer
dur
atio
n
Num
ber
of u
lcer
epi
sode
s
Gra
de o
f ulc
er (e
.g. W
agne
r)
Prev
ious
am
puta
tion
Pres
ence
of n
ecro
tic t
issue
Pres
ence
of c
allu
s
Bact
erio
logy
Prio
r/cu
rren
t us
e of
ant
imic
robi
alag
ents
I1: d
escr
iptio
n of
antim
icro
bial
age
ntus
ed, g
ivin
g na
mes
of
antib
iotic
s or
oth
erag
ents
pre
scrib
ed, w
ithdo
se, f
requ
ency
and
dura
tion
ofad
min
istra
tion.
Also
repo
rt d
escr
iptio
n of
othe
r co
ncom
itant
inte
rven
tions
use
d su
chas
top
ical
app
licat
ions
and/
or d
ress
ings
. Rep
ort
num
bers
of p
atie
nts
rece
ivin
g th
is re
gim
en
I2: d
escr
iptio
n of
alte
rnat
ive
antim
icro
bial
agen
t us
ed, a
s ab
ove.
Repo
rt n
umbe
rs o
fpa
tient
s re
ceiv
ing
this
regi
men
C: d
escr
iptio
n of
con
trol
regi
men
, e.g
. sta
ndar
dca
re, g
ivin
g de
tails
of
any
agen
ts p
resc
ribed
,w
ith d
ose,
freq
uenc
yan
d du
ratio
n of
adm
inist
ratio
n. A
lsore
port
des
crip
tion
ofot
her
conc
omita
ntin
terv
entio
ns u
sed
such
as t
opic
al a
pplic
atio
nsan
d/or
dre
ssin
gs. R
epor
tnu
mbe
rs o
f pat
ient
sre
ceiv
ing
this
regi
men
Stat
istic
al m
etho
ds
Mor
talit
y (a
ll)
Mor
talit
y (r
elat
ed t
o am
puta
tion)
Am
puta
tion
(inci
denc
e an
d ty
pe,
e.g.
maj
or/m
inor
)
Inci
denc
e of
ost
eom
yelit
is
Num
ber/
dura
tion
of h
ospi
tal
adm
issio
ns fo
r D
FU p
robl
ems
Prop
ortio
n of
pat
ient
s ac
hiev
ing
com
plet
e he
alin
g
Tim
e to
com
plet
e he
alin
g
Cha
nge
in u
lcer
are
a (a
bsol
ute
orpe
rcen
tage
val
ues)
Rem
aini
ng w
ound
are
a
Hea
ling
rate
(abs
olut
e or
rel
ativ
e)
Cha
nge
in u
lcer
dep
th (a
bsol
ute
or r
elat
ive)
Cha
nge
in u
lcer
vol
ume
(abs
olut
eor
rel
ativ
e)
Recu
rren
ce o
f ulc
er
Pain
(in
patie
nts
with
out
neur
opat
hy)
Bact
eria
l pro
file
Acq
uisit
ion
of r
esist
ant
orga
nism
s
Rela
tions
hip
betw
een
ulce
rhe
alin
g an
d ba
cter
iolo
gy
Cha
nge
in m
obili
ty
Cha
nge
in le
vel o
f dep
ende
nce
Adv
erse
eve
nts
Qua
lity
of li
fe
Adh
eren
ce w
ith t
reat
men
tre
gim
en
Num
bers
of
with
draw
als
per
trea
tmen
t gr
oup
Reas
ons
for
with
draw
al
Ratio
nale
for
defin
ing
the
stud
yag
ent
as a
nan
timic
robi
al a
gent
,if
nece
ssar
y
Not
es a
bout
dupl
icat
epu
blic
atio
n
Lim
itatio
ns o
f the
stud
y as
not
ed b
yau
thor
s or
revi
ewer
Stud
y sp
onso
rshi
p
Appendix 3
124 Que
stio
n 5b
: ass
essi
ng t
he c
ost-
effe
ctiv
enes
s of
tre
atm
ent
in d
iabe
tic
foot
ulc
ers
Stud
y id
enti
fier
and
Key
ele
men
ts o
f the
stu
dyC
linic
al e
ffect
iven
ess
data
Econ
omic
ana
lysi
sR
esul
tsC
omm
ents
obje
ctiv
e
Firs
t au
thor
, yea
r,co
untr
y
Obj
ectiv
e(s)
of t
hest
udy
Type
of e
cono
mic
eva
luat
ion,
e.g.
CEA
, CU
A, C
BA
Pers
pect
ive,
e.g
. NH
S,pa
tient
, ins
uran
ce c
ompa
ny,
soci
ety
Sett
ings
of c
linic
alef
fect
iven
ess
stud
y an
dec
onom
ic e
valu
atio
n
Spec
ify d
ates
to
whi
ch d
ata
rela
te fo
r cl
inic
alef
fect
iven
ess
data
, res
ourc
eus
e an
d pr
ices
use
d
Stat
e so
urce
s, e
.g. s
ingl
e st
udy,
synt
hesis
of s
tudi
es, e
xper
top
inio
n/au
thor
s’ a
ssum
ptio
ns,
com
bina
tion
of a
bove
. Spe
cify
stud
y de
sign,
e.g
. RC
T,sy
stem
atic
rev
iew
and
met
hods
of d
ata
anal
ysis
used
(e.g
.in
tent
ion-
to-t
reat
)
Part
icip
ants
– d
escr
ibe
char
acte
ristic
s
Inte
rven
tions
– p
rovi
de d
etai
lsof
inte
rven
tions
/reg
imen
s us
ed
Clin
ical
out
com
es a
sses
sed,
incl
udin
g ad
vers
e ef
fect
s
Brie
f des
crip
tion
of r
esul
ts
If sin
gle
stud
y us
ed, d
escr
ibe
link
betw
een
clin
ical
effe
ctiv
enes
s an
d co
st d
ata
Mea
sure
of h
ealth
ben
efits
use
d
Des
crip
tion
of c
osts
(sep
arat
ede
scrip
tions
for
dire
ct a
ndin
dire
ct c
osts
), in
clud
ing
spec
ific
cost
s ta
ken
into
acc
ount
, sou
rce
of c
ost
data
/met
hods
of
estim
atio
n, d
iscou
ntin
g (if
appl
icab
le)
Cur
renc
y
Met
hods
use
d fo
r st
atist
ical
anal
ysis
of q
uant
ities
and
cos
ts
Met
hod
used
for
sens
itivi
tyan
alys
es (e
.g. o
ne-w
ay o
r m
ulti-
way
ana
lysis
); de
scrib
e re
leva
ntva
riabl
es a
nd a
ny a
ssum
ptio
nsus
ed
Des
crib
e m
odel
s (if
any
) use
d fo
res
timat
ion
of b
enef
its a
nd/o
rco
sts
Repo
rt e
stim
ated
hea
lthbe
nefit
s
Repo
rt e
stim
ated
cos
ts
Repo
rt r
esul
ts o
fsy
nthe
sis o
f cos
ts a
ndbe
nefit
s, e
.g. i
ncre
men
tal
cost
–util
ity o
f tre
atm
ent
Repo
rt r
esul
ts o
fse
nsiti
vity
ana
lyse
s, a
ndde
scrib
e th
e ra
nge
ofva
lues
der
ived
Not
es a
bout
dup
licat
epu
blic
atio
n
Lim
itatio
ns o
f the
stu
dy–
com
men
t on
the
follo
win
g: c
hoic
e of
com
para
tor;
val
idity
of
estim
ates
of
effe
ctiv
enes
s, h
ealth
bene
fits
and
cost
s;ex
tern
al v
alid
ity o
ffin
ding
s; a
utho
rs’ o
wn
note
s ab
out
limita
tions
of t
he s
tudy
. Sta
tew
heth
er t
he a
utho
rs’
conc
lusio
ns w
ere
just
ified
giv
en t
helim
itatio
ns o
f the
stu
dy
Stud
y sp
onso
rshi
p
ABP
I, an
kle
brac
hial
pre
ssur
e in
dex;
BM
I, bo
dy m
ass
inde
x; C
, con
trol
gro
up; C
BA, c
ost–
bene
fit a
naly
sis; C
CT,
con
trol
led
clin
ical
tria
l; C
EA, c
ost–
effe
ctiv
enes
s an
alys
is; C
UA
, cos
t-ut
ility
ana
lysis
; DFU
, dia
betic
foot
ulc
er; H
bA1 C
, gly
cosy
late
d ha
emog
lobi
n co
ncen
trat
ion;
I1, f
irst
inte
rven
tion
grou
p; I2
, sec
ond
inte
rven
tion
grou
p; R
CT,
ran
dom
ised
cont
rolle
d tr
ial;
ROC
, rec
eive
r op
erat
ing
char
acte
ristic
; SD
, sta
ndar
d de
viat
ion;
TCPO
2, t
rans
cuta
neou
s pr
essu
re o
f oxy
gen.
Health Technology Assessment 2006; Vol. 10: No. 12
125
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Appendix 4
Data extraction tables
Appendix 4
126 Dia
gnos
is d
ata
extr
acti
on
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sTe
st d
etai
lsRe
sults
With
draw
als
Com
men
ts
Gar
dner
(200
1),90
,95,
145
USA
Stud
y de
sign:
Cro
ss-s
ectio
nal
Met
hod
of p
atie
ntse
lect
ion:
Not
stat
ed
Out
com
eas
sess
men
t:A
dry
gauz
edr
essin
g w
asap
plie
d to
the
wou
nd a
nd le
ft in
plac
e fo
r 1ho
ur in
orde
r to
stan
dard
iseco
nditi
ons f
oras
sess
ing
wou
ndex
udat
e. A
fter
1ho
ur, t
hedr
essin
g w
asre
mov
ed a
nd th
ew
ound
and
dres
sing
wer
eas
sess
ed u
sing
the
CSS
C. T
his s
tep
was
repe
ated
inde
pend
ently
by
a se
cond
nur
sera
ter
Setti
ng –
4ce
ntre
s. Si
te A
–ac
ute
care
vete
rans
’ fac
ility
outp
atie
nts c
linics
;
Inclu
sion
crite
ria:
Site
s A–C
: n
= 2
6 (A
20,
B 4
,C
2):
Age
at le
ast
18 y
ears
; pre
senc
eof
full-
thick
ness
,no
n-ar
teria
lch
roni
c w
ound
;w
hite
blo
od c
ell
coun
t >
1500
cel
ls/m
m3
or to
tal
lymph
ocyt
e co
unt
>80
0 ce
lls/m
m3 ;
plat
elet
cou
nt>
125,
000/
mm
; no
coag
ulop
athi
es,
not o
nan
ticoa
gulat
ion
ther
apy
Site
D: n
= 1
0Ag
e at
leas
t18
year
s; pr
esen
ceof
non
-art
erial
chro
nic
wou
nd;
wou
nd b
iops
ype
rform
ed w
ithin
8ho
urs o
f dat
aco
llect
ion
Non
-art
erial
chro
nic
wou
nds
wer
e de
fined
as
wou
nds a
ssoc
iated
with
ven
ous
insu
fficie
ncy,
36 p
artic
ipan
ts re
crui
ted
Gen
der:
M 3
1 (8
6%),
F 5
(14%
)
Ethn
icity
: C
auca
sian:
35
(97%
)
Num
ber o
f wou
nds p
er p
artic
ipan
t:O
ne c
hron
ic w
ound
: 23
(63%
)Tw
o ch
roni
c w
ound
s: 6
(17%
)Th
ree
chro
nic
wou
nds:
6 (1
7%)
Four
chr
onic
wou
nds:
1 (3
%)
For p
artic
ipan
ts w
ith m
ore
than
one
wou
nd, a
sing
lew
ound
was
sele
cted
rand
omly
for s
tudy
.
Verif
ied
infe
ctio
n st
atus
:11
pat
ient
s had
pos
itive
wou
nd b
iops
y25
pat
ient
s had
neg
ative
wou
nd b
iops
y
Cha
ract
erist
ics fo
r tot
al sa
mpl
e; in
fect
ed a
nd n
on-
infe
cted
gro
ups:
Tota
lIn
f.N
on- I
nf.
Mea
n ±
SD65
.1 ±
64.5
±65
.4 ±
age:
13.2
16.9
11.5
Setti
ng:
Site
A20
(56%
)1
(9%
)19
(76%
)Si
te B
4 (1
1%)
0 (0
%)
4 (1
6%)
Site
C2
(5%
)0
(0%
)2
(8%
)Si
te D
10 (2
8%)
10 (9
1%)
0 (0
%)
Diab
etes
:N
one
20 (5
6%)
6 (5
5%)
14 (5
6%)
Type
12
(5%
)1
(9%
)1
(4%
)Ty
pe 2
14 (3
9%)
4 (3
6%)
10 (4
0%)
Nut
ritio
nal p
aram
eter
s (m
ean
±SD
):Re
d bl
ood
3.89
±0.
664.
06 ±
0.78
3.83
±0.
63ce
llsW
hite
blo
od
9.1
±5.
39.
2 ±
5.0
9.1
±5.
5ce
lls(n
= 3
3)(n
= 8
)(n
= 2
5)Al
bum
in3.
4 ±
0.7
3.5
±0.
83.
4 ±
0.7
(n=
32)
(n=
7)
(n=
25)
Tota
l pro
tein
6.9
±0.
97.
6 ±
0.5
6.8
±0.
9(n
= 3
0)(n
= 5
)(n
= 2
5)
Inde
x te
st:
Usin
g a
CSS
C, 5
indi
vidua
l clas
sic si
gns a
ndsy
mpt
oms o
f acu
tein
fect
ion
in c
hron
icw
ound
s wer
e ev
aluat
ed(p
ain, e
ryth
ema,
oed
ema,
heat
and
pur
ulen
tex
udat
e), p
lus 6
indi
vidua
l sign
s and
sym
ptom
s spe
cific
toin
fect
ion
in se
cond
ary
wou
nds (
sero
us e
xuda
tepl
us c
oncu
rren
tin
flam
mat
ion,
del
ayed
heali
ng, d
iscol
orat
ion
ofgr
anul
atio
n tis
sue,
friab
legr
anul
atio
n tis
sue,
foul
odou
r, an
d w
ound
brea
kdow
n). 3
6 pa
tient
sre
ceive
d th
e te
st
Refe
renc
e te
st:
Qua
ntita
tive
cultu
re o
fvia
ble
wou
nd ti
ssue
acco
rdin
g to
pro
cedu
res
outli
ned
by S
totts
.175
Wou
nd c
lean
sed
with
norm
al sa
line
usin
g st
erile
tech
niqu
e. A
ppro
x.1
g of
non-
necr
otic,
viab
lew
ound
tiss
ue o
btain
edfro
m th
e ce
ntre
of t
heul
cer u
sing
3 or
4 m
mde
rmal
punc
h un
der
ster
ile c
ondi
tions
. Tiss
uetr
ansp
orte
d im
med
iatel
yto
micr
obio
logy
labor
ator
y. M
etho
ds o
f
The
stud
y au
thor
s rep
orte
d 2
×2
diag
nost
ic da
ta fo
r eac
h of
11
clini
cal s
igns a
nd sy
mpt
oms o
fch
roni
c w
ound
infe
ctio
n, a
sfo
llow
s:
Incr
easin
g pa
in
Biop
sy
+–
Tota
l
CSS
C+
40
4–
725
32To
tal
1125
36
Eryt
hem
a
Biop
sy
+–
Tota
l
CSS
C+
68
14–
517
22To
tal
1125
36
Oed
ema
Biop
sy
+–
Tota
l
CSS
C+
77
14–
418
22To
tal
1125
36
Hea
t
Biop
sy
+–
Tota
l
CSS
C+
24
6–
921
30To
tal
1125
36
No
with
draw
alsw
ere
repo
rted
Lim
itatio
ns o
f the
stud
y as
not
ed b
yau
thor
s:
Cro
ss-s
ectio
nal
stud
y de
sign
prec
lude
s cau
sean
d ef
fect
relat
ions
hip
analy
sis. R
eliab
ility
of th
e C
SSC
nee
dsfu
rthe
r exp
lora
tion
with
a la
rger
, mor
ere
pres
enta
tive
sam
ple
ofcli
nicia
ns.
Gen
erali
sabi
lity
offin
ding
s lim
ited
owin
g to
non
-pr
obab
ility
sam
plin
g us
ed. T
heen
rolle
dpa
rtici
pant
s migh
tno
t be
repr
esen
tativ
e of
all c
hron
ic w
ound
patie
nts,
and
only
70%
of e
ligib
lepa
tient
s too
k pa
rtin
the
stud
y.Ag
reem
ent
betw
een
clini
cians
not a
ccou
nted
for
in e
stim
ates
of
valid
ity (e
stim
ates
base
d on
asse
ssm
ent o
f onl
yon
e ob
serv
atio
n).
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
127
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sTe
st d
etai
lsRe
sults
With
draw
als
Com
men
ts
Site
B –
vet
eran
s’lo
ng-te
rm c
are
facil
ity; S
ite C
–ve
tera
ns’ i
npat
ient
facil
ity w
ithnu
rsin
g ho
me
beds
,re
habi
litat
ion
beds
and
inte
rmed
iate
psyc
hiat
ry b
eds;
Site
D –
unive
rsity
-bas
edm
edica
l cen
tre
chro
nic
wou
ndcli
nic
serv
ing
inpa
tient
s and
outp
atie
nts
perip
hera
lne
urop
athy
,su
rgica
l inc
ision
, or
trau
ma,
with
adeq
uate
art
erial
perfu
sion
asde
term
ined
by
palp
able
loca
lpu
lses o
r ank
le-
brac
hial
inde
x>
0.5)
Rece
iving
syst
emic
antib
iotic
s at t
ime
of re
crui
tmen
t:N
o24
(67%
)10
(91%
)14
(56%
)Ye
s12
(33%
)1
(9%
)11
(44%
)
Rece
iving
ant
i-inf
lamm
ator
y m
edica
tion
at ti
me
ofre
crui
tmen
t:N
o20
(56%
)9
(82%
)11
(44%
)Ye
s16
(44%
)2
(18%
)14
(56%
)
Rece
iving
ster
oid
med
icatio
n at
tim
e of
recr
uitm
ent:
No
33 (9
2%)
10 (9
1%)
23 (9
2%)
Yes
3 (8
%)
1 (9
%)
2 (8
%)
Wou
nd ty
pe:
Pres
sure
ulce
r19
(53%
)3
(27%
)16
(64%
)Ve
nous
ulce
r7
(19%
)4
(37%
)3
(12%
)Se
cond
ary
incis
ion
6 (1
7%)
2 (1
8%)
4 (1
6%)
Chr
onic
trau
mat
ic2
(5.5
%)
1 (9
%)
1 (4
%)
Diab
etic
ulce
r2
(5.5
%)
1 (9
%)
1 (4
%)
Wou
nd si
ze:
Mea
n ±
SDar
ea (c
m2 )
4.5
±6.
95.
5 ±
6.1
4.1
±7.
3M
ean
±SD
dept
h (c
m)
1.3
±1.
60.
8 ±
0.9
1.4
±1.
8
Mea
n ±
SDw
ound
dur
atio
n (d
ays)
:61
6.6
1002
447.
1±
1742
.8±
2673
.3±
1163
.6
Num
ber (
%) o
f pat
ient
s with
nec
rotic
tiss
ue:
Non
e15
(42%
)1
(9%
)14
(56%
)<
25%
9 (2
5%)
5 (4
5%)
4 (1
6%)
25–5
0%8
(22%
)4
(36%
)4
(16%
)>
50 a
nd <
75%
3 (8
%)
1 (9
%)
2 (8
%)
75–1
00%
1 (3
%)
0 (0
%)
1 (4
%)
Type
of t
opica
l age
nts i
n us
e:N
one
24 (6
7%)
7 (6
4%)
17 (6
8%)
Gro
wth
fact
or4
(11%
)1
(9%
)3
(12%
)Si
lver s
ulfa
diaz
ine
4 (1
1%)
1 (9
%)
3 (1
2%)
Antib
iotic
3 (8
%)
2 (1
8%)
1 (4
%)
Wou
nd g
el
1 (3
%)
0 (0
%)
1 (4
%)
labor
ator
y cu
lturin
gfo
llow
ed th
ose
of K
rizek
and
Robs
on 17
6Ti
ssue
was
wei
ghed
,ho
mog
enise
d an
d se
rially
dilu
ted
and
plat
ed. E
ach
serie
s of d
ilutio
ns w
aspl
ated
und
er a
erob
ic an
dan
aero
bic
cond
ition
s.O
rgan
isms w
ere
iden
tifie
d us
ing
stan
dard
micr
obio
logic
alpr
oced
ures
. 36
patie
nts
rece
ived
the
test
Infe
cted
ulce
rs w
ere
defin
ed a
s tho
se h
avin
g at
leas
t 105
orga
nism
s per
gram
of v
iable
tiss
ue o
rw
ound
s con
tain
ing
haem
olyt
ic St
rept
ococ
cus
at a
ny le
vel.
Non
-in
fect
ed u
lcers
wer
ede
fined
as t
hose
with
spec
imen
s con
tain
ing
less
than
105
orga
nism
s per
gram
of t
issue
Tim
ing:
At
site
s A, B
and
C,
tissu
e bi
opsy
was
obta
ined
less
than
1ho
uraf
ter a
sses
smen
t with
the
CSS
C. A
t site
D, t
hew
ound
bio
psy
was
perfo
rmed
with
in
8 ho
urs o
f ass
essm
ent
with
CSS
C
Asse
ssm
ent o
f int
er-r
ater
relia
bilit
y:Th
e in
ter-
rate
r rel
iabilit
y
Puru
lent
exu
date
Biop
sy
+–
Tota
l
CSS
C+
29
11–
916
25To
tal
1125
36
Sero
us e
xuda
te p
lus c
oncu
rren
tin
flam
mat
ion
Biop
sy
+–
Tota
l
CSS
C+
67
13–
518
23To
tal
1125
36
Del
ayed
hea
ling
Biop
sy
+–
Tota
l
CSS
C+
99
18–
216
18To
tal
1125
36
Disc
olou
ratio
n
Biop
sy
+–
Tota
l
CSS
C+
711
18–
414
18To
tal
1125
36
Friab
le g
ranu
latio
n Biop
sy
+–
Tota
l
CSS
C+
96
15–
219
21To
tal
1125
36
Mix
ture
of
wou
nds/s
mall
sam
ple
prec
lude
dan
alysis
by
type
of
wou
nd
Stud
y sp
onso
rshi
p:pa
rt fu
ndin
g by
Nat
iona
l Pre
ssur
eU
lcer A
dviso
ryPa
nel,
Knol
lPh
arm
aceu
tical,
The
Ger
onto
logic
alN
ursin
gIn
terv
entio
nC
ente
r, th
e VA
Pred
octo
ral N
urse
Fello
wsh
ipPr
ogra
m, O
ffice
of
Acad
emic
Affil
iatio
ns,
Dep
artm
ent o
fVe
tera
ns A
ffairs
,an
Inst
itutio
nal
NRS
A fe
llow
ship
(Res
earc
h Tr
ainin
gin
Ger
onto
logic
alN
ursin
g) fr
om th
eN
atio
nal I
nstit
ute
of N
ursin
gRe
sear
ch, N
atio
nal
Inst
itute
s of
Hea
lth, a
nIn
stitu
tiona
l NRS
Afe
llow
ship
(Inte
rdisc
iplin
ary
Rese
arch
Tra
inin
gPr
ogra
m o
n Ag
ing)
from
the
Nat
iona
l
cont
inue
d
Appendix 4
128
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sTe
st d
etai
lsRe
sults
With
draw
als
Com
men
ts
of th
e ite
ms o
n th
ech
eckl
ist w
as a
sses
sed
usin
g w
ound
obse
rvat
ions
mad
ein
depe
nden
tly b
y th
epr
incip
al in
vest
igato
r and
one
of fi
ve sp
ecifi
cally
train
ed n
urse
sre
pres
entin
g ea
ch st
udy
site.
The
�ra
nge
was
0.53
–1.0
0. N
oag
reem
ent w
as fo
und
for
one
clini
cal s
ign(p
ocke
ting
of th
e w
ound
base
) due
to n
on-
occu
rren
ce o
f the
sign
inth
e st
udy
sam
ple.
Ther
efor
e, th
e di
agno
stic
perfo
rman
ce o
f thi
s sign
was
not
eva
luat
ed
Foul
odo
ur
Biop
sy
+–
Tota
l
CSS
C+
43
7–
722
29To
tal
1125
36
Wou
nd b
reak
dow
n Biop
sy
+–
Tota
l
CSS
C+
50
5–
625
31To
tal
1125
36
Resu
lts fo
r tot
al sa
mpl
e (n
= 3
6)Se
nsiti
vity
and
spec
ificit
y of
eac
hsig
n or
sym
ptom
(calc
ulat
ed b
yst
udy
auth
ors a
nd c
heck
ed b
yre
view
er):
SeSp
Incr
easin
g pa
in36
%10
0%Er
ythe
ma
55%
68%
Oed
ema
64%
72%
Hea
t18
%84
%Pu
rule
nt e
xuda
te18
%64
%Se
rous
+
infla
mm
atio
n55
%72
%D
elay
ed h
ealin
g81
%64
%D
iscol
orat
ion
64%
56%
Friab
le g
ranu
latio
n82
%76
%Fo
ul o
dour
36%
88%
Wou
nd b
reak
dow
n46
%10
0%
Pred
ictive
valu
es (P
PV c
alcul
ated
by st
udy
auth
ors a
nd c
heck
ed b
yre
view
er; N
PV c
alcul
ated
by
revie
wer
):
Inst
itute
on
Agin
g,N
atio
nal I
nstit
utes
of H
ealth
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
129
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sTe
st d
etai
lsRe
sults
With
draw
als
Com
men
ts
PPV
NPV
Incr
easin
g pa
in10
0%78
%Er
ythe
ma
43%
77%
Oed
ema
50%
82%
Hea
t33
%70
%Pu
rule
nt e
xuda
te18
%64
%Se
rous
+
infla
mm
atio
n46
%78
%D
elay
ed h
ealin
g50
%89
%D
iscol
orat
ion
39%
78%
Friab
le g
ranu
latio
n60
%90
%Fo
ul o
dour
57%
76%
Wou
nd b
reak
dow
n10
0%81
%
Like
lihoo
d ra
tios (
+LR
calc
ulat
edby
stud
y au
thor
s and
che
cked
by
revie
wer
/–LR
calc
ulat
ed b
yre
view
er):
+LR
–LR
Incr
easin
g pa
in18
.18
0.64
Eryt
hem
a1.
710.
67O
edem
a2.
270.
5H
eat
1.14
0.97
Puru
lent
exu
date
0.51
a1.
28a
Sero
us +
in
flam
mat
ion
1.95
0.63
Del
ayed
hea
ling
2.27
0.28
Disc
olor
atio
n1.
450.
65Fr
iable
gra
nulat
ion
3.41
0.24
Foul
odo
ur3.
030.
72W
ound
bre
akdo
wn
22.7
30.
55
cont
inue
d
Appendix 4
130
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sTe
st d
etai
lsRe
sults
With
draw
als
Com
men
ts
Resu
lts fo
r pat
ient
s with
ven
ous
leg
ulce
rs (n
= 7
)
Sens
itivit
y (c
alcul
ated
by
stud
yau
thor
s, re
view
er u
nabl
e to
chec
k as
2 ×
2 da
ta n
otpr
ovid
ed):
Incr
easin
g pa
in5%
Eryt
hem
a50
%O
edem
a10
0%H
eat
25%
Puru
lent
exu
date
67%
Sero
us +
infla
mm
atio
n25
%D
elay
ed h
ealin
g10
0%D
iscol
orat
ion
25%
Friab
le g
ranu
latio
n75
%Fo
ul o
dour
25%
Wou
nd b
reak
dow
n75
%
CSS
C, c
linica
l sign
s and
sym
ptom
s che
cklis
t; F,
fem
ale; I
nf, i
nfec
ted;
LR,
like
lihoo
d ra
tio; M
, male
; Non
-inf,
non-
infe
cted
; NPV
, neg
ative
pre
dict
ive v
alue;
PPV
, pos
itive
pre
dict
ive v
alue;
SD
, sta
ndar
d de
viatio
n; S
e, se
nsiti
vity;
Ser
ous +
infla
mm
atio
n, se
rous
exu
date
plu
s con
curr
ent i
nflam
mat
ion;
Sp,
spec
ificit
y; T
ot, t
otal.
a Fo
r pur
ulen
t exu
date
, the
valu
es fo
r LRs
are
the
oppo
site
to w
hat w
ould
nor
mall
y be
exp
ecte
d, th
at is
, the
+LR
in th
is ca
se is
less
than
1 a
nd th
e –L
R is
grea
ter t
han
1. T
his m
ay b
e ex
plain
ed a
s fol
low
s.Fo
r the
+LR
, the
ratio
is d
erive
d fro
m th
e ve
ry lo
w se
nsiti
vity
for t
his c
linica
l sign
(18%
) and
the
relat
ively
high
num
ber o
f fals
e po
sitive
s exp
ress
ed a
s a p
ropo
rtio
n of
the
tota
l with
out d
iseas
e as
verif
ied
by th
e re
fere
nce
stan
dard
. For
the
–LR
the
ratio
is d
erive
d fro
m th
e lar
ge p
ropo
rtio
n of
false
neg
ative
s rel
ative
to th
e to
tal w
ith d
iseas
e an
d th
e sp
ecifi
city
of 6
4%. T
hese
find
ings
are
as w
ould
be e
xpec
ted
for a
test
that
exc
lude
s dise
ase
as o
ppos
ed to
iden
tifyin
g it.
The
con
clusio
n fro
m th
ese
data
is th
at p
urul
ent e
xuda
te is
a v
ery
poor
test
of t
he p
rese
nce
of in
fect
ion
and
that
abs
ence
of t
his
clini
cal s
ign is
mor
e lik
ely
to in
dica
te in
fect
ion
than
its p
rese
nce.
Health Technology Assessment 2006; Vol. 10: No. 12
131
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sTe
st d
etai
lsRe
sults
With
draw
als
Com
men
ts
Ratli
ff (2
002)
,92
USA
Stud
y de
sign:
Pros
pect
iveco
hort
Met
hod
of p
atie
ntse
lect
ion:
Patie
nts w
ere
recr
uite
d w
hoat
tend
ed th
e cli
nic
from
Nov
embe
r20
01 to
Apr
il20
02
Out
com
eas
sess
men
t:2
×2
diag
nost
icda
ta w
ere
repo
rted
for
diffe
rent
crit
eria
to d
efin
e in
fect
ion
usin
g se
mi-
quan
titat
ivean
alysis
tech
niqu
es
Setti
ng:
Uni
vers
ity-b
ased
wou
nd c
are
clini
c
Eligi
bilit
y cr
iteria
for i
nclu
sion
in th
est
udy:
Patie
nts w
ithw
ound
s pre
sent
for m
ore
than
6m
onth
s (co
uld
inclu
de a
ny ty
pe o
fcu
tane
ous w
ound
at a
ny b
ody
site)
Exclu
sion
crite
ria:
Wou
nds w
ithgr
oss s
urfa
ceco
ntam
inat
ion,
necr
otic
tissu
e,pu
rule
nt d
rain
age
or e
scha
r
n=
124
wou
nds o
n 12
4 pa
tient
s
Gen
der:
male
74,
fem
ale 5
0
Mea
n ag
e: N
ot re
port
ed
Type
of d
iabet
es: N
ot re
port
ed
Wou
nd ty
pe:
Pres
sure
ulce
rs 4
4Ve
nous
ulce
rs 2
7N
euro
path
ic or
diab
etic
ulce
rs 2
9Lo
wer
ext
rem
ity a
rter
ial u
lcers
8O
ther
aet
iolo
gies 1
6
Wou
nd tr
eatm
ent p
rior t
osa
mpl
ing:
The
wou
nd w
as c
lean
ed to
rem
ove
surfa
ce c
onta
min
atio
nus
ing
a st
erile
4 ×
4 cm
gau
zem
oist
ened
with
ster
ile sa
line
Inde
x te
st: s
emi-q
uant
itativ
ean
alysis
(124
pat
ient
s):
Usin
g st
erile
tech
niqu
e, a
nalg
inat
e-tip
ped
appl
icato
r was
rota
ted
over
a 1
cm
2ar
ea fo
r5
seco
nds w
ith su
fficie
ntpr
essu
re to
cau
se ti
ssue
flui
d to
be e
xpre
ssed
. The
tip
of th
esw
ab w
as b
roke
n of
f int
o a
ster
ile tr
ansp
ort t
ube.
The
sam
ple
was
tran
spor
ted
imm
ediat
ely
to th
e lab
orat
ory
for p
roce
ssin
g. T
he sw
ab w
aspr
oces
sed
usin
g a
sem
i-qu
antit
ative
tech
niqu
e. A
blo
odag
ar p
late
was
stre
aked
thre
etim
es o
n on
e qu
adra
nt a
nd th
enth
ree
times
on
each
rem
ainin
gqu
adra
nt in
sequ
ence
(I, I
I, III
,IV
) usin
g a
ster
ile lo
op fo
r eac
hqu
adra
nt, i
n or
der t
o cr
eate
dilu
tions
of t
he o
rigin
al sw
ab in
each
qua
dran
t. Th
e m
ore
bact
eria
on th
e or
igina
l sw
ab,
the
mor
e qu
adra
nts s
how
ing
bact
erial
gro
wth
. All
plat
edsp
ecim
ens w
ere
incu
bate
dun
der a
erob
ic co
nditi
ons a
t37
ºC. A
fter 2
4ho
urs,
the
plat
esw
ere
visua
lly in
spec
ted
and
colo
nies
of b
acte
ria c
ount
ed in
the
four
qua
dran
ts
2 ×
2 ta
ble
for s
emi-q
uant
itativ
ede
finiti
on o
f inf
ectio
n as
gro
wth
in q
uadr
ant I
II or
qua
dran
ts II
Ian
d IV
:
Qua
ntita
tive
+–
Tota
l
Sem
i-qua
nt.
+42
749
–11
6475
Tota
l53
7112
4
Sens
itivit
y 79
%Sp
ecifi
city
90%
Oth
er m
easu
res (
calcu
lated
by
revie
wer
):
PPV
86%
NPV
85%
+LR
8.0
4–L
R 0.
23
2 ×
2 ta
ble
for s
emi-q
uant
itativ
ede
finiti
on o
f inf
ectio
n as
gro
wth
in q
uadr
ant I
I, qu
adra
nts I
I and
III
or q
uadr
ants
II, I
II an
d IV
:
Qua
ntita
tiv
+–
Tota
l
Sem
i-qua
nt.
+53
2679
–0
4545
Tota
l53
7112
4
Der
ived
mea
sure
s (ca
lculat
ed b
yre
view
er):
Sens
itivit
y 10
0%Sp
ecifi
city
63%
PPV
67%
NPV
100
%
+LR
2.7
3–L
R 0.
015
Ther
e w
ere
now
ithdr
awals
Sugg
estio
ns fo
rfu
ture
rese
arch
, as
sugg
este
d by
the
auth
ors:
Com
paris
on o
fco
tton-
tippe
dsw
abs a
nd c
alciu
malg
inat
e-tip
ped
swab
s sho
uld
bepe
rform
ed(a
lgina
te sw
abs
wer
e us
ed in
this
stud
y be
caus
eco
tton-
tippe
dsw
abs m
ay b
eba
cter
iost
atic
seco
ndar
y to
the
oxid
ative
ster
ilisat
ion
proc
edur
e;alg
inat
e sw
ab is
mor
e ex
pens
iveth
an c
otto
n sw
ab)
Lim
itatio
ns o
f the
stud
y as
not
ed b
yre
view
er:
Mix
ed p
opul
atio
nin
term
s of w
ound
aetio
logy
Stud
y sp
onso
rshi
p:N
ot st
ated
cont
inue
d
Appendix 4
132
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sTe
st d
etai
lsRe
sults
With
draw
als
Com
men
ts
Refe
renc
e te
st: q
uant
itativ
ean
alysis
(124
pat
ient
s):
Follo
win
g th
e ac
quisi
tion
of th
esw
ab sa
mpl
e fo
r sem
i-qu
antit
ative
ana
lysis,
ano
ther
swab
was
obt
ained
from
the
sam
e sit
e us
ing
the
sam
ete
chni
que.
The
tip
of th
e sw
abw
as b
roke
n of
f and
plac
ed in
to a
ster
ile tr
ansp
ort t
ube
cont
ainin
g5
ml o
f nor
mal
salin
e. T
hesa
mpl
e w
as tr
ansp
orte
dim
med
iatel
y to
the
labor
ator
yfo
r pro
cess
ing.
The
swab
was
proc
esse
d us
ing
a qu
antit
ative
tech
niqu
e. S
erial
dilu
tions
of t
hesw
abs w
ere
perfo
rmed
and
plat
ed o
n st
erile
aga
r med
ium
.Al
l plat
ed sp
ecim
ens w
ere
incu
bate
d un
der a
erob
icco
nditi
ons a
t 37º
C. A
fter 2
4ho
urs,
the
plat
es w
ere
visua
llyin
spec
ted
and
colo
nies
of
bact
eria
coun
ted.
CFU
s wer
eut
ilised
to d
eter
min
e th
e to
tal
bact
erial
cou
nt o
n ea
ch p
late
Soft
tissu
e in
fect
ion
was
de
fined
as t
he p
rese
nce
of
>10
5C
FU c
m2
Tim
ing:
The
swab
for q
uant
itativ
ean
alysis
was
obt
ained
afte
r the
swab
for s
emi-q
uant
itativ
ean
alysis
. The
tim
e in
terv
albe
twee
n th
e ac
quisi
tion
of th
etw
o sp
ecim
ens w
as n
ot st
ated
2 ×
2 ta
ble
for s
emi-q
uant
itativ
ede
finiti
on o
f inf
ectio
n as
gro
wth
in q
uadr
ant I
, qua
dran
ts I
and
II,qu
adra
nts I
, II a
nd II
I or
quad
rant
s I, I
I, III
and
IV:
Qua
ntita
tive
+–
Tota
l
Sem
i-qua
nt+
5345
98–
026
26To
tal
5371
124
Der
ived
mea
sure
s (ca
lculat
ed b
yre
view
er):
Sens
itivit
y 10
0%Sp
ecifi
city
37%
PPV
54%
NPV
100
%
+LR
1.5
8–L
R 0.
026
2 ×
2 ta
ble
for s
emi-q
uant
itativ
ede
finiti
on o
f inf
ectio
n as
gro
wth
in q
uadr
ants
I, II
, III
and
IV:
Qua
ntita
tive
+–
Tota
l
Sem
i-qua
nt.
+14
115
–39
7010
9To
tal
5371
124
Der
ived
mea
sure
s (ca
lculat
ed b
yre
view
er):
Sens
itivit
y 26
%Sp
ecifi
city
99%
PPV
93%
NPV
64%
+LR
18.
75–L
R 0.
75
Health Technology Assessment 2006; Vol. 10: No. 12
133
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sTe
st d
etai
lsRe
sults
With
draw
als
Com
men
ts
Bill
(200
1),91
USA
Stud
y de
sign:
Cro
ss-s
ectio
nal
Met
hod
of p
atie
ntse
lect
ion:
Con
secu
tive
Out
com
eas
sess
men
t:C
orre
latio
nbe
twee
n re
sults
of q
uant
itativ
ew
ound
bio
psy
and
swab
cul
ture
Setti
ng:
Uni
vers
ity-b
ased
,m
ultid
iscip
linar
ych
roni
c w
ound
cent
re
Eligi
bilit
y cr
iteria
for i
nclu
sion
in th
est
udy:
Willi
ng p
artic
ipan
tsw
ith in
form
edco
nsen
t. An
ycu
tane
ous w
ound
,at
any
bod
y sit
e,pr
esen
t for
mor
eth
an 6
mon
ths.
(Pat
ient
s with
gros
s sur
face
cont
amin
atio
n of
the
wou
nd,
necr
otic
tissu
e,pu
rule
nt d
rain
age
or e
scha
r wer
eno
t cul
ture
d)
n=
38
Gen
der:
M 2
5, F
13
Ethn
icity
: Afri
can–
Amer
ican:
12
Cau
casia
n: 2
6
Mea
n ag
e: 5
9ye
ars
Type
of d
iabet
es: N
ot st
ated
Wou
nd ty
pe:
Pres
sure
ulce
rs 1
8Lo
wer
ext
rem
ity d
iabet
ic w
ound
s10 W
ound
s sec
onda
ry to
ven
ous
stas
is di
seas
e 5
Arte
rial u
lcers
5
Wou
nd tr
eatm
ent p
rior t
o sa
mpl
ing:
A st
erile
4 × 4
cm
gau
ze w
as m
oist
ened
with
ster
ilesa
line
and
the
wou
nd su
rface
wip
edvig
orou
sly to
rem
ove
surfa
ce c
onta
min
atio
n.If
>1
wou
nd w
as p
rese
nt p
er p
atie
nt, t
helar
gest
was
sele
cted
for s
tudy
Inde
x te
st: S
wab
cul
ture
(38
patie
nts)
: us
ing
a st
erile
tech
niqu
e, a
n alg
inat
e-tip
ped
appl
icato
r rot
ated
ove
r a 1
× 1
cm a
rea
for
5se
cond
s with
suffi
cient
pre
ssur
e to
exp
ress
tissu
e flu
id. S
ampl
e ta
ken
from
the
cent
re o
fth
e w
ound
. Tip
of t
he sw
ab b
roke
n of
f int
o a
ster
ile tr
ansp
ort t
ube
cont
ainin
g 5
ml o
fsa
line.
Ser
ial d
ilutio
ns o
f sw
ab sa
mpl
epe
rform
ed a
nd p
lated
on
ster
ile a
gar
med
ium
Refe
renc
e te
st: w
ound
bio
psy
(38
patie
nts)
:5
mm
pun
ch b
iops
y w
as ta
ken
from
the
cent
re o
f the
swab
site
. Ste
rile
forc
eps u
sed
to tr
ansfe
r the
sam
ple
to th
e tr
ansp
ort v
ialbe
fore
imm
ediat
e tr
ansfe
r to
the
labor
ator
y.Ti
ssue
bio
psy
sam
ples
wei
ghed
and
hom
ogen
ised
with
a st
erile
tiss
ue g
rinde
rbe
fore
bei
ng p
lated
on
a st
erile
aga
r med
ium
All p
lated
spec
imen
s inc
ubat
ed u
nder
aero
bic
cond
ition
s (37
°C).
Afte
r 24
hour
s,pl
ates
visu
ally
insp
ecte
d an
d ba
cter
ia co
loni
esco
unte
d. C
FUs u
sed
to d
eter
min
e to
tal
bact
erial
cou
nt o
f eac
h pl
ate
Auth
ors d
efin
ed so
ft tis
sue
infe
ctio
n >
105
CFU
sg o
f tiss
ue fo
r qua
ntita
tive
wou
nd b
iops
y an
d >
105
CFU
scm
2fo
r sw
abcu
lture
.
Tim
ing:
bio
psy
follo
wed
imm
ediat
ely
afte
rsw
ab c
ultu
re o
btain
ed
2 ×
2 ta
ble:
Biop
sy
+–
Tota
l
Swab
+22
426
–6
612
Tota
l28
1038
Der
ived
mea
sure
s (ca
lculat
ed b
yre
view
er):
Sens
itivit
y 79
%Sp
ecifi
city
60%
PPV
85%
NPV
50%
+LR
1.9
6–L
R 0.
36
Num
ber o
fpa
tient
s los
t to
follo
w-u
p: n
one
Lim
itatio
ns o
f the
stud
y as
not
ed b
yau
thor
s: fu
rthe
rre
sear
ch sh
ould
inclu
de m
ore
patie
nts w
ithlar
ger n
umbe
r of
wou
nd a
etio
logie
s
Lim
itatio
ns o
f the
stud
y as
not
ed b
yre
view
er: t
he sm
allnu
mbe
r of p
atie
nts
recr
uite
d ov
erall
and
the
hete
roge
neou
sna
ture
of t
hegr
oup
with
rega
rdto
wou
nd ty
pem
ean
that
the
deriv
ed d
iagno
stic
mea
sure
s sho
uld
be in
terp
rete
dw
ith g
reat
cau
tion
The
stud
y au
thor
sw
ere
cont
acte
dan
d re
ques
ted
topr
ovid
e 2
×2
diag
nost
ic da
ta o
nth
e pa
tient
s with
DFU
s, bu
t dat
aw
ere
unav
ailab
le
Appendix 4
134 Effe
ctiv
enes
s da
ta e
xtra
ctio
n ta
bles
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Apel
qvist
(199
6),12
2,12
6
Swed
en
Stud
y de
sign:
RC
T, o
pen
desig
n
Met
hod
ofra
ndom
isatio
n:C
ompu
ter-
gene
rate
d lis
t.Pa
tient
s wer
e st
ratif
ied
acco
rdin
g to
size
and
type
of t
he u
lcer
(Wag
ner g
rade
1 o
r 2)
Uni
t of a
lloca
tion:
Pat
ient
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
des
crib
ed
Out
com
e as
sess
men
t:Pa
tient
s wer
e ex
amin
edat
the
end
of w
eeks
1, 4
,8
and
12. C
olou
rph
otog
raph
s with
scale
sw
ere
take
n at
the
visits
to th
e fo
ot c
are
team
.Ph
otog
raph
s wer
eev
aluat
ed b
lind
at th
een
d of
the
stud
y by
two
inde
pend
ent p
hysic
ians.
In th
e ev
ent o
fdi
sagr
eem
ent i
n th
eev
aluat
ion
ofph
otog
raph
s, th
eas
sess
men
t by
the
foot
care
team
was
dec
isive
.Th
e ou
tcom
e w
ascla
ssifi
ed a
s suc
cess
ful i
fth
e in
itial
ulce
r are
a w
asre
duce
d by
>50
% o
r an
Inclu
sion
crite
ria:
Cau
casia
n,>
40ye
ars o
ld, w
itha
hist
ory
of d
iabet
esm
ellit
us a
nd a
nex
udin
g ca
vity
ulce
rbe
low
the
ankl
e(W
agne
r gra
de 1
or
2) w
ith u
lcer a
rea
>1
cm2
and
syst
olic
toe
pres
sure
>30
mm
Hg
orsy
stol
ic an
kle
pres
sure
>80
mm
Hg
Wag
ner g
rade
1 w
ascla
ssifi
ed a
s asu
perfi
cial u
lcer
brea
king
thro
ugh
subc
utan
eous
tiss
uean
d gr
ade
2 as
ade
ep u
lcer
Onl
y on
e ul
cer w
asst
udie
d in
eac
hpa
tient
. If t
here
wer
e se
vera
l ulce
rs,
the
large
st fu
lfillin
gth
e in
clusio
n cr
iteria
was
cho
sen
Exclu
sion
crite
ria:
Patie
nts w
ith u
lcer
area
>25
cm
2 ,pr
esen
ce o
f dee
pab
sces
s,os
teom
yelit
is, o
rga
ngre
ne (W
agne
rgr
ade
3 or
4),
Base
line
char
acte
ristic
s wer
e no
tre
port
ed in
det
ail; h
owev
er, t
heau
thor
s sta
ted
that
ther
e w
ere
nom
ajor d
iffer
ence
s bet
wee
n th
e tw
otr
eatm
ent g
roup
s in
clini
cal
char
acte
ristic
s
All p
atie
nts h
ad si
gns o
f sev
ere
sens
ory
neur
opat
hy, a
nd in
all
exce
pt tw
o ca
ses,
a pr
ecip
itatin
gca
use
of th
e ul
cer w
as se
en, o
fw
hich
mec
hani
cal s
tres
s was
the
mos
t com
mon
(n=
27)
Appr
oxim
atel
y 50
% o
f pat
ient
s had
prev
ious
am
puta
tions
, mos
tly d
ue to
deep
infe
ctio
n pr
ior t
o in
clusio
n
I: To
pica
l tre
atm
ent w
ithca
dexo
mer
iodi
ne o
intm
ent
(Iodo
sorb
®).
Dre
ssin
gs w
ere
chan
ged
once
dail
y du
ring
the
first
wee
k an
d da
ily o
r eve
ryse
cond
or t
hird
day
dur
ing
the
follo
win
g w
eeks
dep
endi
ng o
nth
e de
gree
of e
xuda
tion
(n =
22)
C: S
tand
ard
topi
cal t
reat
men
tco
nsist
ing
of:g
enta
mici
nso
lutio
n 80
mg/
ml (
Gar
amyc
in®
,Sc
herin
g-Pl
ough
), pr
escr
ibed
twice
dail
y if
an u
lcer w
asin
fect
ed (i
.e. c
ellu
litis
pres
ent);
stre
ptod
orna
se/st
rept
okin
ase
(Var
idas
e®, L
eder
le),
used
for
moi
st, n
ecro
tic le
sions
,ch
ange
d tw
ice d
aily;
or d
rysa
line
gauz
e (M
esalt
®),
used
as
an a
bsor
ptive
dre
ssin
g an
dch
ange
d on
ce o
r tw
ice d
aily
acco
rdin
g to
the
degr
ee o
fex
udat
ion
(n=
19)
All p
atie
nts:
Ora
l ant
ibio
tics (
cipro
floxa
cin,
ceph
alosp
orin
s, m
etro
nida
zole
,cli
ndam
ycin
) wer
e us
ed if
sign
sof
infe
ctio
n (i.
e. c
ellu
litis)
wer
epr
esen
t. Th
e ul
cers
wer
ecle
aned
with
ster
ile sa
line
and
dres
sed
acco
rdin
g to
the
man
ufac
ture
rs’
reco
mm
enda
tions
by
the
usua
lnu
rsin
g st
aff.
Whe
n ul
cers
wer
eno
long
er p
rodu
cing
exud
ate,
vase
line
gauz
e (Je
lone
t®, S
mith
Stat
istica
l met
hods
:D
iffer
ence
s bet
wee
n or
with
ingr
oups
wer
e te
sted
usin
g th
eM
ann–
Whi
tney
U–t
est (
two-
taile
d). T
he a
nalys
is w
as b
ased
on
trea
tmen
t com
plet
ers o
nly
(18
inC
and
17
in I)
. The
aut
hors
repo
rted
no
majo
r diff
eren
ces
betw
een
the
two
grou
ps in
outc
omes
at 1
2w
eeks
. p-V
alues
of th
e di
ffere
nces
wer
e no
tre
port
ed
Surg
ical r
evisi
on p
erfo
rmed
:I:
3/17
(18%
)C
: 5/1
8 (2
8%)
Com
plet
e he
aling
:I:
5/17
(29%
)C
: 2/1
8 (1
1%)
Wou
nd a
rea
redu
ctio
n of
>50
%or
impr
ovem
ent i
n W
agne
rgr
ade:
I: 12
/17
(71%
)C
: 13/
18 (7
2%)
Adve
rse
effe
cts:
The
auth
ors r
epor
ted
that
non
ew
ere
docu
men
ted
With
draw
als:
C: 4
/22
(18%
)I:
2/19
(11%
)
Reas
ons f
orw
ithdr
awal
(not
repo
rted
per
grou
p):
Viol
atio
n of
inclu
sion
crite
ria
n =
2H
ospi
talis
atio
n n
= 2
Non
-adh
eren
ce
n =
1In
suffi
cient
dat
aon
reso
urce
use
n
= 1
Not
e: th
e da
tash
own
here
are
take
n fro
m tw
opa
pers
122,
126
Eligi
bilit
y of
the
inte
rven
tion
for
this
revie
w:
The
auth
ors
desc
ribe
cade
xom
er io
dine
oint
men
t as b
eing
“high
ly flu
id-
abso
rbin
g,an
tibac
teria
land
able
to d
issol
vede
bris
and
necr
otic
tissu
e”,
and
prov
ide
supp
ortin
gre
fere
nces
Stud
y sp
onso
rshi
p:Pe
rsto
rp P
harm
a,Lu
nd, S
wed
en, a
ndth
e Sw
edish
Diab
etes
Asso
ciatio
n cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
135
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
impr
ovem
ent i
n W
agne
rgr
ade
was
seen
. Hea
ling
was
def
ined
as i
ntac
tsk
in. U
lcer a
rea
was
mea
sure
d by
mul
tiplyi
ngm
axim
um le
ngth
by
max
imum
wid
th
Setti
ng a
nd le
ngth
of
trea
tmen
t:Si
ngle
-cen
tre
stud
y.O
utpa
tient
s dep
artm
ent,
invo
lving
am
ultid
iscip
linar
y fo
otca
re te
am (d
iabet
olog
ist,
orth
opae
dic
surg
eon,
orth
otist
, pod
iatris
t,di
abet
es n
urse
). Tr
ialdu
ratio
n 12
wee
ks
unde
rgoi
ng th
yroi
dgla
nd in
vest
igatio
ns,
unlik
ely
to a
dher
ew
ith st
udy
prot
ocol
wer
e ex
clude
d
Patie
nts w
ere
with
draw
n fro
m th
est
udy
in th
e ca
se o
fho
spita
lisat
ion,
lack
of a
dher
ence
, ulce
rde
terio
ratio
n(W
agne
r gra
de 3
or
4), >
100%
incr
ease
in u
lcer a
rea
orad
vers
e re
actio
ns to
the
topi
cal
trea
tmen
t
& N
ephe
w M
edica
l) w
asap
plie
d
Prio
r to
inclu
sion,
foot
wea
rw
as c
orre
cted
or s
pecia
lfo
otw
ear p
rovid
ed if
loca
lpr
essu
re re
lief w
as re
quire
d
Appendix 4
136 Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Bout
er (1
996)
,106
The
Net
herla
nds
Stud
y de
sign:
RC
T, o
pen
Met
hod
ofra
ndom
isatio
n:C
ompu
ter-
gene
rate
dra
ndom
num
bers
tabl
e
Uni
t of a
lloca
tion:
Patie
nt
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
repo
rted
Out
com
e as
sess
men
t:Pa
tient
s wer
e ex
amin
edat
bas
elin
e, c
ompl
etio
nof
ant
ibio
tic tr
eatm
ent,
and
ever
y 3
days
dur
ing
ther
apy.
X-r
ay o
f the
affe
cted
lim
b w
as d
one
at st
udy
entr
y an
d du
ring
stud
y pe
riod
if in
dica
ted.
Clin
ical r
espo
nse
totr
eatm
ent w
as a
sses
sed
afte
r com
plet
ion
ofan
tibio
tic th
erap
y an
dw
as c
lassif
ied
as c
ured
(disa
ppea
ranc
e of
the
initi
al in
fect
ion)
,im
prov
ed (i
nitia
lin
fect
ion
unde
r con
trol
),fa
ilure
(per
siste
nce
orag
grav
atio
n of
initi
alin
fect
ion,
requ
iring
chan
ge o
f the
rapy
), or
deat
h. B
lood
cul
ture
san
d w
ound
cul
ture
s(u
sing
puru
lent
Popu
latio
n:Pa
tient
s hos
pita
lised
for d
iabet
ic fo
otle
sions
with
Wag
ner
class
ifica
tions
of 2
, 3an
d 4
in th
e Bo
sch
Med
iCen
tre,
Den
Bosc
h an
d th
eEe
mlan
d H
ospi
tal,
Amer
sfoor
t, Th
eN
ethe
rland
s
Inclu
sion
crite
ria:
Ankl
e/br
achi
al in
dex
of a
t lea
st 0
.45
(der
ived
by d
ividi
ngth
e an
kle
syst
olic
pres
sure
by
the
brac
hial
arte
rysy
stol
ic pr
essu
re);
norm
al re
nal a
ndliv
er fu
nctio
n
Exclu
sion
crite
ria:
Hyp
erse
nsiti
vity
toan
y of
the
stud
ydr
ugs;
rece
ived
antim
icrob
ialth
erap
y ef
fect
iveag
ainst
the
infe
ctin
gpa
thog
ens w
ithin
48ho
urs p
rior t
ost
udy
trea
tmen
t;hi
gh p
roba
bilit
y of
deat
h w
ithin
48ho
urs;
infe
ctio
nw
ithm
icroo
rgan
isms
resis
tant
to th
est
udy
drug
s
Num
bers
male
/fem
ale:
I1: 8
/14
I2: 1
2/12
Mea
n ±
SDag
e (y
ears
):I1
: 71.
9 ±
8.2
I2: 7
0.9
±11
.3
Num
bers
with
Typ
e 1/
Type
2di
abet
es:
I1: 2
/20
I2: 3
/21
Mea
n ±
SDdu
ratio
n of
diab
etes
(yea
rs):
I1: 9
.9 ±
8.6
I2: 1
1.3
±6.
4
Num
bers
clas
sifie
d as
Wag
ner 2
/3/4
:I1
: 9/9
/4I2
: 9/9
/6
Mea
n ±
SDan
kle
brac
hial
inde
x:I1
: 0.7
0 ±
0.23
I2: 0
.71
±0.
22
Back
grou
nd h
eart
dise
ase
(%):
I1: 3
3.3
I2: 5
4.2
Retin
opat
hy (%
):I1
: 59.
1I2
: 33.
3
Nep
hrop
athy
(%):
I1: 5
4.5
I2: 5
4.2
Neu
ropa
thy
(%):
I1: 4
5.5
I2: 5
4.2
I1: I
/C 5
00m
g q.
d.s i
.v.M
inim
um d
urat
ion
oftr
eatm
ent w
as 1
0da
ys
(n=
22)
The
dose
of i
mip
enem
was
redu
ced
in c
ases
of r
enal
dysfu
nctio
n (5
00 o
r 25
0 m
g b.
d.)
I2: P
iper
acilli
n 30
00m
g q.
d.s.
i.v. i
n co
mbi
natio
n w
ithcli
ndam
ycin
600
mg
t.d.s.
i.v.
Min
imum
dur
atio
n of
trea
tmen
t was
10
days
(n
= 2
4)
The
dose
of p
iper
acilli
n w
asre
duce
d in
cas
es o
f ren
aldy
sfunc
tion
(200
0 or
100
0 m
gq.
d.s.)
. The
dos
e of
clind
amyc
in w
as re
duce
d in
case
s of l
iver d
ysfu
nctio
n.(R
evie
wer
’s no
te: i
t is
pres
umed
that
, sin
cepa
rtici
pant
s had
to h
ave
norm
alre
nal f
unct
ion
to b
e in
clude
d in
the
trial
, the
redu
ced
dose
sw
ere
adm
inist
ered
if re
nal
dysfu
nctio
n w
as d
etec
ted
durin
g th
e st
udy
perio
d)
All p
atie
nts:
Antib
iotic
ther
apy
was
disc
ontin
ued
if th
e pa
tient
’scli
nica
l con
ditio
n w
orse
ned
afte
r 72
hour
s. Pa
tient
s wer
ere
stric
ted
to b
ed re
st d
urin
gth
erap
y an
d th
rom
bolyt
ictr
eatm
ent w
as p
resc
ribed
.To
pica
l app
licat
ion
of a
ntib
iotic
sw
as n
ot p
erm
itted
. In
case
s of
Stat
istica
l met
hods
:�
2te
st w
ith Y
ate’
s cor
rect
ion
orFi
sher
’s ex
act t
est (
both
two-
taile
d)
No
patie
nts r
ecei
ved
conc
omita
nt sy
stem
ic or
topi
cal
antib
iotic
s
Mea
n ±
SDdu
ratio
n of
ther
apy
(day
s):
I1: 2
3.6
±11
.5I2
: 24.
3 ±
20.6
The
foot
infe
ctio
ns w
ere
polym
icrob
ial in
55%
of c
ases
.St
aphy
loco
ccus
aur
eusw
ascu
lture
d in
16
patie
nts,
haem
olyt
ic st
rept
ococ
ci in
8pa
tient
s and
ent
eroc
occi
in10
patie
nts.
Ente
roba
cter
iacea
ew
ere
isolat
ed fr
om 1
7 an
dan
aero
bes f
rom
4 p
atie
nts.
Pseu
dom
onas
spec
ies w
ere
not
cultu
red
at th
e tim
e of
adm
issio
nin
any
pat
ient
alth
ough
Xant
hom
onas
mal
toph
iliaw
ascu
lture
d in
one
pat
ient
with
asu
perin
fect
ion
Num
bers
(%) w
ith c
linica
lre
spon
se to
trea
tmen
t I1/
I2:
Cur
ed: 4
(19.
0)/6
(25.
0)Im
prov
ed: 1
6 (7
6.2)
/12
(62.
2)Fa
iled:
0/2
(8.3
)D
ied:
1 (4
.8)/4
(16.
7)Th
e au
thor
s rep
orte
d th
at n
one
of th
e di
ffere
nces
in c
linica
lou
tcom
es o
f the
two
stud
ygr
oups
wer
e st
atist
ically
signi
fican
t. H
owev
er, p
-valu
esw
ere
not r
epor
ted
One
pat
ient
in I1
was
inad
vert
ently
inclu
ded
twice
and
was
ther
efor
eno
t eva
luab
le
For a
nalys
is of
bact
erio
logic
alre
spon
se to
trea
tmen
t:O
ne p
atie
nt in
each
gro
up w
asno
t eva
luab
leow
ing
to a
nega
tive
base
line
cultu
re
Stud
y sp
onso
rshi
p:N
ot st
ated
It is
not c
lear
whe
ther
all
patie
nts r
ecei
ved
antib
iotic
ther
apy
for t
he st
ipul
ated
min
imum
trea
tmen
t per
iod
of 1
0da
ys
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
137
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
disc
harg
e, in
fect
ed ti
ssue
or su
perfi
cial s
wab
s if
form
er m
ater
ials n
otav
ailab
le) w
ere
obta
ined
prio
r to
enro
lmen
t.G
ram
stain
s wer
epe
rform
ed ro
utin
ely
onsp
ecim
ens f
rom
all
sites
with
kno
wn
orpr
esum
ed in
fect
ion.
Bact
erio
logic
al re
spon
seof
bas
elin
e pa
thog
ens
was
reco
rded
3–5
day
saf
ter s
tart
ing
ther
apy
and
1–3
days
afte
rco
mpl
etio
n of
trea
tmen
t.Re
spon
se w
as c
lassif
ied
as e
radi
catio
n, p
artia
ler
adica
tion,
failu
re,
supe
rinfe
ctio
n, re
lapse
(afte
r com
plet
ion
ofth
erap
y) o
r non
-ev
aluab
le o
win
g to
nega
tive
base
line
cultu
re.
All o
bser
ved
and
mon
itore
d ad
vers
eef
fect
s wer
e re
cord
edan
d cla
ssifi
ed a
s mild
,m
oder
ate
or se
vere
.H
aem
atol
ogy
and
bioc
hem
istry
wer
epe
rform
ed a
t 2–3
day
saf
ter e
nrol
men
t and
3–da
ys a
fter c
ompl
etio
nof
ther
apy
Setti
ng a
nd le
ngth
of
trea
tmen
t:H
ospi
tal.
Min
imum
trea
tmen
t dur
atio
n10
days
chro
nic
oste
omye
litis,
ant
ibio
ticth
erap
y w
as c
ontin
ued
with
cipro
floxa
cin 5
00m
g b.
d. o
rally
or o
floxa
cin 4
00m
g b.
d. o
rally
and/
or c
linda
myc
in 6
00m
gt.d
.s. d
epen
ding
on
cultu
rere
sults
Mor
talit
y:I1
: One
pat
ient
die
d of
back
grou
nd h
eart
dise
ase
whi
lehi
s diab
etic
foot
was
con
sider
edto
be
clini
cally
impr
oved
I2: F
our p
atie
nts d
ied
over
all. I
ntw
o pa
tient
s, di
abet
ic fo
otin
fect
ion
was
con
sider
ed to
be
the
caus
e of
dea
th. O
ne p
atie
nt d
ied
of b
ackg
roun
d ca
rdio
vasc
ular
dise
ase
whi
le th
e co
nditi
on o
f his
diab
etic
foot
was
con
sider
ed to
be
impr
oved
. One
oth
er p
atie
nt d
ied
of b
ackg
roun
d ca
rdio
vasc
ular
dise
ase
befo
re a
mel
iora
tion
of th
edi
abet
ic fo
ot c
ould
be
repo
rted
Num
bers
(%) w
ith b
acte
riolo
gical
resp
onse
to tr
eatm
ent I
1/I2
:Er
adica
tion:
9 (4
5.0)
/16
(70.
0)Pa
rtial
era
dica
tion:
3 (1
5.0)
/1 (4
.3)
Failu
re: 1
(5.0
)/3 (1
3.0)
Supe
rinfe
ctio
n: 4
(20.
0)/3
(13.
0)Re
lapse
: 3 (1
5.0)
/0Th
e au
thor
s rep
orte
d th
atdi
ffere
nces
in b
etw
een
grou
psw
ere
not s
tatis
ticall
y sig
nific
ant
Num
bers
(%) e
xper
ienc
ing
adve
rse
even
ts p
roba
bly
relat
edto
stud
y dr
ugs:
I1: 3
(19.
0)I2
: 12
(50.
0)p
< 0
.05
Clas
sifica
tions
of s
ever
ity o
fad
vers
e ev
ents
(mild
/mod
erat
e/se
vere
) was
not
repo
rted
as d
escr
ibed
in th
em
etho
ds
cont
inue
d
Appendix 4
138
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Diar
rhoe
a w
as th
e sin
gle m
ost
repo
rted
adv
erse
effe
ct (n
= 4
);Cl
ostri
dium
diff
icile
toxi
n w
asde
tect
ed in
one
of t
hese
pat
ient
s.In
I2 o
ne p
atie
nt d
evel
oped
vasc
uliti
s tha
t was
asc
ribed
to th
eus
e of
clin
dam
ycin
. Inc
reas
edliv
er e
nzym
es w
ere
obse
rved
inan
othe
r pat
ient
. In
I1 o
ne p
atie
ntex
perie
nced
Can
dida
stom
atiti
san
d 2
patie
nts c
ompl
ained
of
naus
ea. C
andi
dast
omat
itis w
asals
o ob
serv
ed in
one
pat
ient
inI2
.
NB:
it w
as n
ot c
lear
from
the
text
whi
ch a
dver
se e
vent
soc
curr
ed in
whi
ch g
roup
Health Technology Assessment 2006; Vol. 10: No. 12
139
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Brad
sher
(198
4),43
USA
Stud
y de
sign:
RC
T
Met
hod
ofra
ndom
isatio
n:Ra
ndom
num
ber c
ode
Uni
t of a
lloca
tion:
Patie
nt
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
repo
rted
Out
com
e as
sess
men
t:C
ultu
re a
nd se
nsiti
vity
ofm
ater
ial fr
om in
fect
ion
sites
wer
e pe
rform
edbe
fore
initi
atio
n of
ther
apy
and
ever
y2–
3da
ys d
urin
g th
erap
yun
til c
ultu
re n
egat
ive o
rco
nclu
sion
of th
erap
y(a
naer
obic
cultu
res n
otro
utin
ely
take
n). R
esul
tsof
bac
terio
logic
alas
sess
men
t wer
ecla
ssifi
ed a
s elim
inat
ion
(no
furt
her i
solat
ion
ofpa
thog
en),
redu
ctio
n(d
ecre
ased
num
ber o
fsa
me
orga
nism
on
subs
eque
nt c
ultu
res)
,pe
rsist
ent (
sam
e or
grea
ter n
umbe
rs o
f the
origi
nal o
rgan
ism),
relap
se (r
etur
n of
the
origi
nal o
rgan
ism a
fter
com
plet
ion
of th
erap
y),
rein
fect
ion
(isol
atio
n of
ase
para
te p
atho
geni
cor
gani
sm w
ith c
linica
l
Popu
latio
n:Ad
ults
with
susp
ecte
d se
rious
bact
erial
skin
and
soft
tissu
ein
fect
ions
,ho
spita
lised
at t
heU
nive
rsity
of
Arka
nsas
for
Med
ical S
cienc
es o
rth
e C
arra
way
Met
hodi
st C
ente
r
Inclu
sion
crite
ria:
As a
bove
Exclu
sion
crite
ria:
Patie
nts w
ho h
adre
ceive
d an
tibio
tics
in th
e pr
evio
us72
hour
s; pa
tient
sw
ith re
nal f
ailur
e,pr
egna
ncy,
lacta
tion,
neut
rope
nia
orsig
nific
ant p
enici
llinhy
pers
ensit
ivity
Num
ber m
ale/fe
male
:I1
: 15/
27I2
: 24/
18
Num
ber b
lack/
whi
te:
I1: 2
5/17
I2: 2
4/18
Mea
n ag
e (y
ears
):I1
: 57
I2: 5
4
Num
ber w
ith u
nder
lying
dise
ase:
I1: 3
0I2
: 29
The
unde
rlyin
g di
seas
es in
clude
ddi
abet
es m
ellit
us, n
eopl
astic
dise
ase,
ster
oid
imm
unos
uppr
essio
n,alc
ohol
ism a
nd v
ascu
lar in
suffi
cienc
y.Th
e pr
evale
nce
of th
ese
per g
roup
was
not
repo
rted
Num
ber o
f typ
e of
infe
ctio
n tr
eate
dI1
/I2:
Supp
urat
ive D
FU 1
0/10
Bact
erio
logic
ally
prov
en c
ellu
litis
20/1
7C
ultu
re-n
egat
ive c
ellu
litis
6/6
Soft
tissu
e ab
sces
s 3/6
Supp
urat
ive th
rom
boph
lebi
tis 2
/0Su
ppur
ative
dec
ubitu
s ulce
r 0/2
Gon
ococ
cal d
erm
atiti
s 1/0
Surg
ical w
ound
infe
ctio
n 0/
1
Infe
ctio
ns c
ause
d by
mul
tiple
path
ogen
s (in
clude
s sup
pura
tive
diab
etic
foot
and
dec
ubitu
s ulce
rsan
d in
fect
ions
relat
ed to
vas
cular
insu
fficie
ncy)
, num
ber o
f pat
ient
s in
I1/I2
:M
ultip
le G
ram
-neg
ative
bac
illi a
ndSt
aphy
loco
ccus
aure
usiso
lated
6/8
I1: C
eftr
iaxon
e 1
g giv
en a
ssin
gle d
aily
dose
eith
er i.
m. i
nlid
ocain
e 1%
susp
ensio
n or
i.v.
infu
sed
in 1
00m
l of d
extr
ose
5% in
wat
er o
ver 3
0m
inut
es(n
= 4
2)
I2: C
efaz
olin
1g
t.d.s.
at t
heU
nive
rsity
of A
rkan
sas f
orM
edica
l Scie
nces
and
1 g
q.d
.s.at
the
Car
raw
ay M
etho
dist
Med
ical C
entr
e, g
iven
i.v.
infu
sed
in 1
00m
l of d
extr
ose
5% in
wat
er o
ver 3
0m
inut
es(n
= 4
2)
Stat
istica
l met
hods
:N
ot st
ated
. No
p-va
lues
wer
ere
port
ed.
Mea
n da
ily d
ose
of c
epha
losp
orin
used
(mg/
kg) (
all p
atie
nts)
:I1
: 15.
4I2
: 48.
5
Num
ber w
ith b
acte
riolo
gical
resp
onse
I1/I2
(DFU
pat
ient
son
ly):
Elim
inat
ion
6/4
Redu
ctio
n 3/
2Pe
rsist
ence
1/4
Relap
se 0
/0Re
infe
ctio
n 0/
0Th
e ab
ove
was
also
repo
rted
for
othe
r inf
ectio
n ty
pes
Num
ber o
f pat
ient
s with
clin
ical
outc
omes
in I1
/I2 w
ith in
fect
ions
caus
ed b
y m
ultip
le p
atho
gens
(inclu
des s
uppu
rativ
e di
abet
ic fo
otan
d de
cubi
tus u
lcers
and
infe
ctio
ns re
lated
to v
ascu
larin
suffi
cienc
y):
Patie
nts t
reat
ed (h
ad su
rger
y) 1
2(5
)/13
(6)
Clin
ical f
ailur
es (s
urge
ry) 0
/5(4
)C
linica
l im
prov
emen
t 2/2
Clin
ical c
ure
(sur
gery
) 10
(5)/6
(2)
Num
ber u
nder
goin
g su
rgica
lpr
oced
ures
I1/I2
(all
patie
nts)
:Am
puta
tion
7/4
Incis
ion
with
dra
inag
e an
dde
brid
emen
t 8/8
Som
e pa
tient
s had
mor
e th
an o
nepr
oced
ure
Thre
e of
6pa
tient
s with
soft
tissu
e ab
sces
s had
no b
acte
rial
grow
th o
n th
ein
itial
cultu
re a
ndth
eref
ore
wer
eno
t inc
lude
d in
the
bact
erio
logic
alas
sess
men
t
No
with
draw
alsw
ere
repo
rted
for
the
DFU
pat
ient
s
Revie
wer
’s no
tes:
Cul
ture
s and
sens
itivit
ies n
otre
port
ed p
er ty
peof
infe
ctio
n. M
ost
resu
lts w
ere
not
stra
tifie
d by
infe
ctio
n ty
pe.
Give
n th
is an
d th
esm
all p
ropo
rtio
nof
pat
ient
s with
DFU
recr
uite
d(2
4%),
it is
diffi
cult
to d
erive
use
ful
outc
omes
that
coul
d be
conf
iden
tlyge
nera
lised
to a
wid
er p
opul
atio
nw
ith D
FU
Stud
y sp
onso
rshi
p:N
ot st
ated
cont
inue
d
Appendix 4
140
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
signs
of i
nfec
tion)
and
colo
nisa
tion
(org
anism
siso
lated
dur
ing
ther
apy
with
no
asso
ciate
dcli
nica
l sign
s of i
nfec
tion)
.Fo
r the
clin
ical
evalu
atio
n, p
atie
nts w
ere
cons
ider
ed c
ured
whe
nth
ere
was
reso
lutio
n of
signs
and
sym
ptom
s of
infe
ctio
n. T
he n
umbe
r of
days
requ
ired
for
reso
lutio
n of
feve
r was
reco
rded
dail
y, as
wer
eth
e cli
nica
l sign
s of
drain
age
and
infla
mm
atio
n. P
atie
nts
wer
e m
onito
red
daily
for
signs
of t
oxici
ty.
Hae
mat
olog
ical,
rena
lan
d he
patic
par
amet
ers
wer
e m
easu
red
ever
y4
days
dur
ing
ther
apy
and
at th
e en
d of
ther
apy
Setti
ng/le
ngth
of
trea
tmen
t:H
ospi
tal/t
reat
men
tdu
ratio
n no
t rep
orte
d
Gro
up B
stre
ptoc
occi,
Gra
m-n
egat
iveba
cilli
and
Stap
hylo
cocc
us a
ureu
siso
lated
6/6
Gro
up A
stre
ptoc
occi,
Gra
m-
nega
tive
bacil
li an
d St
aphy
loco
ccus
aure
usiso
lated
2/1
Gro
up B
stre
ptoc
occi
wer
eiso
lated
from
the
DFU
s, bu
t no
deta
ils p
rovid
ed p
er g
roup
Num
ber w
ith p
ossib
lece
phalo
spor
in-r
elat
ed a
dver
seef
fect
s I1/
I2 (a
ll pa
tient
s):
Eosin
ophi
lia 7
/5Th
rom
bocy
tosis
2/0
Leuc
opoe
nia
0/1
Elev
ated
tran
sam
inas
e 2/
1Ra
sh 0
/3D
iarrh
oea
1/3
The
num
ber o
f day
s req
uire
d fo
rre
solu
tion
of fe
ver,
as st
ated
inth
e m
etho
ds, w
as n
ot re
port
ed
Health Technology Assessment 2006; Vol. 10: No. 12
141
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Cha
ntel
au (1
996)
,74
Ger
man
y
Stud
y de
sign:
RC
T(d
oubl
e-bl
ind)
Met
hod
ofra
ndom
isatio
n:C
ompu
ter-
gene
rate
dco
de
Uni
t of a
lloca
tion:
Patie
nt
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
repo
rted
Out
com
e as
sess
men
t:Ra
te o
f red
uctio
n of
ulce
r size
(sur
face
are
aca
lculat
ed b
y pl
anim
etry
,tr
ansfo
rmed
into
a c
ircle
,ch
ange
s of t
he c
ircle
radi
us o
ver t
ime
wer
ere
cord
ed).
Freq
uenc
y of
com
plet
ehe
aling
(sta
ndar
dise
dph
otog
raph
s).
Adve
rse
effe
cts.
Com
plian
ce w
ithpr
essu
re re
lief (
grad
ed a
sop
timal,
suffi
cient
, or
insu
fficie
nt, a
ccor
ding
tocli
nica
l jud
gem
ent).
Wou
nds c
ultu
res
perfo
rmed
usin
g de
epsw
ab, w
ith m
ater
ialpl
aced
into
tran
spor
tm
ediu
m a
nd se
aled
imm
ediat
ely
for
dete
rmin
atio
n of
aer
obic
and
anae
robi
c ba
cter
ia.
Inclu
sion
crite
ria:
Diab
etic
patie
nts
with
polyn
euro
path
y,w
ith sk
in a
nd so
fttis
sue
lesio
ns o
f the
fore
foot
, age
>18
year
s wer
ein
clude
d, w
ith fo
otle
sions
gra
ded
1A to
2A, a
ccor
ding
toW
agne
r and
Har
kles
scla
ssifi
catio
n
Exclu
sion
crite
ria:
Know
nhy
pers
ensit
ivity
tote
st m
edica
tion,
antib
iotic
trea
tmen
tdu
ring
the
prec
edin
g 7
days
,bi
later
al fo
ot le
sions
,pr
esen
ce o
fos
teom
yelit
is or
perip
hera
l vas
cular
dise
ase,
pre
gnan
cy,
seru
m c
reat
inin
ele
vel >
130
µmol
/1,
imm
une
depr
essio
ndu
e to
und
erlyi
ngdi
seas
e, p
rior o
rgan
tran
splan
tatio
n,im
mun
osup
pres
sive
drug
ther
apy,
micr
oorg
anism
sun
resp
onsiv
e to
test
med
icatio
n, in
abilit
yto
com
ply
with
prot
ocol
Gen
der m
ale/fe
male
:I:
16/6
C: 1
2/10
Mea
n (9
5% C
I) ag
e (y
ear)
:I:
58 (5
4 to
62)
C: 5
9 (5
5 to
63)
Mea
n (9
5% C
I) ul
cer a
rea
(mm
2 ):I:
214
(154
to 2
74)
C: 2
20 (1
62 to
422
)
Dat
a w
ere
not r
epor
ted
for u
lcer
grad
e
Mea
n (9
5% C
I) di
abet
es d
urat
ion
(yea
r):
I: 22
(17
to 2
7)C
: 19
(14
to 2
4)
Insu
lin d
epen
dent
:I:
11/2
2 (5
0%)
C: 1
2/22
(55%
)
Num
ber o
f pat
ient
s cur
rent
lysm
okin
g:I:
2/22
(9%
)C
: 5/2
2 (2
3%)
Num
ber o
f pat
ient
s with
HbA
1 c<
8%:
I: 9
/22
(41%
)C
: 10/
22 (4
5%)
Num
ber o
f pat
ient
s with
diab
etic
retin
opat
hy:
I: 13
/22
(59%
)C
: 12/
22 (5
5%)
Num
ber o
f pat
ient
s with
pro
tein
uria
>50
0m
g/1:
I: 4/
22 (1
8%)
C: 2
/22
(9%
)
I: Am
oxyc
illin
500
mg
plus
clavu
lanic
acid
125
mg,
ora
llytd
s (n
= 2
2)
C: I
dent
ical p
laceb
o t.d
.s.
(n=
22)
All p
atie
nts:
Stud
y m
edica
tion
was
star
ted
with
in 6
hour
s of i
nitia
l wou
ndcu
lture
.
All r
ecei
ved
mec
hani
cal
debr
idem
ent.
The
lesio
n w
ascle
aned
with
a to
pica
ldi
sinfe
ctan
t (D
ibro
mol
solu
tion)
and
dre
ssed
with
cotto
n ga
uze
and
para
ffina
ted
non-
adhe
ring
gauz
e. P
ress
ure
relie
f was
pro
vided
thro
ugh
the
use
of a
half
-sho
e, c
rutc
hes a
ndw
heel
chair
s
Out
patie
nt tr
eatm
ent w
asca
rrie
d ou
t by
a qu
alifie
d nu
rse
repe
atin
g th
e ab
ove
wou
ndca
re p
roce
dure
dail
y at
the
patie
nt’s
hom
e
The
stud
y w
as st
oppe
d w
hen
the
antib
iotic
pro
ved
unsu
itabl
eac
cord
ing
to b
asel
ine
cultu
res
(at d
ays 3
or 6
), or
if n
o cli
nica
lim
prov
emen
t was
seen
with
in6
days
or i
f the
stud
y pr
otoc
olw
as v
iolat
ed o
win
g to
inco
mpl
ete
pres
sure
relie
f or
adve
rse
effe
cts o
f the
med
icatio
n
Stat
istica
l met
hods
:�
2an
d t-
test
s.
At 2
0 da
ys:
Mea
n (9
5% C
I) re
duct
ion
inul
cer r
adiu
s (m
m2 da
y):
I: 0.
27 (0
.15
to 0
.39)
C: 0
.41
(0.2
1 to
0.6
1)(n
s)
Com
plet
e he
aling
:I:
6/2
2 (2
7%)
C: 1
0/22
(45%
)(n
s)
Adve
rse
effe
cts:
One
cas
e of
diar
rhoe
a in
the
antib
iotic
gro
up, w
hich
did
not
requ
ire w
ithdr
awal
Com
plian
ce ra
ted
as o
ptim
al(a
sses
sed
in 3
9 pa
tient
s):
I: 16
/19
(84%
) pat
ient
sC
: 18/
20 (9
0%) p
atie
nts
(ns)
Micr
obio
logy
Num
ber o
f pat
ient
s with
micr
obio
logic
al fin
ding
s at
entr
y/da
y 6/
end
of st
udy:
Gra
m st
ains
Posit
ive c
occi
C: 1
5/6/
2I:
19/9
/4Po
sitive
rods
C: 1
/0/0
I: 5/
0/1
Neg
ative
rods
C: 6
/1/2
I: 4/
4/1
No
micr
obes
C: 0
/13/
6I:
0/6/
7
I: 3/
22 (1
3.6%
)C
: 2/2
2 (9
.1%
)
The
abov
epa
tient
s wer
ew
ithdr
awn
with
in6
days
of t
he st
art
of th
e tr
ial o
win
gto
non
-co
mpl
iance
, or
bact
eria
unre
spon
sive
toth
e an
tibio
tic
Stud
y sp
onso
rshi
p:Th
e au
thor
sac
know
ledg
ed th
eco
oper
atio
n of
Smith
Klin
e-Be
echa
m, M
unich
,G
erm
any,
but i
tw
as u
ncle
ar fr
omth
is w
heth
er th
eco
mpa
nysp
onso
red
the
rese
arch
cont
inue
d
Appendix 4
142
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Cul
ture
s wer
e ta
ken
atba
selin
e, d
ay 6
and
day
20 in
cas
es o
f inc
ompl
ete
ulce
r hea
ling.
Wou
ndas
sess
men
ts a
ndph
otog
raph
s wer
ere
peat
ed o
n da
ys 3
, 6,
14 a
nd 2
0 (o
r at
com
plet
e clo
sure
of t
hele
sion)
Setti
ng a
nd le
ngth
of
trea
tmen
t:It
appe
ars t
hat s
ome
patie
nts w
ere
trea
ted
asin
patie
nts a
nd so
me
asou
tpat
ient
s, bu
t the
re is
no b
reak
dow
n by
num
bers
. The
dur
atio
nof
the
trial
was
20
days
Isolat
esSt
aphy
loco
ccus
aur
eus
C: 5
/5/3
I: 9/
3/2
Stap
hylo
cocc
us e
pide
rmis
C: 4
/3/4
I: 6/
1/1
E. c
oli
C: 0
/0/1
I: 1/
3/0
Stre
ptoc
occu
s BC
: 3/1
/0I:
3/0/
0St
rept
ococ
cus f
aeca
lisC
: 3/0
/0I:
2/1/
0O
ther
sC
: 8/3
/3I:
8/5/
6N
o iso
lates
C: 1
/10/
1I:
0/9/
4
Health Technology Assessment 2006; Vol. 10: No. 12
143
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
de L
alla
(200
1),11
9Ita
ly
Stud
y de
sign:
RC
T (1
:1)
Met
hod
ofra
ndom
isatio
n: N
otst
ated
Uni
t of a
lloca
tion:
Patie
nt
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
repo
rted
Out
com
e as
sess
men
t:Fo
ot le
sions
wer
eev
aluat
ed b
y on
ein
vest
igato
r (bl
ind
tora
ndom
isatio
n), b
yre
cord
ing
degr
ee o
fde
brid
emen
t, co
nditi
onof
gra
nulat
ion
tissu
e,st
ate
of u
lcer m
argin
s,an
d ul
cer w
idth
. Aph
otog
raph
of t
he le
sion
was
take
n at
eac
has
sess
men
t.M
icrob
iolo
gical
asse
ssm
ent w
aspe
rform
ed a
t bas
elin
ean
d at
day
s 7 a
nd 2
1.Fo
llow
ing
surg
ical
debr
idem
ent,
scru
bbin
g,an
d cle
ansin
g w
ith st
erile
gauz
e so
aked
in st
erile
salin
e, a
supe
rficia
l sw
absp
ecim
en a
nd a
dee
ptis
sue
biop
sy w
ere
colle
cted
from
the
deep
base
of t
he u
lcer.
Sam
ples
wer
e in
sert
edin
to a
tran
spor
t tub
e
Popu
latio
n:Ad
ult d
iabet
icpa
tient
s of e
ither
gend
er a
dmitt
ed to
the
Diab
etes
Cen
tre
of th
e Sa
n Bo
rtol
oH
ospi
tal,
Vice
nza,
Italy
for s
ever
e,lim
b-th
reat
enin
gfo
ot in
fect
ion
(def
ined
by
the
pres
ence
of f
ull-
thick
ness
ulce
r,m
ore
than
2cm
of
cellu
litis
with
or
with
out
lymph
angit
is, b
one
or jo
int
invo
lvem
ent,
orsy
stem
ic to
xicit
y)
Inclu
sion
crite
ria:
As a
bove
Exclu
sion
crite
ria:
Trea
tmen
t with
antib
iotic
s for
any
prov
en o
r sus
pect
edin
fect
ion
durin
g th
e2
wee
ks p
rece
ding
recr
uitm
ent;
supe
rficia
l, no
n-lim
b-th
reat
enin
gin
fect
ion;
imm
ediat
eris
k of
majo
r abo
ve-
ankl
e am
puta
tion
for c
ritica
l leg
ischa
emia
(ank
lesy
stol
ic bl
ood
pres
sure
<50
mm
Hg
or
Num
ber m
ale/fe
male
:C
: 14/
6I:
16/4
Mea
n ±
SD(r
ange
) age
(yea
rs):
C: 5
9.8
±9.
6 (4
4–85
)I:
56.6
±8.
6 (4
2–74
)
Mea
n ±
SD(r
ange
) dur
atio
n of
diab
etes
inye
ars:
C: 1
8.5
±8.
6 (1
2–30
)I:
15.6
±8.
6 (1
–46)
Num
ber (
%) o
f pat
ient
s with
Wag
ner
grad
e 3/
4:C
: 14
(70)
/6 (3
0)I:
13 (6
5)/7
(35)
Num
ber (
%) o
f pat
ient
s with
neur
opat
hic/
ischa
emic/
mix
ed le
sions
:C
: 14
(70)
/ 0
/ 6 (3
0)I:
13 (6
5) /
2 (1
0) /
5 (2
5)
Mea
n ±
SDan
kle–
brac
hial
bloo
d pr
essu
rein
dex:
C: 1
.29
±0.
50I:
0.96
±0.
34
Mea
n ±
SDvib
rato
r per
cept
ion
thre
shol
d:C
: 43.
2 ±
0.47
I: 35
.8 ±
14.6
0
Num
ber (
%) o
f pat
ient
s with
whi
te c
ell
coun
t >10
,000
/mm
3 :C
: 5/2
0 (2
5)I:
1/20
(5)
Mea
n ±
SDne
utro
phil
coun
t (m
m)3 :
C: 8
300
±35
00I:
7800
±35
00
Num
ber (
%) o
f pat
ient
s with
ES
R >
70m
m/h
:C
: 13/
20 (6
5)I:
11/2
0 (5
5)
C: C
onve
ntio
nal
trea
tmen
t alo
ne (l
ocal
trea
tmen
t plu
s sys
tem
ican
tibio
tic th
erap
y)
(n=
20)
I: C
onve
ntio
nal t
reat
men
t(lo
cal t
reat
men
t plu
ssy
stem
ic an
tibio
ticth
erap
y) p
lus G
-CSF
26
3 µg
dail
y s.c
. for
21da
ys. T
he d
ose
of G
-C
SF w
as te
mpo
raril
yre
duce
d to
175
µg
if th
ene
utro
phil
coun
tex
ceed
ed 3
5,00
0ce
lls/m
m3 . G
-CSF
was
disc
ontin
ued
if th
ene
utro
phil
coun
t was
ove
r50
,000
cel
ls/m
m3
and
was
re-c
omm
ence
d on
ly if
the
coun
t fel
l to
less
than
35,0
00 c
ells/
mm
3(n
= 2
0)
All p
atie
nts:
Loca
l tre
atm
ent c
onsis
ted
of d
ebrid
emen
t of s
oft
tissu
e an
d bo
ne a
ten
rolm
ent a
nd th
erea
fter
of d
aily
insp
ectio
n,cle
ansin
g w
ith st
erile
wat
er, d
isinf
ectio
n w
ithpo
vidon
e io
dine
, sur
gical
rem
oval
of n
ecro
tic ti
ssue
as re
quire
d an
d oc
clusiv
edr
essin
g of
foot
lesio
ns.
Empi
rical
antib
iotic
ther
apy
was
bas
ed o
n th
eco
mbi
natio
n of
cipro
floxa
cin a
ndcli
ndam
ycin
. I.v.
ther
apy
Stat
istica
l met
hods
:O
ne-s
ampl
e t-
test
for
com
paris
on o
f con
tinuo
usva
riabl
es a
nd M
ann–
Whi
tney
U-
test
for c
ateg
orica
l var
iable
s.
Num
ber (
%) u
nder
goin
gam
puta
tion
at 2
1 da
ys:
C: 5
/20
(25)
I: 1/
20 (5
)p
= 0
.08
Num
ber (
%) u
nder
goin
gam
puta
tion
at 9
-wee
k fo
llow
-up:
C: 9
/20
(45)
I: 3/
20 (1
5)p
= 0
.038
Num
ber u
nder
goin
g m
ajor
ampu
tatio
n:C
: 2 (a
t 21
and
30da
ys)
I: 0
Num
ber u
nder
goin
g am
puta
tion
of m
etat
arsa
l bon
es:
C: 1
(at d
ay 2
5)I:
1 (a
t day
45)
Adve
rse
even
ts:
No
adve
rse
even
ts a
ssoc
iated
with
G-C
SF w
ere
obse
rved
.D
osag
e ha
d to
be
redu
ced
in 2
patie
nts o
win
g to
neu
trop
hil
coun
t high
er th
an 3
5,00
0ce
lls/m
m3 . T
he n
eutr
ophi
l cou
ntdi
d no
t exc
eed
50,0
00 c
ells/
mm
3
in a
ny p
atie
nt
Ther
e w
ere
now
ithdr
awals
durin
g th
e 21
-day
trial
or a
t the
9-
wee
k fo
llow
-up
At 6
mon
ths,
4pa
tient
s fro
mIw
ere
lost
tofo
llow
-up
Stud
y sp
onso
rshi
p:N
ot st
ated
cont
inue
d
Appendix 4
144
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
cont
ainin
g so
lid m
ediu
msu
itabl
e fo
r bot
h ae
robi
can
d an
aero
bic
micr
oorg
anism
s and
deliv
ered
to th
elab
orat
ory
for i
mm
ediat
epr
oces
sing.
The
foot
lesio
ns w
ere
evalu
ated
at
wee
ks 3
and
9 a
ndcla
ssifi
ed a
s one
of t
hefo
llow
ing:
cur
e(c
ompl
ete
closu
re o
f the
ulce
r with
out s
igns o
fun
derly
ing
bone
infe
ctio
n); i
mpr
ovem
ent
(era
dica
tion
of p
atho
gens
indi
cate
d by
neg
ative
swab
or t
issue
cul
ture
,co
uple
d w
ith m
arke
d or
com
plet
e re
duct
ion
ofce
llulit
is bu
t inc
ompl
ete
closu
re o
f the
ulce
r or
closu
re o
f the
ulce
r but
pers
isten
t sign
s of a
ctive
unde
rlyin
g bo
ne in
fect
ion
such
as l
ocal
pain
,er
ythe
ma
and
swel
ling)
;or
failu
re (a
bsen
ce o
fcli
nica
l im
prov
emen
tirr
espe
ctive
of c
ultu
rere
sults
). Am
puta
tion,
defin
ed a
s any
exc
ision
of b
one
segm
ent,
was
cons
ider
ed fa
ilure
whe
nits
indi
catio
n w
as d
ue to
pers
isten
t inf
ectio
n af
ter
15da
ys o
f app
ropr
iate
antib
iotic
ther
apy
and
loca
l tre
atm
ent.
Indi
catio
n fo
r am
puta
tion
ankl
e/br
achi
al bl
ood
pres
sure
inde
x<
0.5)
; any
crit
ical
cond
ition
with
imm
ediat
e ris
k of
deat
h; re
nal
impa
irmen
t; hi
stor
yof
alle
rgic
reac
tion
to c
ipro
floxa
cin o
rcli
ndam
ycin
; any
cont
ra-in
dica
tion
toG
-CSF
adm
inist
ratio
n
Num
ber (
%) o
f pat
ient
s with
pos
itive
bloo
d cu
lture
s:C
: 2/2
0 (1
0)I:
0
Det
ectio
n of
ost
eom
yelit
is:Al
l pat
ient
s had
ost
eom
yelit
is at
bas
elin
e,de
tect
ed b
y po
sitive
bon
e pr
obe.
15
patie
nts (
6 in
C a
nd 9
in I)
had
diag
nosis
conf
irmed
by
indi
um-la
belle
d le
ukoc
yte
scan
com
bine
d w
ith te
chne
tium
-99m
bone
scan
Num
ber (
%) o
f pat
ient
s with
exp
osed
bone
:C
: 4/2
0 (2
0)I:
6/20
(30)
Num
ber (
%) o
f pat
ient
s with
life
-th
reat
enin
g in
fect
ion:
C: 2
/20
(10)
I: 0
Mea
n ±
SDnu
mbe
r of u
lcers
per
pat
ient
:C
: 1.4
±1.
0I:
1.4±
0.6
Num
ber (
%) o
f pat
ient
s with
mor
e th
anon
e ul
cer:
C: 5
/20
(25)
I: 6/
20 (3
0)
Mea
n ±
SDnu
mbe
r of i
solat
es p
erpa
tient
:C
: 2.3
0 ±
1.6
I: 2.
05 ±
1.2
Num
ber (
%) o
f pat
ient
s with
polym
icrob
ial in
fect
ion:
C: 1
0/20
(50)
I: 14
/20
(70)
(cip
roflo
xacin
400
mg
b.i.d
. plu
s clin
dam
ycin
90
0 m
g t.i
.d.)
was
adm
inist
ered
in th
e ca
seof
mor
e se
rious
infe
ctio
n(fe
brile
dise
ase,
ext
ende
dce
llulit
is w
ith ly
mph
angit
is,in
com
plet
e de
brid
emen
tof
nec
rotic
tiss
ue, o
rex
tens
ive b
one
invo
lvem
ent)
and
the
ther
apy
was
switc
hed
toth
e or
al ro
ute
whe
nap
prop
riate
. The
ora
lre
gimen
(cip
roflo
xacin
at
750
mg
b.i.d
. plu
scli
ndam
ycin
300
mg
q.d.
s.)w
as c
onsid
ered
appr
opria
te fo
r les
s crit
ical
patie
nts.
Adju
stm
ents
totr
eatm
ent w
ere
mad
e on
the
basis
of w
ound
cultu
res a
nd se
nsiti
vitie
s
Insu
lin w
as g
iven
eith
er b
yco
ntin
uous
i.v.
infu
sion
ora
mul
tiple
-dos
e re
gimen
.
Mea
n ±
SDne
utro
phil
coun
ts(c
ells/
mm
3):
C: 6
,500
±4,
400
I: 25
,200
±3,
500
p=
0.0
02
Trea
tmen
t out
com
es fo
r num
ber
(%) o
f pat
ient
s 3 w
eeks
afte
rst
art o
f tre
atm
ent C
/I:C
ure:
0/0
Impr
ovem
ent:
9 (4
5)/1
2 (6
0) (n
s)Fa
ilure
: 11
(55)
/8 (4
0) (n
s)
Trea
tmen
t out
com
es fo
r num
ber
(%) o
f pat
ient
s 9 w
eeks
afte
rst
art o
f tre
atm
ent C
/I:C
ure:
7 (3
5)/7
(35)
(ns)
Impr
ovem
ent:
8 (4
0)/4
(20)
(ns)
Failu
re: 5
(25)
/9 (4
5) (n
s)
Both
pat
ient
s with
life
-th
reat
enin
g in
fect
ion
at ti
me
ofra
ndom
isatio
n (b
oth
in C
) wer
ecla
ssifi
ed a
s im
prov
ed a
t wee
k 9
Trea
tmen
t out
com
es fo
r num
ber
(%) o
f pat
ient
s at 6
-mon
thfo
llow
-up
C/I
(eva
luat
ed in
20
patie
nts i
n C
and
16
in I,
as 4
wer
e lo
st to
follo
w-u
p):
Cur
e or
stab
le: 1
5/20
(75)
/13/
16(8
1)W
orse
ned:
5/2
0 (2
5)/3
/16
(19)
ns Num
ber o
f pat
ient
s with
bact
erial
isol
ates
C/I
afte
r3
wee
ks o
f tre
atm
ent:
Gra
m-p
ositi
ve a
erob
es:
CN
S-M
R 3/
5SA
-MS
0/1
SA-M
R 1/
2
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
145
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
was
ass
esse
d by
orth
opae
dic
staf
f at t
heho
spita
l who
wer
e no
tin
volve
d in
the
stud
y, an
dha
d no
t bee
n bl
inde
d to
trea
tmen
t allo
catio
n
Setti
ng a
nd le
ngth
of
trea
tmen
t:H
ospi
tal.
Leng
th o
f tria
l21
days
. Fol
low
-up
at9
wee
ks a
nd 6
mon
ths.
Num
ber (
%) o
f pat
ient
s with
cel
lulit
isdi
amet
er >
2 cm
:C
: 15/
20 (7
5)I:
10/2
0 (5
0)
Num
ber (
%) o
f pat
ient
s with
visi
ble
infe
cted
wet
gan
gren
e of
the
toes
:C
: 4/2
0 (2
0)I:
4/20
(20)
Num
ber (
%) p
atie
nts w
ith a
n ab
sces
s:C
: 3/2
0 (1
5)I:
1/20
(5)
Num
ber (
%) p
atie
nts w
ith u
lcer d
iamet
er>
2cm
:C
: 11/
20 (5
5)I:
13/2
0 (6
5)
Num
ber o
f pat
ient
s with
bac
teria
l iso
lates
C/I:
Gra
m-p
ositi
ve a
erob
es:
CN
S-M
S 5/
1SA
-MS
8/8
SA-M
R 2/
2Co
ryne
bact
eriu
msp
ecie
s 2/2
Ente
roco
ccus
spec
ies 3
/7St
rept
ococ
cusa
galac
tiae
4/4
Stre
ptoc
occu
spyo
gene
s 0/2
Gra
m-n
egat
ive a
erob
es:
Esch
erich
ia c
oli1
/4Pr
oteu
s mira
bilis
2/0
Ente
roba
cter
aer
ogen
es1/
0Kl
ebsie
lla p
neum
onia
e1/
0An
aero
bes:
n2/
5Fu
soba
cter
ium
spec
ies 1
/2Pe
ptos
trept
ococ
cuss
pecie
s 1/4
Prev
otel
la b
ivia
0/1
Tota
l 33
(34%
)/41
(55%
)
Cory
neba
cter
ium
spec
ies 1
/2G
ram
-neg
ative
aer
obes
:Ps
eudo
mon
as a
erug
inos
a1/
1Es
cher
ichia
col
i2/0
Tota
l 8 (4
2%)/1
1 (5
8%)
Mea
n nu
mbe
r of i
solat
es p
erpa
tient
at d
ay 7
:C
: 1.0
5I:
0.95
Mea
n nu
mbe
r of i
solat
es p
erpa
tient
at d
ay 2
1:C
: 0.5
5I:
0.55
Num
ber (
%) o
f pat
ient
sre
quiri
ng a
djus
tmen
t of e
mpi
rical
antib
iotic
ther
apy
durin
g th
est
udy
perio
d:C
: 12/
20 (6
0)I:
12/2
0 (6
0)
Mea
n ±
SD/m
edian
(ran
ge)
dura
tion
of a
ntib
iotic
ther
apy
(day
s):
C: 5
8.7
±23
.7/6
0 (3
0–11
9)I:
68.9
±29
.2/6
2.5
(30–
163)
Num
ber (
%) o
f pat
ient
sun
derg
oing
ora
l/i.v.
ant
ibio
ticth
erap
y du
ring
the
stud
y pe
riod:
C: 1
1/20
(55)
/9/2
0 (4
5)I:
13/2
0 (6
5)/7
/20
(35)
ns Vasc
ular
reco
nstr
uctio
n w
as n
otun
dert
aken
in a
ny p
atie
nt d
urin
gth
e st
udy
perio
d
Glu
cose
met
abol
ism w
asad
equa
tely
cont
rolle
d in
all
patie
nts
CN
S-M
R, m
ethi
cillin
-res
istan
t, co
agul
ase
nega
tive
stap
hylo
cocc
i; C
NS-
MS,
met
hicil
lin-s
ensit
ive, c
oagu
lase
nega
tive
stap
hylo
cocc
i; SA
-MR,
met
hicil
lin-r
esist
ant,
Stap
hylo
cocc
us a
ureu
s; SA
-MS,
met
hicil
lin-
sens
itive
, Sta
phylo
cocc
us a
ureu
s.
Appendix 4
146
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Dw
ivedi
(200
0),12
7In
dia
Stud
y de
sign:
RCT
Met
hod
ofra
ndom
isatio
n:
Not
spec
ified
Uni
t of a
lloca
tion:
Pa
tient
Calc
ulat
ion
of st
atist
ical
pow
er: N
ot re
port
ed
Out
com
e as
sess
men
t:Am
puta
tion
rate
Mea
sure
men
t of u
lcer
mar
gins (
cent
imet
re ta
peby
Sm
elo’
s dev
ice),
pres
ence
of g
ranu
latio
ntis
sue,
abs
ence
of
puru
lent
disc
harg
e (v
iana
ked
eye
exam
inat
ion)
hist
olog
ical c
hang
es (v
iatis
sue
biop
sies)
,ro
entg
enog
ram
of
affe
cted
par
t, ar
teria
lcir
culat
ion
(ultr
asou
ndD
oppl
er/A
B in
dex)
,im
mun
olog
ical c
hang
es(Ig
G, I
gA, I
gM v
ia sin
glera
dial
diffu
sion
(Fah
ey19
65)33
1 ), to
tal p
rote
ins
Gra
ding
of r
esul
ts b
ym
ild, m
oder
ate,
goo
dre
cove
ry
Setti
ng a
nd le
ngth
of
trea
tmen
t: D
iabet
iccli
nic/
5ye
ars
Inclu
sion
crite
ria:
100
patie
nts w
ithno
n-he
aling
diab
etic
foot
ulce
r of
6–12
mon
ths
dura
tion
Exclu
sion
crite
ria:
Non
e st
ated
Gen
der m
ale/fe
male
:70
/30
50 p
atie
nts e
ach
in 1
1 an
d 12
;ge
nder
split
not
give
n
Age
rang
e: 3
1–70
yea
rsAg
e-m
atch
ed g
roup
s (no
t sta
ted
how
don
e)
Dur
atio
n of
dia
bete
s:30
% 0
–5 y
ears
; 40%
6–1
0 ye
ars;
40%
>10
yea
rs
Diab
etic
cont
rol b
oth
grou
ps b
ysu
itabl
e hy
pogly
caem
ic ag
ents
or
insu
lin
Die
tary
hab
it:
Both
gro
ups 1
500–
2000
cal
per d
ay
Socia
l sta
tes:
60%
rura
l; 40
% u
rban
I1: 5
0 pa
tient
s rec
eive
d su
itabl
esy
stem
ic an
tibio
tics (
acco
rdin
gto
ant
ibio
tic se
nsiti
vity)
plu
sm
etro
nida
zole
, loc
al an
tisep
tics
and
perip
hera
l vas
cular
dila
tor
(Pen
toxi
fyllin
e).
I2: 5
0 pa
tient
s rec
eive
d a
wat
er-s
olub
le so
lid e
xtra
ct to
Man
jisht
ha (R
ubia
cor
difo
lia) a
ndAs
hvag
andh
a (W
ithan
iaso
mni
fera
) eac
h 50
0m
g or
ally,
3 ×
day.
Patie
nts a
lso re
quire
dto
kee
p af
fect
ed p
art d
ippe
d in
luke
war
m d
ecoc
tion
of ro
ots
of b
oth
plan
ts m
ixed
toge
ther
for 3
0m
inut
es d
aily.
Wou
nds
dres
sed
with
out a
nyco
nven
tiona
l loc
al an
tisep
tic
Both
gro
ups r
ecei
ved
regu
larsu
rgica
l tre
atm
ent c
onsis
ting
ofin
cisio
n, d
rain
age
of a
bsce
sses
and
wou
nd d
ebrid
emen
t (as
and
whe
n re
quire
d)
Con
trol
gro
up d
ata
avail
able
for i
mm
unog
lobu
lins a
nd to
tal
prot
eins
. Valu
es ta
ken
from
stan
dard
read
ings
of a
ge-
mat
ched
non
-diab
etics
of
imm
unop
atho
logy
labo
rato
ry(In
stitu
te o
f Med
ical S
cienc
es,
Bana
ras H
indu
Uni
vers
ity)
Resu
lts ta
bles
ava
ilabl
e on
ly fo
rim
mun
oglo
bulin
s, to
tal p
rote
ins
and
arte
rial c
ircul
atio
n
I1: A
mpu
tatio
n: 3
0% o
f gro
upun
derw
ent t
otal
or p
artia
lam
puta
tion
(per
sona
lco
mm
unica
tion)
(50%
inab
stra
ct.12
7 )
IgG
leve
ls ra
ised
signi
fican
tlybe
fore
and
afte
r tre
atm
ent
(t-va
lue:
0.1
60; p
< 0
.05)
. Whe
naf
ter t
reat
men
t com
pare
d to
cont
rol d
ata,
t-va
lue:
7.3
2;
p <
0.0
01Pa
tient
s sho
wed
mild
tom
oder
ate
reco
very
I2: A
mpu
tatio
n: 1
6% o
f pat
ient
sun
derw
ent p
artia
l am
puta
tion
(per
sona
l com
mun
icatio
n) (2
0%in
abs
trac
t.127 )
Stat
istica
lly si
gnifi
cant
cha
nges
note
d in
IgG
(t-v
alue:
0.1
63;
p<
0.0
5), I
gA (t
-valu
e: 1
.985
; p
< 0
.05)
, IgM
(t-v
alue:
1.7
34;
p<
0.0
1) a
nd to
tal p
rote
in le
vels
(t-va
lue:
0.9
79; p
<0.
01) w
hen
com
pare
d be
fore
and
afte
rtr
eatm
ent.
Com
pare
d w
ithco
ntro
l dat
a, o
nly
IgG
(t v
alue:
7.44
; p<
0.0
01),
IgA
(1.4
988;
p
< 0
.05)
and
tota
l pro
tein
(0.8
785;
p<
0.0
5) sh
owed
signi
fican
t im
prov
emen
tPa
tient
s sho
wed
mod
erat
e to
good
reco
very
and
dem
onst
rabl
ehi
stol
ogica
l cha
nges
in re
duce
dsu
bepi
thel
ial o
edem
a, re
duce
dex
udat
es, v
ascu
lar c
hann
el
No
deta
ilsRa
tiona
le fo
rde
finin
g th
e st
udy
agen
t as a
nan
timicr
obial
agen
t: au
thor
sju
stify
effe
ctive
ness
of M
anjis
htha
on
basis
of a
bilit
y of
rem
ove
micr
oang
iopa
thic
and
athe
rosc
lero
ticch
ange
s ins
ide
the
arte
ries/c
apilla
ries
in w
ound
are
a,th
us fa
cilita
ting
bloo
d su
pply,
nutr
ition
and
rem
oval
ofm
icrob
es. A
lsoth
at A
shva
gand
haim
prov
edim
mun
olog
ical
stat
us o
f pat
ient
s
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
147
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
prof
ilera
tion
and
appe
aran
ce o
fhe
alth
gran
ulat
ion
tissu
e. G
ood
impr
ovem
ent i
n ar
teria
lcir
culat
ion
of a
ffect
ed p
art a
lsono
ted.
Con
trol
of p
urul
ent
disc
harg
e (m
aggo
tssp
onta
neou
sly d
ischa
rged
afte
r4–
6 di
ppin
gs)
At 3
mon
ths:
both
gro
ups
show
ed st
atist
ically
sign
ifica
ntch
ange
s (p
< 0
.01)
in a
nkle
brac
hial
pres
sure
inde
x(A
Bin
dex)
Appendix 4
148
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Erst
ad (1
997)
,107
USA
Stud
y de
sign:
RC
T (D
B)
Met
hod
ofra
ndom
isatio
n:N
ot st
ated
Uni
t of a
lloca
tion:
Patie
nt
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
men
tione
d
Out
com
e as
sess
men
t:Ti
ssue
isch
aem
iaas
sess
ed u
sing
Dop
pler
-de
rived
ank
le–b
rach
ialin
dex
and
palp
atio
n of
pulse
s (fe
mor
al,po
plite
al, p
oste
rior t
ibial
,an
d do
rsali
s ped
is).
Clin
ical r
espo
nse
class
ified
as:
cure
(com
plet
e re
solu
tion
ofpr
esen
ting
signs
and
sym
ptom
s);
impr
ovem
ent (
part
ialim
prov
emen
t of
pres
entin
g sig
ns a
ndsy
mpt
oms)
; fail
ure
(no
impr
ovem
ent o
rw
orse
ning
of p
rese
ntin
gsig
ns a
nd sy
mpt
oms)
.Pa
tient
s who
requ
ired
surg
ery
wer
e co
nsid
ered
evalu
able
if th
ean
timicr
obial
was
give
nfo
r at l
east
5da
ys p
rior
to su
rger
y or
if th
ean
timicr
obial
was
requ
ired
post
oper
ative
ly
Popu
latio
n:Ag
e at
leas
t18
year
s, w
ithin
sulin
or n
on-in
sulin
depe
nden
t diab
etes
atte
ndin
g th
eVa
scul
ar S
urge
rySe
rvice
at a
300
-bed
unive
rsity
med
ical
cent
re in
Sou
ther
nAr
izona
Inclu
sion
crite
ria:
At le
ast g
rade
I fo
otin
fect
ion
(see
belo
w);
not
rece
ived
succ
essfu
lan
timicr
obial
ther
apy
with
in th
epr
evio
us 4
days
,as
sess
ed b
y cli
nica
lim
prov
emen
t
Exclu
sion
crite
ria:
Know
nhy
pers
ensit
ivity
tope
nicil
lins o
rce
phalo
spor
ins;
crea
tinin
e cle
aran
cele
ss th
an15
ml/m
inut
e;re
cent
hist
ory
ofdr
ug o
r alco
hol
abus
e; c
onco
mita
ntin
fect
ion
at a
site
othe
r tha
n th
e fo
otth
at re
quire
dad
ditio
nal
antim
icrob
ials;
term
inal
illnes
s;ne
utro
peni
c;
Gen
der
Not
repo
rted
Mea
n (r
ange
) age
(yea
rs):
I1: 6
0.7
(31–
77)
I2: 5
7.8
(34–
93)
Num
ber (
%) w
ith ty
pe 1
/type
2di
abet
es:
I1: 1
3/18
(72)
/5/1
8 (2
8)I2
: 12/
18 (6
7)/6
/18
(33)
Mea
n du
ratio
n of
diab
etes
(yea
rs):
I1: 1
2.8
I2: 1
3.3
Num
ber (
%) w
ith g
rade
of w
ound
infe
ctio
n I1
/I2:
Gra
de I:
2/1
8 (1
1%)/1
/18
(6%
)G
rade
II: 8
/18
(44%
)/12/
18 (6
7%)
Gra
de II
I: 6/
18 (3
3%)/5
/18
(28%
)G
rade
IV: 2
/18
(11%
)/0
The
degr
ee o
f tiss
ue is
chae
mia
asde
term
ined
by
pulse
palp
atio
n an
dan
kle–
brac
hial
inde
x w
asco
mpa
rabl
e be
twee
n th
e 2
grou
ps(d
etail
s pro
vided
in th
e pa
per)
Num
ber (
%) w
ho h
ad e
xper
ienc
edfa
iled
outp
atie
nt a
ntim
icrob
ialth
erap
y pr
ior t
o ad
miss
ion:
I1: 1
0/18
(56%
) (6
patie
nts r
ecei
ved
cipro
floxa
cin)
I2: 7
/18
(39%
) (re
ceive
d a
varie
ty o
fan
timicr
obial
age
nts)
Mea
n an
kle–
brac
hial
pres
sure
inde
xof
righ
t leg
:I1
: 0.9
3I2
: 0.9
0
I1: A
/S 3
g q.
d.s.
if cr
eatin
ine
clear
ance
mor
e th
an50
ml/m
inut
e. S
ame
dose
was
given
t.d.
s. or
b.d
. if c
reat
inin
ecle
aran
ce 3
0–50
or
15–3
0 m
l/min
ute,
resp
ectiv
ely.
Dur
atio
n of
ther
apy
at le
ast
5da
ys (n
= 1
8)
I2: C
efox
itin
2g
q.d.
s. if
crea
tinin
e cle
aran
ce m
ore
than
50m
l/min
ute.
Sam
e do
se w
asgiv
en t.
d.s.
or b
.d, i
f cre
atin
ine
clear
ance
30–
50 o
r 15
–30
ml/m
inut
e re
spec
tivel
y.D
urat
ion
of th
erap
y at
leas
t5
days
(n=
18)
All p
atie
nts:
No
addi
tiona
l ant
imicr
obial
sw
ere
adm
inist
ered
dur
ing
hosp
italis
atio
n un
less
a p
atie
ntfa
iled
to re
spon
d to
the
stud
yan
timicr
obial
ther
apy
with
in48
hour
s, in
whi
ch c
ase
the
patie
nt w
as w
ithdr
awn.
Surg
ical i
nter
vent
ions
wer
epe
rform
ed a
s req
uire
d
Stat
istica
l met
hods
:�
2te
st u
sed
for c
linica
l and
bact
erio
logic
al ev
aluat
ions
and
Wilc
oxon
rank
sum
test
use
d to
com
pare
gro
ups f
or m
ean
dura
tion
of h
ospi
talis
atio
n an
dm
ean
chan
ges i
n cli
nica
l sign
s and
sym
ptom
s fro
m st
udy
entr
y to
end
of th
erap
y. Fi
sher
’s ex
act
test
(tw
o-ta
iled)
use
d to
com
pare
the
trea
tmen
tou
tcom
es (s
ucce
sses
and
failu
res)
of th
e 2
grou
ps. A
nalys
is w
asba
sed
on in
tent
ion-
to-tr
eat.
Num
ber (
%) w
ith c
linica
lre
spon
se to
trea
tmen
t I1/
I2:
Cur
ed: 1
/18
(6)/7
/18
(39)
Impr
oved
: 14/
18 (7
8)/9
/18
(50)
Faile
d: 2
/18
(11)
/1/1
8 (6
)In
dete
rmin
ate
resu
lt: 1
/18
(6)/1
/18
(6)
p=
0.0
3 fo
r pat
ient
s clas
sifie
d as
cure
d, b
ut n
o sig
nific
ant
diffe
renc
e w
hen
cure
and
impr
ovem
ent c
onsid
ered
toge
ther
Ther
e w
as n
o sig
nific
ant
diffe
renc
e be
twee
n gr
oups
in th
epr
opor
tion
of p
atie
nts w
ho h
adch
ange
s in
clini
cal s
igns a
ndsy
mpt
oms f
rom
bas
elin
e to
end
of th
erap
y
Num
ber (
%) w
ith b
acte
riolo
gical
resp
onse
to th
erap
y I1
/I2:
Erad
icatio
n: 6
/6 (1
00%
)/8/1
1(7
3%)
Part
ial e
radi
catio
n: 0
/2/1
1 (1
8%)
Pers
isten
ce: 0
/1/1
1 (9
%)
Num
ber o
fpa
tient
s not
com
plet
ing
5-da
yco
urse
of
trea
tmen
t:I1
: 1 (d
ue to
adve
rse
even
tun
relat
ed to
stud
ym
edica
tion)
I2: 2
(1 d
ue to
inad
equa
tere
spon
se to
ther
apy,
1 du
e to
requ
irem
ent f
orco
ncom
itant
ther
apy
for a
vagin
al in
fect
ion)
Num
ber o
fpa
tient
s eva
luab
lefo
r bac
terio
logic
alou
tcom
e (i.
e.cu
ltura
ble
mat
erial
ava
ilabl
efro
m in
fect
ed si
teat
bas
elin
e):
I1: 6
I2: 1
1
Revie
wer
’sco
mm
ent:
mos
t,bu
t not
all
of th
epa
tient
s in
this
stud
y ha
d a
DFU
(33/
36)
The
trial
aut
hors
com
men
ted
that
“the
unc
ontr
olle
din
fect
ious
pro
cess
had
ofte
n le
d to
loss
of f
oot
arch
itect
ure
befo
reho
spita
lisat
ion
and
i.v. a
ntim
icrob
ialth
erap
y w
asin
dica
ted
topr
otec
t aga
inst
sept
icaem
iabe
fore
, dur
ing
and
afte
rde
brid
emen
t”
Stud
y sp
onso
rshi
p:N
ot st
ated
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
149
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
to c
ontr
ol re
sidua
l sign
sof
infe
ctio
n at
the
affe
cted
site
(equ
atin
g to
at le
ast 5
tota
l day
s of
ther
apy)
. Pat
ient
s who
wer
e th
ough
t not
tore
quire
an
ampu
tatio
nba
sed
on th
e ad
miss
ion
inve
stiga
tions
, but
subs
eque
ntly
requ
ired
one
due
to d
iseas
epr
ogre
ssio
n, w
ere
class
ified
as c
linica
lfa
ilure
s.Ba
cter
ial e
radi
catio
n(a
sses
sed
by n
eedl
eas
pira
tion,
or d
eep
tissu
eor
bon
e sa
mpl
ing
durin
gop
erat
ive d
ebrid
emen
t)w
as d
efin
ed a
s the
disa
ppea
ranc
e of
cultu
rabl
e m
ater
ial o
rel
imin
atio
n of
pat
hoge
nsat
the
end
of th
erap
y an
dat
2-w
eek
follo
w-u
p. If
the
path
ogen
was
elim
inat
ed b
ut a
diff
eren
tpa
thog
en e
mer
ged
durin
g or
afte
r the
rapy
,th
e ev
aluat
ion
was
term
ed e
radi
catio
n/su
perin
fect
ion.
Par
tial
erad
icatio
n w
as d
efin
edas
disa
ppea
ranc
e of
som
e, b
ut n
ot a
ll of
the
path
ogen
s. Pe
rsist
ence
was
def
ined
as p
rese
nce
of in
itial
path
ogen
s at t
heen
d of
ther
apy.
Inde
term
inat
e: re
sults
preg
nant
;br
east
feed
ing
Seve
rity
scale
for
diab
etic
foot
infe
ctio
n us
ed in
the
trial
:G
rade
I: c
ellu
litis,
no
skin
bre
akG
rade
II: c
ellu
litis,
supe
rficia
l ulce
ran
d/or
pun
ctur
ew
ound
pre
sent
Gra
de II
I: ce
llulit
is,de
ep u
lcer a
nd/o
rpu
nctu
re w
ound
with
susp
ecte
dos
teom
yelit
isG
rade
IV: c
ellu
litis,
deep
ulce
r, an
dos
teom
yelit
is w
ithde
stru
ctio
n of
foot
arch
itect
ure
and/
orw
et g
angr
ene
Mea
n an
kle–
brac
hial
pres
sure
inde
xof
left
leg:
I1: 0
.90
I2
: 0.8
3
No
signi
fican
t diff
eren
ces w
ere
foun
d be
twee
n gr
oups
The
over
all m
ean
±SD
num
ber
of is
olat
es p
er p
atie
nt w
as3.
4±1.
1 (n
ot re
port
ed p
ergr
oup)
. At l
east
one
spec
ies o
fSt
aphy
loco
ccus
was
isol
ated
from
all p
atie
nts,
and
all b
ut o
nepa
tient
had
at l
east
one
spec
ies
of S
trept
ococ
cuso
r Ent
eroc
occu
s.Al
l of t
he S
taph
yloco
ccus
and
Stre
ptoc
occu
siso
lates
wer
esu
scep
tible
to b
oth
stud
yan
tibio
tic re
gimen
s, bu
t the
Ente
roco
ccus
isolat
es (2
5% o
fpa
tient
s, all
in I1
) wer
esu
scep
tible
onl
y to
A/S
. Eac
hpa
tient
with
isol
ates
susc
eptib
leto
the
pres
crib
ed a
ntim
icrob
ialag
ent h
ad c
linica
l im
prov
emen
tor
cur
e, e
xcep
t for
one
pat
ient
inI1
who
requ
ired
are
vasc
ular
isatio
n pr
oced
ure
shor
tly a
fter a
dmiss
ion.
Of t
hepa
tient
s with
one
or m
ore
orga
nism
s res
istan
t to
the
stud
yan
timicr
obial
(25%
of p
atie
nts i
nea
ch g
roup
), all
had
clin
ical
impr
ovem
ent d
urin
g th
erap
y
Num
ber o
f pat
ient
s und
ergo
ing
ampu
tatio
ns I1
/I2:
Toe
only
3/6
Toe
and
ray
4/1
Belo
w k
nee
1/1
Num
ber o
f pat
ient
s und
ergo
ing
reva
scul
arisa
tion
proc
edur
es:
I1: f
emor
otib
ial b
ypas
s 1Ao
rtob
ifem
oral
bypa
ss a
nd to
eam
puta
tion
1
cont
inue
d
Appendix 4
150
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
wer
e th
ose
that
did
not
fit in
to a
ny c
ateg
ory
for
both
clin
ical a
ndba
cter
iolo
gical
asse
ssm
ent.
Spec
imen
sw
ere
plac
ed in
ster
ileco
ntain
ers a
ndtr
ansp
orte
d to
the
labor
ator
y. Sp
ecim
ens
wer
e te
sted
for a
erob
ican
d an
aero
bic
orga
nism
sw
ith su
bseq
uent
susc
eptib
ility
test
ing
that
inclu
ded
dete
rmin
atio
nof
min
imum
inhi
bito
ryco
ncen
trat
ion
of is
olat
es.
In a
dditi
on, t
he n
umbe
rof
isol
ates
iden
tifie
d,su
rgica
l pro
cedu
res
requ
ired,
dur
atio
n of
hosp
italis
atio
n, a
ndad
vers
e ev
ents
wer
ere
cord
ed
Setti
ng/le
ngth
of
trea
tmen
t:H
ospi
tal.
Initi
al fo
llow
-up
was
2w
eeks
pos
t-ho
spita
l disc
harg
e. L
ater
follo
w-u
p w
as 1
yea
r
I2: p
oplit
eal–
tibial
byp
ass a
ndbe
low
-kne
e am
puta
tion
1Be
low
kne
e fe
mor
opop
litea
lby
pass
1Ili
ac a
ngio
plas
ty 1
Popl
iteal
angio
plas
ty 1
Mea
n (r
ange
) dur
atio
n of
hosp
italis
atio
n (d
ays)
:I1
: 21.
1 (6
.0–5
8.0)
I2: 1
2.1
(4.0
–39.
0)p
= 0
.06
Prop
ortio
n of
pat
ient
sex
perie
ncin
g ga
stro
inte
stin
alad
vers
e ev
ents
:I1
: 39%
I2: 3
3%
Thre
e pa
tient
s in
grou
p I1
suffe
red
a se
rious
adv
erse
eve
nt(w
orse
ning
of c
onge
stive
car
diac
failu
re) w
hich
the
auth
ors
cons
ider
ed to
be
unre
lated
to th
est
udy
trea
tmen
t
Health Technology Assessment 2006; Vol. 10: No. 12
151
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Gou
gh (1
997)
,100
UK
Dup
licat
e pu
blica
tion:
Gou
gh (1
998)
174
Stud
y de
sign:
RC
T (D
B)
Met
hod
ofra
ndom
isatio
n:Ra
ndom
num
ber l
ist
Uni
t of a
lloca
tion:
Patie
nt
Calc
ulat
ion
of st
atist
ical
pow
er:
A sa
mpl
e siz
e of
40
patie
nts w
as e
stim
ated
base
d on
evid
ence
of a
mea
n tim
e to
reso
lutio
nof
infe
ctio
n of
13.
0(S
D6.
5) d
ays i
n sim
ilar
patie
nts.
A re
duct
ion
of6
days
was
take
n as
clini
cally
sign
ifica
nt w
ith�
= 0
.05
and
pow
er o
f0.
8
Out
com
es a
sses
sed:
Tim
e to
hos
pita
ldi
scha
rge
(elig
ibilit
ycr
iteria
for d
ischa
rge
wer
e re
solu
tion
ofce
llulit
is, i.
e.di
sapp
eara
nce
clini
cally
of so
ft-tis
sue
eryt
hem
a,no
furt
her e
xuda
te fr
omth
e ul
cer,
skin
tem
pera
ture
diff
eren
cew
ithin
nor
mal
limits
, and
nega
tive
foot
ulce
rcu
lture
s)
Popu
latio
n:Pa
tient
s adm
itted
from
a sp
ecial
istdi
abet
ic fo
ot c
linic
Inclu
sion
crite
ria:
Adul
t (>
18ye
ars)
diab
etic
patie
nts
with
ext
ensiv
ece
llulit
is, d
efin
ed a
san
acu
te sp
read
ing
infe
ctio
n of
the
skin
with
invo
lvem
ent o
fth
e su
bcut
aneo
ustis
sues
, clin
ically
char
acte
rised
by
eryt
hem
a (>
2cm
indi
amet
er) i
nas
socia
tion
with
puru
lent
disc
harg
e,w
ith o
r with
out
lymph
angit
is
If a
patie
nt h
adse
vera
l ulce
rs, t
hem
ost s
ever
ely
affe
cted
one
was
stud
ied
Exclu
sion
crite
ria:
Abso
lute
neu
trop
hil
coun
t of <
1.0
×10
9 /l or
>50
×10
9 /l;hi
stor
y of
mali
gnan
tdi
sord
er; b
lood
dysc
rasia
; HIV
infe
ctio
n; se
rum
crea
tinin
e>
250
µmol
/l or
rena
l rep
lacem
ent
ther
apy;
hep
atic
dise
ase;
pre
vious
Num
ber m
ale/fe
male
:C
: 15/
5I:
14/6
Num
ber w
hite
/Afro
-Car
ibbe
an:
C: 1
5/5
I: 18
/2
Med
ian (r
ange
) age
in (y
ears
):C
: 66
(58–
81)
I: 65
(30–
86)
Med
ian (r
ange
) dur
atio
n of
diab
etes
in (y
ears
):C
: 19
(1–4
4)I:
18.5
(0.1
–50)
Num
ber i
nsul
in d
epen
dent
/non
-in
sulin
dep
ende
nt:
C: 4
/16
I: 6/
14
Num
ber t
reat
ed w
ith in
sulin
:C
: 15
I: 13
Med
ian (r
ange
) glyc
ated
haem
oglo
bin
(%):
C: 8
.70
(5.5
–12.
9)I:
9.25
(5.5
–13.
7)
Med
ian (r
ange
) bod
y m
ass i
ndex
in(k
g/m
2 ):C
: 24.
9 (2
1.1–
40.7
)I:
28.4
(21.
0–40
.8)
Num
ber w
ith n
ephr
opat
hy:
C: 5
I: 5
Med
ian (r
ange
) vib
ratio
n pe
rcep
tion
thre
shol
d (v
olts
):C
: 37.
4 (8
.3–5
0.0)
I: 35
.7 (1
8.3–
50.0
)
I: G
-CSF
give
n at
an
initi
al do
seof
5µg
/k/d
ay, r
educ
ed to
2.5
µg/k
g/da
y, if,
afte
r 2 d
oses
,th
e ab
solu
te n
eutr
ophi
l cou
ntw
as h
igher
than
25
×10
9 /l. If
the
abso
lute
neu
trop
hil c
ount
rem
ained
abo
ve th
is va
lue
afte
ra
furt
her 2
dos
es, 2
.5µg
/kg
was
give
n on
alte
rnat
e da
ys. I
fat
any
poi
nt th
e ab
solu
tene
utro
phil
coun
t was
>50
×10
9 /l or
the
tota
l whi
te c
ell
coun
t was
>75
×10
9 /l, G
-CSF
was
stop
ped
until
the
abso
lute
neut
roph
il co
unt f
ell b
elow
10
×10
9 /l. G
-CSF
was
adm
inist
ered
as a
dail
ysu
bcut
aneo
us in
ject
ion
for
7da
ys (n
= 2
0)
C: P
laceb
o, c
onsis
ting
of a
salin
e so
lutio
n, id
entic
al in
appe
aran
ce w
ith a
ctive
prep
arat
ion,
adm
inist
ered
as a
daily
subc
utan
eous
inje
ctio
n fo
r7
days
(n=
20)
All p
atie
nts:
A co
mbi
natio
n of
4 a
ntib
iotic
s(c
efta
zidim
e, a
mox
icillin
,flu
cloxa
cillin
and
met
roni
dazo
le) w
as g
iven
i.v.
until
cel
lulit
is an
d ul
cer
disc
harg
e re
solve
d. M
ost
patie
nts r
ecei
ved
the
follo
win
gre
spec
tive
dose
s dail
y: 3
, 1.5
, 2an
d 1.
5g.
Alte
rnat
ively,
vanc
omyc
in i.
v. w
as u
sed
ifth
ere
was
kno
wn
peni
cillin
hype
rsen
sitivi
ty o
r if t
he p
atie
ntw
as o
r had
bee
n co
loni
sed
or
Stat
istica
l met
hods
:�
2te
st w
ith Y
ate’
s cor
rect
ion
for
small
num
bers
was
use
d fo
rca
tego
rical
data
, and
log-
rank
test
used
for t
ime
to e
vent
dat
a
The
med
ian (r
ange
) dos
e of
G
-CSF
ove
r the
7da
ys w
as 3
02(2
00–4
40) µ
g/da
y, w
ith 9
pat
ient
sre
quiri
ng a
redu
ctio
n in
dos
e
Num
ber o
f pat
ient
s who
rece
ived
antib
iotic
regim
enco
nsist
ing
of c
efta
zidim
e,am
oxici
llin, f
luclo
xacil
lin, a
ndm
etro
nida
zole
(give
n i.v
. the
n by
mou
th if
app
ropr
iate)
:C
: 15
I: 17
Num
ber o
f pat
ient
s who
rece
ived
vanc
omyc
in:
C: 4
(3 h
ad M
RSA,
1 h
adpe
nicil
lin a
llerg
y)I:
3 (2
had
MRS
A, 1
had
pen
icillin
aller
gy)
Num
ber o
f pat
ient
s with
evid
ence
of o
steo
mye
litis:
C: 1
2I:
12
Patie
nts w
ith o
steo
mye
litis
rece
ived
com
bine
d or
al an
d i.v
.th
erap
y fo
r at l
east
10
wee
ks
Med
ian (r
ange
) tim
e to
hos
pita
ldi
scha
rge
in d
ays:
C: 1
7.5
(9–1
00)
I: 10
(7–3
1)p
= 0
.02
Med
ian (r
ange
) tim
e to
reso
lutio
n
Ther
e w
ere
now
ithdr
awals
Auth
ors’
note
:G
-CSF
ther
apy
was
ass
ociat
edw
ith th
ede
velo
pmen
t of
leuc
ocyt
osis,
due
almos
t ent
irely
toan
incr
ease
inne
utro
phil
coun
t
Nor
mal
rang
es fo
rha
emat
olog
yan
alyse
s, as
sugg
este
d by
trial
auth
ors:
Tota
l whi
te c
ells
(4.0
–10.
0) ×
109 /l
Neu
trop
hils
(2.5
–7.5
) ×10
9 /lLy
mph
ocyt
es(1
.3–4
.0) ×
109 /L
Mon
ocyt
es(0
.2–1
.5) ×
109 /L
Ratio
nale
for
defin
ing
the
stud
yag
ent a
s an
antim
icrob
ialag
ent:
Endo
geno
us
G-C
SFco
ncen
trat
ions
rise
durin
g ba
cter
ialse
psis
in b
oth
neut
rope
nic
and
non-
neut
rope
nic
stat
es, s
ugge
stin
gth
at G
-CSF
may
have
a c
entr
al ro
lein
the
neut
roph
ilre
spon
se to
cont
inue
d
Appendix 4
152
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Tim
e to
reso
lutio
n of
cellu
litis
(ass
esse
d by
skin
tem
pera
ture
usin
gin
frare
d th
erm
omet
eran
d co
mpa
ring
aver
age
of3
read
ings
with
in a
rea
ofce
llulit
is w
ith th
ose
take
nfro
m th
e co
rres
pond
ing
site
on th
e no
n-in
fect
edfo
ot, a
diff
eren
ce o
f mor
eth
an 2
°C b
eing
def
ined
as
abno
rmal)
Tim
e to
with
draw
al of
antib
iotic
s
Tim
e to
neg
ative
swab
cultu
re (a
sses
sed
usin
gda
ily sw
abs t
aken
from
the
deep
est p
art o
f the
wou
nd a
fter c
lean
sing
the
ulce
r with
ster
ilesa
line
and
rem
ovin
gsu
perfi
cial d
ebris
;sp
ecim
ens w
ere
analy
sed
for a
erob
ic an
dan
aero
bic
cultu
re, a
ndsa
mpl
ing
was
repe
ated
until
cul
ture
s wer
ene
gativ
e on
2co
nsec
utive
day
s)
Requ
irem
ent f
or su
rger
y
Ulce
r hea
ling
Requ
irem
ent f
oran
giogr
aphy
and
asso
ciate
d pr
oced
ures
Diag
nosis
of
oste
omye
litis
(usin
g pl
ainra
diog
raph
y an
d pr
obe
orga
ntr
ansp
lanta
tion;
imm
unos
uppr
essiv
eth
erap
y in
cludi
ngco
rtico
ster
iods
;pr
egna
ncy;
lact
atio
n;m
ultip
le o
rgan
failu
re; s
econ
dary
tose
ptica
emia;
crit
ical
leg
ischa
emia
(ank
lesy
stol
ic pr
essu
re<
50m
mH
g or
ankl
e/br
achi
al bl
ood
pres
sure
inde
x<
0.5)
; dor
sal
tran
scut
aneo
usox
ygen
pre
ssur
e<
30m
mH
g
Neu
trop
hils
from
10
healt
hy v
olun
teer
s,m
atch
ed b
y ag
e an
dge
nder
to th
edi
abet
ic pa
tient
s,w
ere
used
as
cont
rols
for
neut
roph
il fu
nctio
nas
says
Med
ian (r
ange
) Dop
pler
inde
x fo
ran
kle/
brac
hial
bloo
d pr
essu
re ra
tio:
C: 0
.99
(0.6
5–1.
50)
I: 1.
00 (0
.53–
1.28
)
Num
ber w
ith re
tinop
athy
:C
: 13
I: 12
Num
ber r
ecei
ving
antib
iotic
s on
recr
uitm
ent t
o th
e tr
ial:
C: 3
I: 3
Num
ber c
urre
ntly
smok
ing:
C: 2
I: 3
Num
ber w
ith h
istor
y of
cor
onar
y or
cere
brov
ascu
lar d
iseas
e:C
: 10
I: 7
Num
ber w
ith p
revio
us m
inor
ampu
tatio
n or
deb
ridem
ent:
C: 1
3I:
9
Num
ber w
ith u
lcers
in th
efo
refo
ot/m
idfo
ot/h
indf
oot:
C: 1
7/2/
1I:
15/2
/2In
add
ition
, one
pat
ient
in g
roup
Iha
d ex
tens
ive c
ellu
litis
seco
ndar
y to
a pa
rony
chia
with
out u
lcera
tion
Num
ber w
ith m
ultip
le u
lcers
:C
: 9I:
7
Med
ian (r
ange
) dur
atio
n of
foot
ulce
r (da
ys):
C: 3
9.5
(2–1
825)
I: 21
.0 (2
–127
8)
infe
cted
dur
ing
the
past
yea
rw
ith M
RSA.
If a
n in
fect
ing
path
ogen
was
iden
tifie
d be
fore
adm
issio
n an
d en
rolm
ent,
the
appr
opria
te a
ntib
iotic
s wer
eus
ed a
s firs
t-lin
e th
erap
y.Su
bseq
uent
cha
nges
toan
tibio
tic tr
eatm
ent w
ere
guid
ed b
y m
icrob
iolo
gical
cultu
res a
nd se
nsiti
vitie
s.G
lycae
mic
cont
rol w
asop
timise
d w
ith in
sulin
in a
llpa
rtici
pant
s, us
ing
a co
ntin
uous
i.v. i
nfus
ion
or a
mul
tiple
-dos
ere
gimen
. Onl
y st
anda
rd fo
amdr
essin
gs w
ere
used
. All
rece
ived
appr
opria
te p
odiat
rictr
eatm
ent.
Dec
ision
s abo
utsu
rgica
l deb
ridem
ent o
ram
puta
tion
wer
e ba
sed
oncli
nica
l sign
s, in
cludi
ng th
epr
esen
ce o
f non
-viab
le ti
ssue
,th
e de
velo
pmen
t of g
angr
ene,
absc
ess f
orm
atio
n an
d lac
k of
impr
ovem
ent d
espi
te o
ptim
uman
timicr
obial
ther
apy
of c
ellu
litis
in d
ays:
C: 1
2 (5
–93)
I: 7
(5–2
0)p
= 0
.03
Med
ian (r
ange
) tim
e to
with
draw
al of
i.v.
antib
iotic
s in
(day
s):
C: 1
4.5
(8–6
3)I:
8.5
(5–3
0)p
= 0
.02
Med
ian (r
ange
) tim
e to
neg
ative
swab
cul
ture
in (d
ays)
:C
: 8 (2
–79)
(pos
itive
swab
beca
me
ster
ile in
15
patie
nts)
I: 4
(2–1
0) (p
ositi
ve sw
ab b
ecam
est
erile
in 1
6 pa
tient
s)p
= 0
.02
Med
ian (r
ange
) foo
t tem
pera
ture
diffe
renc
e in
(ºC
) at d
ay 7
:C
: 2.1
(0.1
–5.8
)I:
1.1
(0.1
–2.8
)p
= 0
.011
Num
ber r
equi
ring
surg
ery
(deb
ridem
ent u
nder
gen
eral
anae
sthe
sia a
nd/o
r ray
ampu
tatio
n):
C: 4
pat
ient
s (1
durin
g fir
st7
days
, 3 a
fter f
irst 7
days
; 2 h
adto
e am
puta
tion,
2 h
ad e
xten
sive
debr
idem
ent u
nder
ana
esth
esia)
I: no
nep
= 0
.114
Num
ber (
%) o
f pat
ient
s with
reso
lutio
n of
cel
lulit
is at
day
7:
C: 4
(20%
)I:
11 (5
5%)
p=
0.0
5
infe
ctio
n. E
xter
nal
adm
inist
ratio
n of
G-C
SF is
thou
ght
to in
crea
se th
ere
leas
e of
neut
roph
ils fr
omth
e bo
ne m
arro
wan
d im
prov
ene
utro
phil
func
tion
Stud
y sp
onso
rshi
p:Th
e le
ad a
utho
rw
as su
ppor
ted
bya
gran
t fro
mAm
gen
CA,
USA
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
153
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
to b
one)
Hae
mat
olog
y (s
ampl
esta
ken
by st
aff n
otin
volve
d in
clin
ical
asse
ssm
ent o
f the
patie
nts;
resu
lts g
iven
toth
e ph
arm
acist
, who
unde
rtoo
k ch
ange
s in
dose
s of G
-CSF
, whi
chw
ere
conc
eale
d fro
m th
ein
vest
igato
rs)
Effe
cts o
f G-C
SF o
n th
ege
nera
tion
of n
eutr
ophi
lsu
pero
xide
: mea
sure
d by
a sp
ectr
opho
tom
etric
assa
y
Adve
rse
effe
cts
Patie
nts w
ere
revie
wed
daily
by
3 in
depe
nden
tcli
nicia
ns. A
ll cli
nica
lde
cisio
ns (r
egar
ding
need
for s
urge
ry o
rel
igibi
lity
for h
ospi
tal
disc
harg
e) w
ere
mad
ein
depe
nden
tly o
f stu
dytr
eatm
ent a
nd w
hite
-cel
lco
unt
Setti
ng a
nd le
ngth
of
trea
tmen
t:H
ospi
tal;
7da
ys
Med
ian (r
ange
) dur
atio
n of
cel
lulit
is(d
ays)
:C
: 4 (2
–21)
I: 5
(1–1
4)
Med
ian (r
ange
) foo
t tem
pera
ture
diffe
renc
e (º
C):
C: 3
.1 (0
–9.1
)I:
4.3
(1.4
–11.
2)
Med
ian (r
ange
) tot
al w
hite
cel
lco
unt (
×10
9 /l):
C: 7
.8 (3
.7–1
1.1)
I: 7.
6 (4
.8–1
7.1)
Med
ian (r
ange
) neu
trop
hil c
ount
(×
109 /l)
:C
: 5.5
(1.4
–7.9
)I:
5.6
(2.6
–15.
9)
Med
ian (r
ange
) lym
phoc
yte
coun
t (×
109 /l)
:C
: 1.9
(0.8
–3.3
)I:
1.8
(0.9
–3.3
)
Med
ian (r
ange
) mon
ocyt
e co
unt
(×10
9 /l):
C: 0
.47
(0.1
–1.1
)I:
0.39
(0.1
–0.9
)
Micr
obio
logy
resu
lts (n
umbe
r of
patie
nts i
n C
/I):
Posit
ive w
ound
cul
ture
15/
16
Gra
m-p
ositi
ve a
erob
es:
Stap
hylo
cocc
us a
ureu
s5/1
1St
rept
ococ
cus a
gala
ctia
e0/
1St
rept
ococ
cusC
0/1
Stre
ptoc
occu
sG 0
/2Es
cher
ichia
col
i3/0
MRS
A 3/
2
Num
ber (
%) o
f pat
ient
with
ulce
r hea
led
at d
ay 7
:C
: 0I:
4 (2
1%)
p=
0.0
9
In p
atie
nts w
ith m
ultip
le u
lcers
,th
ere
was
no
dete
riora
tion
in a
nyse
cond
ary
ulce
rs
Med
ian (r
ange
) blo
od g
luco
se(m
mol
/l):
C: 1
1.5
(2.7
–24.
4)I:
12.4
(3.0
–27.
2)p
= 0
.42
Med
ian (r
ange
) ins
ulin
dos
e in
(U/k
g/da
y):
C: 0
.48
(0.1
5–1.
01)
I: 0.
58 (0
.11–
1.12
)p
= 0
.38
Num
ber o
f pat
ient
s und
ergo
ing
angio
grap
hy:
C: 7
I: 4
p=
0.5
Num
ber o
f pat
ient
s und
ergo
ing
perc
utan
eous
tran
slum
inal
ballo
on a
ngio
plas
ty/v
ascu
larsu
rger
y/no
inte
rven
tion:
C: 3
/3/1
– p
atie
nt re
fuse
d fu
rthe
rin
terv
entio
nI:
2/1/
1 –
had
vasc
ular
dise
ase
unsu
itabl
e fo
r int
erve
ntio
np
= 0
.449
for b
etw
een-
grou
pdi
ffere
nce
for p
ropo
rtio
ns o
fpa
tient
s und
ergo
ing
angio
plas
tyor
surg
ery
Ther
e w
ere
no si
gnifi
cant
chan
ges i
n ha
emog
lobi
n or
in
cont
inue
d
Appendix 4
154
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Gra
m-n
egat
ive a
erob
es:
Ente
roba
cter
spec
ies 2
/3Ac
inet
obac
ters
pecie
s 0/1
Serra
tiasp
ecie
s 2/0
Kleb
siella
spec
ies 3
/0Pr
oteu
sspe
cies 2
/0Es
cher
ichia
col
i2/0
Oth
er 4
/1
Anae
robe
s:Ba
cter
iode
s fra
gilis
1/1
Oth
er 2
/2
Polym
icrob
ial in
fect
ion
9/6
plat
elet
cou
nts i
n ei
ther
gro
updu
ring
the
stud
y pe
riod
Med
ian (r
ange
) tot
al w
hite
cel
lco
unt (
×10
9 /l) a
t day
3:
C: 6
.9 (3
.8–1
1.5)
I: 25
.8 (1
7.6–
45.5
)p
< 0
.000
1
Med
ian (r
ange
) neu
trop
hil c
ount
(x 1
09 /l) a
t day
3:
C: 4
.5 (2
.5–8
.5)
I: 19
.9 (1
5.5–
41.9
)p
< 0
.000
1
Med
ian (r
ange
) lym
phoc
yte
coun
t(×
109 /l)
at d
ay 3
:C
: 1.8
(1.0
–2.9
)I:
2.3
(0.7
–4.5
)p
= 0
.07
Med
ian (r
ange
) mon
ocyt
e co
unt
(×10
9 /l) a
t day
3:
C: 0
.44
(0–1
.5)
I: 0.
48 (0
–3.9
)p
= 0
.201
Med
ian (r
ange
) tot
al w
hite
cel
lco
unt (
×10
9 /l) a
t day
7:
C: 6
.1 (4
.1–1
2.3)
I: 27
.8 (1
0.8–
41.0
)p
< 0
.000
1
Med
ian (r
ange
) neu
trop
hil c
ount
(×10
9 /l) a
t day
7:
C: 3
.8 (1
.0–6
.7)
I: 22
.4 (7
.9–3
7.1)
p<
0.0
001
Med
ian (r
ange
) lym
phoc
yte
coun
t(×
109 /l)
at d
ay 7
:C
: 1.8
(1.0
–5.1
)I:
2.6
(1.5
–4.9
)p
= 0
.012
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
155
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Med
ian (r
ange
) mon
ocyt
e co
unt
(×10
9 /l) a
t day
7:
C: 0
.54
(0.2
–1.1
)I:
0.69
(0.2
–3.7
)p
= 0
.044
Med
ian (r
ange
) neu
trop
hil
supe
roxi
de p
rodu
ctio
n in
nmol
/106
neut
roph
il in
30m
inut
es:
C: 7
.3 (2
.1–1
1.5)
I: 16
.1 (4
.2–2
4.2)
Num
ber o
f pat
ient
s with
tran
sient
rise
in se
rum
alk
aline
phos
phat
ase:
C: 1
I: 7
p<
0.0
5
Num
ber o
f pat
ient
s with
tran
sient
bon
e pa
in n
ot re
quiri
ngan
alges
ia:C
: not
repo
rted
I: 3
Appendix 4
156
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Gra
yson
(199
4),44
USA
Stud
y de
sign:
RC
T (D
B)
Met
hod
ofra
ndom
isatio
n:C
ompu
ter-
gene
rate
dco
de
Uni
t of a
lloca
tion:
Patie
nts,
but m
ost
outc
omes
are
repo
rted
in te
rms o
f the
num
ber
of in
fect
ions
per
stud
yar
m
Calc
ulat
ion
of st
atist
ical
pow
er:
Assu
min
g re
crui
tmen
t of
40 p
atie
nts p
er st
udy
arm
, it w
as e
stim
ated
that
, with
an
expe
cted
clini
cal r
espo
nse
rate
of
80%
for I
/C, t
he p
ower
of th
e st
udy
to d
etec
tth
at A
/S w
as n
ot m
ore
than
20%
less
effe
ctive
than
I/C
wou
ld b
e 0.
7
Out
com
e as
sess
men
t:
Clin
ical a
ndm
icrob
iolo
gical
end-
poin
ts w
ere
asse
ssed
afte
r 5 d
ays o
f em
piric
altr
eatm
ent a
nd a
tco
mpl
etio
n of
i.v.
ther
apy
Blin
d cli
nica
l ass
essm
ent
of si
gns a
nd sy
mpt
oms
was
con
duct
ed b
y 2
phys
ician
s dail
y fo
r the
first
6da
ys, t
hen
atre
gular
inte
rvals
unt
il th
e
Popu
latio
n:D
iabet
ic pa
tient
sw
ith li
mb-
thre
aten
ing
infe
ctio
nof
the
feet
or l
egs
iden
tifie
d by
Vasc
ular
and
Podi
atry
Ser
vices
at
the
New
Eng
land
Dea
cone
ss H
ospi
tal,
Bost
on, M
A, U
SA
Inclu
sion
crite
ria:
Requ
irem
ent f
orho
spita
lisat
ion;
age
at le
ast 1
8ye
ars;
and
pres
ence
of
diab
etes
and
lim
b-th
reat
enin
g in
fect
ion
invo
lving
the
low
erex
trem
ity. L
imb-
thre
aten
ing
infe
ctio
nw
as d
efin
ed b
y at
leas
t the
pre
senc
eof
cel
lulit
is, w
ith o
rw
ithou
t ulce
ratio
nor
pur
ulen
tdi
scha
rge
Exclu
sion
crite
ria:
Know
nhy
pers
ensit
ivity
to�
-lact
am a
ntib
iotic
s;re
quire
men
t for
othe
r con
com
itant
antib
iotic
trea
tmen
t;se
rum
cre
atin
ine
leve
l of 3
.5m
g/dl
or
grea
ter;
preg
nanc
y;ex
pect
ed d
eath
with
in 4
8ho
urs;
Num
ber m
ale/fe
male
:I1
: 30/
17I2
: 37/
9
Mea
n ag
e (y
ear)
:I1
: 59
I2: 6
1
Mea
n du
ratio
n of
diab
etes
(yea
rs):
I1: 2
0I2
: 19
Num
ber (
%) o
f inf
ectio
ns w
ithin
sulin
-dep
ende
nt d
iabet
es:
I1: 3
8 (7
9)I2
: 38
(79)
Num
ber (
%) o
f inf
ectio
ns w
ithse
nsor
y ne
urop
athy
:I1
: 43
(90)
I2: 4
6 (9
6)
Num
ber (
%) o
f inf
ectio
ns w
ithim
paire
d re
nal f
unct
ion
(def
ined
as
crea
tinin
e le
vel >
1.3
mg/
dl):
I1:
9 (1
9)I2
: 14
(29)
Num
ber (
%) o
f inf
ectio
ns w
ithte
mpe
ratu
re o
f >37
.8°C
:I1
: 21
(44)
I2: 1
3 (2
7)
Num
ber (
%) o
f inf
ectio
ns w
ith u
lcer
pres
ent:
I1: 4
2 (9
2)I2
: 46
(96)
Num
ber (
%) o
f inf
ectio
ns w
ithce
llulit
is pr
esen
t:I1
: 48
(100
)I2
: 47
(98)
I1: A
/S re
gimen
. Usu
al do
se(w
hen
crea
tinin
e cle
aran
ce w
asat
leas
t 30
ml/m
inut
e) 2
gam
picil
lin/1
g su
lbac
tam
(tot
al3
g) i.
v. q.
d.s.
In c
ases
of
impa
ired
rena
l fun
ctio
n(c
reat
inin
e cle
aran
ce15
–29
ml/m
inut
e) to
tal d
ose
was
redu
ced
to 1
.5–3
g b.
d.W
hen
crea
tinin
e cle
aran
ce w
asle
ss th
an 1
5 m
l/min
ute,
the
patie
nt w
as e
xclu
ded
from
the
stud
y (n
= 4
7 pa
tient
s with
48
infe
ctio
ns)
I2: I
/C re
gimen
. Usu
al do
se(w
hen
crea
tinin
e cle
aran
cegr
eate
r tha
n 30
ml/m
inut
e)50
0m
g i.v
. q.d
.s. In
cas
es o
fim
paire
d re
nal f
unct
ion
(cre
atin
ine
clear
ance
21–3
0m
l/min
ute)
dos
e w
asre
duce
d to
500
mg
t.d.s.
Whe
ncr
eatin
ine
clear
ance
was
20m
l/min
ute
or le
ss, t
hepa
tient
was
exc
lude
d fro
m th
est
udy
(n=
46
patie
nts w
ith 4
8in
fect
ions
).
All p
atie
nts:
Stud
y m
edica
tion
was
com
men
ced
with
in 1
2ho
urs o
fba
selin
e w
ound
cul
ture
s. Th
efir
st 5
days
of t
reat
men
t wer
ede
fined
as a
per
iod
of e
mpi
rical
ther
apy
as c
ultu
res a
ndse
nsiti
vitie
s wer
e no
t ava
ilabl
ebe
fore
this
time
All p
atie
nts u
nder
wen
t bed
rest
, sur
gical
drain
age
and
debr
idem
ent o
f inf
ecte
d ul
cers
Stat
istica
l met
hods
:�
2te
st fo
r cat
egor
ical d
ata;
Stud
ent’s
t-te
st fo
r con
tinuo
usda
ta
Mea
n ±
SD/m
edian
(ran
ge)
num
ber o
f dos
es o
f ant
ibio
ticth
erap
y:I1
: 47
±26
/41
(10–
121)
I2: 5
5 ±
35/4
8 (1
3–17
8)p
= 0
.20
Mea
n ±
SD/m
edian
(ran
ge)
dura
tion
of a
ntib
iotic
ther
apy
inda
ys:
I1: 1
3 ±
6.5/
12 (4
–32)
I2: 1
5 ±
8.6/
13 (5
–45)
p=
0.2
5
Num
ber o
f inf
ectio
ns w
ithem
piric
al tr
eatm
ent c
ompl
eted
(20
dose
s):
I1: 4
5I2
: 45
Num
ber o
f inf
ectio
ns w
ithsig
nific
ant s
tudy
vio
latio
ns(m
issin
g m
edica
tion
dose
s):
I1: 3
I2: 6
p=
0.4
8
Num
ber o
f inf
ectio
ns re
quiri
ngdo
se re
duct
ion:
I1: 2
I2: 3
Num
ber o
f inf
ectio
ns w
here
non
-pr
otoc
ol i.
v. an
tibio
tics w
ere
given
due
to fa
ilure
of s
tudy
agen
t/oth
er re
ason
:I1
: 8/3
I2: 6
/3
All p
atie
nts w
ere
inclu
ded
in th
eev
aluat
ion
at th
een
d of
ther
apy
Num
ber (
%) o
fpa
tient
s los
t to
follo
w-u
p:I1
: 8/4
7 (1
7)I2
: 5/4
6 (1
1)
Trial
aut
hors
’co
mm
ent:
I/C h
asan
ant
imicr
obial
activ
ity a
gain
st a
broa
d sp
ectr
um o
for
gani
sms.
A/S
has
activ
ity si
mila
r to,
but l
ess b
road
than
, tha
t of I
/C
Trial
aut
hors
’co
mm
ent:
in tr
ials
of th
is ty
pe th
ere
are
majo
rdi
ffere
nces
betw
een
evalu
atio
ns in
term
s of t
he ro
leof
surg
ery
intr
eatin
gos
teom
yelit
is as
wel
l as t
hede
finiti
ons o
fsu
cces
s and
failu
re.
Thes
e di
ffere
nces
limit
the
relia
bilit
yof
com
paris
ons o
fou
tcom
e of
antib
iotic
ther
apy
for f
oot i
nfec
tion
in d
iabet
ic pa
tient
sst
udie
d in
var
ious
trial
s
Trial
aut
hors
’co
mm
ent:
the
resu
lts c
anno
t be
gene
ralis
ed to
diab
etic
patie
nts
with
a li
fe-
thre
aten
ing co
ntin
ued
Health Technology Assessment 2006; Vol. 10: No. 12
157
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
com
plet
ion
of th
erap
y.Th
e as
sess
men
t inc
lude
ddo
cum
enta
tion
of th
edi
amet
er a
nd d
epth
of
ulce
rs, a
nd th
e ex
tent
of
cellu
litis,
lym
phan
gitis,
tissu
e ne
cros
is an
dpu
rule
nt d
ischa
rge.
Dail
yin
sulin
dos
ages
and
surg
ical p
roce
dure
s wer
ere
cord
ed
Aero
bic
and
anae
robi
ccu
lture
s of t
he d
eep
wou
nd (f
ollo
win
g sh
arp
debr
idem
ent)
orde
brid
ed ti
ssue
wer
epe
rform
ed o
n da
ys 0
, 3,
5 an
d on
the
final
day
ofi.v
. ant
ibio
tic tr
eatm
ent.
Whe
n pr
esen
t, pu
s was
aspi
rate
d an
d su
bmitt
edfo
r cul
ture
in a
cap
ped
syrin
ge. A
ll id
entif
ied
path
ogen
s wer
e te
sted
for s
usce
ptib
ility
to th
est
udy
drug
s
The
diag
nosis
of
oste
omye
litis
was
mad
eus
ing
hist
opat
holo
gy,
radi
olog
y an
d cli
nica
lsig
ns
Clin
ical e
nd-p
oint
s wer
e:cu
re (r
esol
utio
n of
soft
tissu
e in
fect
ion)
;im
prov
emen
t (all
eviat
ion
of a
t lea
st 2
pre
sent
ing
signs
or s
ympt
oms o
fin
fect
ion)
; fail
ure
(inad
equa
te
seve
re u
nder
lying
dise
ase
that
migh
tin
terfe
re w
ithev
aluat
ion
of th
eth
erap
eutic
resp
onse
; im
mun
ede
pres
sion
due
toun
derly
ing
dise
ase;
prio
r org
antr
ansp
lanta
tion
orim
mun
osup
pres
sive
drug
ther
apy;
curr
ent i
nvol
vem
ent
in a
clin
ical s
tudy
of
an in
vest
igatio
nal
drug
; rec
ent
trea
tmen
t fail
ure
usin
g an
tibio
tics
with
sim
ilar
antim
icrob
ialsp
ectr
um to
the
stud
y ag
ents
Cre
atin
ine
clear
ance
less
than
15
ml/m
in
Num
ber (
%) o
f inf
ectio
ns w
ithlym
phan
gitis
pres
ent:
I1: 1
4 (2
9)I2
: 19
(40)
Num
ber (
%) o
f inf
ectio
ns w
ithpu
rule
nt d
ischa
rge
pres
ent:
I1: 3
7 (7
7)I2
: 37
(77)
Num
ber (
%) o
f inf
ectio
ns o
nfo
refo
ot:
I1: 4
4 (9
2)I2
: 43
(90)
Num
ber (
%) o
f inf
ectio
ns o
nm
idfo
ot:
I1: 3
(6)
I2: 3
(6)
Num
ber (
%) o
f inf
ectio
ns o
nhi
ndfo
ot:
I1: 1
(2)
I2: 2
(4)
Num
ber (
%) o
f inf
ectio
ns w
ithle
ucoc
ytos
is (>
10,0
00le
ucoc
ytes
/mm
3 ):I1
: 24/
48 (5
0)I2
: 27/
48 (5
6)
Num
ber (
%) o
f inf
ectio
ns w
ithpo
sitive
blo
od c
ultu
re:
I1: 2
/48
(4)
I2: 1
/45
(2)
Num
ber (
%) o
f inf
ectio
ns w
ithos
teom
yelit
is pr
esen
t on
plain
radi
ogra
ph:
I1: 1
3/44
(30)
I2: 1
1/44
(25)
and
necr
otic
tissu
e, v
igoro
usco
ntro
l of d
iabet
es m
ellit
us,
and
use
of st
erile
wou
nddr
essin
gs (g
auze
soak
ed in
norm
al sa
line
or o
ne-q
uart
erst
reng
th p
ovid
one
iodi
ne).
Whe
n ap
prop
riate
, art
erial
circu
latio
n of
the
low
er li
mb
was
eva
luat
ed b
y no
n-in
vasiv
ean
d ar
terio
grap
hic
tech
niqu
es,
and
surg
ery
was
per
form
ed a
sre
quire
d
Antib
iotic
ther
apy
was
revis
edin
cas
es w
here
the
clini
cal
resp
onse
was
uns
atisf
acto
ry(b
lindi
ng w
as m
ainta
ined
).Re
visio
n co
uld
inclu
de u
se o
fre
plac
emen
t or a
dditi
onal
agen
ts. F
ollo
win
g co
mpl
etio
nof
stud
y th
erap
y, pa
tient
sre
ceive
d a
shor
t cou
rse
of o
ral
antib
iotic
s if n
eces
sary
Trea
tmen
t was
with
draw
n if
anur
ticar
ial o
r mor
billif
orm
rash
deve
lope
d
Num
ber (
%) o
f inf
ectio
ns w
houn
derw
ent s
urgic
al de
brid
emen
ton
ly:I1
: 9 (1
9)I2
: 15
(31)
p=
0.2
4
Num
ber (
%) o
f inf
ectio
ns w
houn
derw
ent a
mpu
tatio
n:I1
: 33
(69)
I2: 2
8 (5
8)p
= 0
.25
Num
ber (
%) o
f am
puta
tions
invo
lving
exc
ision
of d
igits
and
dist
al m
etat
arsa
l bon
es:
I1: 3
0/33
(91)
I2: 2
7/28
(96)
p=
0.7
3
Num
ber (
%) o
f inf
ectio
ns w
houn
derw
ent v
ascu
larre
cons
truc
tion:
I1: 7
(15)
I2: 1
5 (3
1)p
= 0
.09
Num
ber w
ith c
linica
l out
com
e at
day
5/en
d of
ther
apy:
Cur
e:I1
: 28/
48 (5
8%)/3
9/48
(81%
)I2
: 29/
48 (6
0%)/4
1/48
(85%
)p
= 0
.78
Impr
ovem
ent:
I1: 1
7/48
(35%
)/0I2
: 18/
48 (3
8%)/0
Failu
re:
I1: 3
/48
(6%
)/8/4
8 (1
7%)
I2: 1
/48
(2%
)/6/4
8 (1
3%)
Inde
term
inat
e:I1
: 0/1
/48
(2%
)I2
: 0/1
/48
(2%
)
infe
ctio
n as
such
patie
nts w
ere
exclu
ded
Stud
y sp
onso
rshi
p:G
rant
supp
ort
prov
ided
by
Pfize
rPh
arm
aceu
ticals
,Ro
erig
Divi
sion,
New
Yor
k, U
SA
cont
inue
d
Appendix 4
158
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
impr
ovem
ent,
nece
ssita
ting
a ch
ange
inan
tibio
tic th
erap
y); a
ndin
dete
rmin
ate
(clin
ical
asse
ssm
ent n
ot p
ossib
ledu
e to
am
puta
tion)
Micr
obio
logic
al en
d-po
ints
wer
e: e
radi
catio
n(c
lear
ance
of p
rincip
alpa
thog
ens f
rom
the
wou
nd; p
artia
l era
dica
tion
(cle
aran
ce o
f som
e bu
tno
t all
path
ogen
s);
pers
isten
ce (p
ersis
tenc
eof
prin
cipal
path
ogen
s);
and
supe
rinfe
ctio
n(e
limin
atio
n of
prin
ciple
path
ogen
s but
em
erge
nce
of a
new
pat
hoge
n du
ring
trea
tmen
t)
Adve
rse
even
ts w
ere
grad
ed a
s: sig
nific
ant
(sev
ere
reac
tion
nece
ssita
ting
with
draw
alof
stud
y ag
ent o
r spe
cific
trea
tmen
t);m
oder
ate/
poss
ible
(are
actio
n th
at d
id n
otne
cess
itate
with
draw
al of
stud
y ag
ent o
r spe
cific
trea
tmen
t); a
ndm
ild/u
nlik
ely
(an
even
tun
cert
ainly
asso
ciate
dw
ith th
e st
udy
drug
)
Setti
ng a
nd le
ngth
of
trea
tmen
t:H
ospi
tal,
single
-cen
tre.
Aver
age
trea
tmen
tdu
ratio
n 14
days
.
Num
ber (
%) o
f inf
ectio
ns w
ithos
teom
yelit
is pr
esen
t on
tech
netiu
mbo
ne sc
an:
I1: 0
/2I2
: 1/1
(100
)
Num
ber (
%) o
f inf
ectio
ns w
ithos
teom
yelit
is pr
esen
t on
hist
olog
ical
asse
ssm
ent o
f bon
e:I1
: 28/
31 (9
0)I2
: 25/
32 (7
8)
Num
ber (
%) o
f inf
ectio
ns w
ithpo
sitive
bon
e cu
lture
:I1
: 11/
12 (9
7)I2
: 7/8
(88)
Num
ber (
%) o
f inf
ectio
ns w
ithpr
esen
ce o
f ost
eom
yelit
is co
nfirm
edby
bon
e hi
stol
ogy,
bone
cul
ture
or
clini
cal p
rese
nce
of p
urul
ent,
non-
viabl
e bo
ne:
I1: 3
2/47
(68)
I2: 2
7/48
(56)
Num
ber (
%) o
f inf
ectio
ns w
ithpe
riphe
ral v
ascu
lar d
iseas
e (d
efin
edby
dim
inish
ed o
r abs
ent p
ulse
s):
I1: 3
9 (8
1)I2
: 38
(79)
Num
ber o
f bac
teria
l iso
lates
per
grou
p (I1
/I2):
Gra
m-p
ositi
ve a
erob
es:
Stap
hylo
cocc
us a
ureu
s29/
25C
oagu
lase-
nega
tive
stap
hylo
cocc
i4/
8St
rept
ococ
ci9/
26En
tero
cocc
i15/
13O
ther
2/1
Gra
m-n
egat
ive a
erob
es:
Pseu
dom
onas
aer
ugin
osa
4/3
Num
ber w
ith m
icrob
iolo
gical
outc
ome
at d
ay 5
/end
of t
hera
py:
Erad
icatio
n:I1
: 17/
48 (3
5%)/3
2/48
(67%
)I2
: 20/
48 (4
2%)/3
6/48
(75%
)p
= 0
.5Pa
rtial
era
dica
tion:
I1: 1
8/48
(38%
)/8/4
8 (1
7%)
I2: 1
5/48
(31%
)/5/4
8 (1
0%)
Pers
isten
ce:
I1: 7
/48
(15%
)/2/4
8 (4
%)
I2: 6
/48
(13%
)/3/4
8 (6
%)
Supe
rinfe
ctio
n:I1
: 0 /
2/48
(4%
)I2
: 0 /
3/48
(6%
)In
dete
rmin
ate:
I1: 6
/48
(13%
)/4/4
8 (8
%)
I2: 7
/48
(15%
)/1/4
8 (2
%)
Num
ber (
%) o
f fail
ures
of
ther
apy
per n
umbe
r of i
nfec
tions
in p
atie
nts w
ith o
steo
mye
litis:
I1: 6
/32
(19%
)I2
: 5/2
7 (1
9%)
Num
ber o
f fail
ures
of t
hera
pype
r num
ber o
f epi
sode
sas
socia
ted
with
resis
tant
path
ogen
s:I1
: 7/1
6 (4
4%)
I2: 4
/5 (8
0%)
Num
ber o
f pat
ient
s ass
essa
ble
atfo
llow
-up:
I1: 3
9I2
: 41
Mea
n ±
SD/m
edian
(ran
ge)
dura
tion
of fo
llow
-up
(wee
ks):
I1: 4
9 ±
36 /
36 (0
-113
)I2
: 53
±35
/ 57
(1-1
08)
p=
0.6
for m
eans
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
159
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Aver
age
dura
tion
offo
llow
-up
1ye
arN
on-a
erug
inos
a Ps
eudo
mon
assp
ecie
s1/
0Xa
ntho
mon
as m
alto
philia
1/1
Ente
roba
cter
spec
ies 3
/6Ac
inet
obac
ters
pecie
s 3 /
4M
orga
nella
spec
ies 2
/1Se
rratia
spec
ies 3
/2Kl
ebsie
llasp
ecie
s 3/2
Prot
euss
pecie
s 6/1
Esch
erich
ia c
oli4
/2O
ther
3/6
Anae
robe
s:Ba
cter
oide
s fra
gilis
3/3
Non
-frag
ilis b
acte
roid
essp
ecie
s 9/1
5Pe
ptoc
occu
sspe
cies 3
/9O
ther
8/6
Cand
ida
spec
ies:
1/2
Num
ber (
%) o
f ide
ntifi
ed p
atho
gens
and
thei
r res
istan
ce to
stud
y ag
ents
:To
tal i
solat
es:
I1: 4
5/48
(94)
I2: 4
7/48
(98)
Mul
tiple
pat
hoge
ns:
I1: 3
7/45
(82)
I2: 4
0/47
(85)
Gra
m-p
ositi
ve a
erob
es a
lone
:I1
: 21/
45 (4
7)I2
: 14/
47 (3
0)G
ram
-neg
ative
aer
obes
alo
ne:
I1: 0
/45
I2: 0
/47
Mix
ed G
ram
-pos
itive
and
Gra
m-
nega
tive
aero
bes a
lone
:I1
: 7/4
5 (9
)I2
: 11/
47 (2
3)M
ixed
aer
obes
and
ana
erob
es:
I1: 1
6/45
(36)
I2: 2
1/47
(45)
Anae
robe
s alo
ne:
I1: 1
/45
(2)
Num
ber w
ith c
linica
l out
com
e at
follo
w-u
p (b
ased
on
39as
sess
able
pat
ient
s in
I1 a
nd 4
1as
sess
able
pat
ient
s in
I2):
Cur
e:I1
: 27/
39 (6
9%)
I2: 3
3/41
(80%
)In
dete
rmin
ate:
I1: 3
/39
(8%
)I2
: 0/4
1Fa
ilure
:I1
: 9/3
9 (2
3%)
I2: 8
/41
(20%
)Re
lapse
:I1
: 6I2
: 9
Num
ber (
%) o
f adv
erse
eve
nts
(den
omin
ator
is n
umbe
r of
infe
ctio
ns):
Sign
ifica
nt:
I1: 7
/48
(15%
)I2
: 9/4
8 (1
9%)
Mod
erat
e/po
ssib
le:
I1: 8
/48
(17%
)I2
: 6/4
8 (1
3%)
Mild
/unl
ikel
y:I1
: 1/4
8 (2
%)
I2: 2
/48
(4%
)To
tal:
I1: 1
6/48
(33%
)I2
: 17/
48 (3
5%)
cont
inue
d
Appendix 4
160
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
I2: 1
/47
(2)
Num
ber o
f iso
latio
ns o
f res
istan
tpa
thog
ens i
n I1
/I2:
A/S-
resis
tant
aer
obes
12/
10O
ther
aer
obes
with
pro
babl
ere
sista
nce
4/5
A/S-
resis
tant
ana
erob
es 0
/0A/
S-su
scep
tibilit
y un
know
n 0/
3I/C
-res
istan
t aer
obes
2/4
I/C-r
esist
ant a
naer
obes
0/0
I/C-s
usce
ptib
ility
unkn
own
3/2
Num
ber o
f pat
ient
s with
pat
hoge
nspo
tent
ially
resis
tant
to th
e as
signe
dst
udy
drug
:I1
: 16
I2: 4
Base
line
ulce
r cha
ract
erist
ics su
ch a
sar
ea o
r dur
atio
n w
ere
not r
epor
ted
Health Technology Assessment 2006; Vol. 10: No. 12
161
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Kast
enba
uer (
2003
),118
Aust
ria
Stud
y de
sign:
RC
T(s
ingle
-blin
d: p
atie
ntbl
inde
d)
Met
hod
ofra
ndom
isatio
n:
Not
stat
ed
Uni
t of a
lloca
tion:
Pa
tient
Out
com
e as
sess
men
t:Re
solu
tion
of c
ellu
litis,
spec
ified
clin
ically
and
by a
n in
fect
ion
sum
mar
y sc
ore
(ISS)
.I1
: G-C
SF (F
ilgra
stim
)vs
I2: p
laceb
o
Setti
ng: I
npat
ient
s
Leng
th o
f tre
atm
ent:
10da
ys
Popu
latio
n:
Diab
etic
patie
nts w
ithin
fect
ed fo
otul
cers
Inclu
sion
crite
ria:
Diab
etic
patie
nts w
ithm
oder
ate-
sized
(diam
eter
0.5–
3cm
)in
fect
edne
urop
athi
c(a
bnor
mal
10g
mon
ofila
men
tte
st) f
oot u
lcer
of W
agne
r’sgr
ade
2 or
3
Exclu
sion
crite
ria:
pres
ence
of
gang
rene
,ha
emat
olog
ical
dise
ases
,pa
ncyt
open
ia,ne
oplas
ia,im
paire
dki
dney
/live
rfu
nctio
n, re
cent
trea
tmen
t with
cyto
kine
s or
imm
unoa
ctive
drug
s
n=
37
I1I2
(n=
20)
(n=
17)
Male
(%)
n=
15
(75)
n=
12
(77)
Type
II D
iabet
esn
= 1
9 (9
5)n
= 8
(94)
(%)
Age
(yea
rs)
60.8
±11
.158
.2 ±
8.1
Diab
etes
Dur
atio
n (y
ears
)14
.7 ±
8.5
15.5
±10
.6H
bA1 C
(%)
8.9
±1.
79.
2 ±
2.6
I1: (
n=
20)
pat
ient
sre
ceive
d an
initi
al do
se o
f5
�g/
kg b
ody
wei
ght G
-C
SF (F
ilgra
stim
: Am
gen,
Vien
na, A
ustr
ia) in
ject
edsu
bcut
aneo
usly
I2: (
n=
17)
pat
ient
sre
ceive
d 5
�g/
kg b
ody
wei
ght p
laceb
o (0
.9%
ster
ile sa
line
solu
tion)
inje
cted
s.c.
All p
atie
nts h
ad to
main
tain
stric
t bed
rest
and
rece
ived
the
sam
e st
anda
rd o
fw
ound
car
e, in
cludi
ngde
brid
emen
t. Al
l pat
ient
str
eate
d w
ith i.
v. an
tibio
tics
(clin
dam
ycin
and
cipro
floxa
cin) u
ntil
infla
mm
atio
n vis
ibly
impr
oved
. Ora
l ant
ibio
tics
adm
inist
ered
ther
eafte
r if
nece
ssar
y
Abso
lute
neu
trop
hil a
ndle
ukoc
yte
coun
ts m
easu
red
daily
. Tre
atm
ent w
asom
itted
if th
e ab
solu
tene
utro
phil
coun
t was
grea
ter t
han
50,0
00/l
and
the
abso
lute
leuk
ocyt
eco
unt g
reat
er th
an75
,000
/l, a
nd w
as re
-in
stall
ed w
hen
neut
roph
ilsdr
oppe
d be
low
30,
000
and
the
leuk
ocyt
e co
unt b
elow
50,0
00.
Clin
ical f
oot i
nspe
ctio
n:ce
llulit
is (e
ryth
ema,
Stat
istica
l met
hods
: mea
ns ±
SD;
Shap
iro–W
ilk W
-test
. Man
n–W
hitn
eyU-
test
, sign
test
, �2
test
s. Ka
plan
-M
eier
ana
lysis
(log-
rank
test
). Pr
imar
yen
d-po
int (
by IS
S) a
nalys
ed b
y IT
Tan
d pe
r pro
toco
l I1I2
Leuk
ocyt
e co
unt (
× 109 /1
):D
ay 1
8.1
±2.
67.
7 ±
1.9
Day
10
40.8
±16
.39.
3 ±
8.3
CRP
(mg/
dl):
Day
11.
73 ±
2.2
1.71
±2.
31
Day
s 2–1
0 (m
ean)
2.14
±2.
271.
04 ±
0.63
Wag
ner g
rade
1/2
/3 (%
):D
ay 1
0/75
/25
0/82
/18
Day
10
13/8
7/0
7/93
/0
Ulce
r vol
ume
(µl):
Day
120
3 ±
203
358
±39
5D
ay 1
083
±14
023
3 ±
235
Prop
ortio
n of
pat
ient
s ach
ievin
gco
mpl
ete
heali
ng (d
ay 1
0):
I1: 0
/20
(0%
)I2
: 2/1
7 (1
1%)
Prop
ortio
n of
pat
ient
s with
unre
solve
d ce
llulit
is (d
ay 1
0):
I1: 2
7%I2
: 17%
(from
surv
ival c
urve
pro
vided
by
the
auth
or)
Mea
n re
duct
ion
afte
r RX
:
Abso
lute
: I1
: 120
µl
I2: 1
25 �
l
Num
bers
of
with
draw
als p
ertr
eatm
ent g
roup
:
I1: 2
(see
adv
erse
even
ts)
I2: 1
(ost
eom
yelit
is)
Stud
y sp
onso
rshi
p:Am
gen,
Aus
tria
(man
ufac
ture
rs o
fFi
lgras
tim)
The
auth
ors
desc
ribe
prim
ary
end-
poin
t as I
SSbu
t thi
s has
not
been
vali
date
d as
am
easu
re o
fin
fect
ion.
Hea
ling
data
wer
e als
oco
llect
ed a
nd th
isis
a cli
nica
llyim
port
ant
outc
ome
cont
inue
d
Appendix 4
162
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
oede
ma,
pus
form
atio
n an
dlym
phan
gitis)
, ISS
, ulce
rvo
lum
e, a
nd W
agne
r’sgr
ade
carr
ied
out d
aily
Pres
ence
of e
ryth
ema
(10
poin
ts fo
r pre
senc
e in
each
sect
ion,
loca
l, do
rsal,
low
er le
g)Ly
mph
angit
is (2
0 po
ints
)D
iffer
ence
incir
cum
fere
nce:
fore
foot
/ank
le/lo
wer
leg
Relat
ive (t
his i
s bias
ed b
y th
em
ismat
ch in
ulce
r vol
ume
at th
e st
art
of th
e tr
ial):
I1: 1
20/2
03 (5
9%)
I2: 1
25/3
58 (3
5%)
Adve
rse
even
ts: w
orse
ned
liver
func
tion,
skin
effl
ores
cenc
e (li
kely
tobe
attr
ibut
ed to
G-C
SF) i
n 2
(I1)
patie
nts
CRP
, C-r
eact
ive
prot
ein;
ESR
, ery
thro
cyte
sed
imen
tatio
n ra
te; I
SS, i
nfec
tion
sum
mar
y sc
ore.
Health Technology Assessment 2006; Vol. 10: No. 12
163
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Lips
ky (2
004)
,109
USA
(stu
dy p
opul
atio
nta
ken
from
8co
untr
ies:
Belgi
um,
Ger
man
y, Ita
ly,Po
rtug
al, S
witz
erlan
d,Sp
ain, U
K, U
SA)
Stud
y de
sign:
RC
T (o
pen-
label
,m
ultic
entr
e –
45 si
tes)
Met
hod
ofra
ndom
isatio
n:
Not
stat
ed
Uni
t of a
lloca
tion:
Pa
tient
Out
com
e as
sess
men
t:C
linica
l cur
e ra
tear
ising
from
the
adm
inist
ratio
n of
Line
zolid
(I1)
vs A
/Cor
A/C
(I2)
. Out
com
ecla
ssifi
ed a
s (1)
cur
ed,
(2) i
mpr
oved
or (
3)fa
iled
Test
of c
ure
evalu
atio
nco
nduc
ted
15–2
1 da
ysaf
ter t
reat
men
t was
com
plet
ed
Setti
ng:
Inpa
tient
/out
patie
nt
Leng
th o
f tre
atm
ent:
Betw
een
7–28
day
s
Inclu
sion
crite
ria:
Con
sent
ing
men
and
wom
en a
ged
18ye
ars o
r ove
r;w
ith d
iabet
esm
ellit
us a
nd a
foot
infe
ctio
n. In
fect
ions
defin
ed b
y cli
nica
lsig
ns a
nd sy
mpt
oms
(dra
inag
e, e
ryth
ema,
fluct
uanc
e, w
arm
th,
pain
, ten
dern
ess,
indu
ratio
n) a
ndca
tego
rised
as o
neor
mor
e of
the
follo
win
g: c
ellu
litis,
paro
nych
ia, in
fect
edul
cer,
deep
soft
tissu
e in
fect
ion,
sept
ic ar
thrit
is,ab
sces
s,os
teom
yelit
is.Pa
tient
s cou
ldun
derg
o an
yne
cess
ary
debr
idem
ent o
rot
her s
urgic
alpr
oced
ures
as l
ong
as th
e en
tire
infe
cted
are
a w
asno
t res
ecte
d or
ampu
tate
d
Exclu
sion
crite
ria:
Crit
ical i
scha
emia
ofth
e af
fect
ed li
mb
(def
ined
as a
bsen
ceof
ped
al pu
lses,
abse
nt o
r abn
orm
alD
oppl
er w
avef
orm
s,
371
patie
nts e
nrol
led:
10
rece
ived
notr
eatm
ent
I1: n
= 2
41I2
: n=
120
Gen
der:
I1I2
Male
:17
1 (7
1%)
86 (7
2%)
Fem
ale:
70 (2
9%)
34 (2
8%)
Ethn
icity
: W
hite
206
(85%
)10
0 (8
3%)
Blac
k27
(11%
)16
(13%
)O
ther
8 (3
%)
4 (3
%)
Mea
n ±
SD63
±12
62 ±
13ag
e (y
ears
)
Type
II d
iabet
es (%
)61
52
Type
of i
nfec
tion:
Infe
cted
ulce
r19
0 (7
9%)
93 (7
8%)
Cel
lulit
is10
1 (4
2%)
60 (5
0%)
Dee
p so
ft tis
sue
37 (1
5%)
16 (1
3%)
tissu
ePa
rony
chia
12 (5
%)
11 (9
%)
Ost
eom
yelit
is57
(24%
)20
(17%
)O
ther
8 (3
%)
5 (4
%)
Foot
isch
aem
ia:n
= 9
8 (4
9%)
Wou
nd a
rea:
“mos
t wer
e ≤2
cm2
in a
rea”
Wou
nd d
epth
:“m
ost w
ere
≤9 m
m d
eep”
Wou
nd d
urat
ion:
“mos
t wer
e <
8 w
eeks
dur
atio
n”
No
data
by
grou
p to
allo
w c
ompa
rison
I1: n
= 2
41 p
atie
nts
rece
ived
linez
olid
(600
mg
ever
y 12
hour
sei
ther
i.v.
or o
rally
)
I2: n
= 1
20 p
atie
nts
rece
ived
A/S
(1.5
–3g
ever
y 6
hour
s i.v.
) or
A/C
(500
–875
mg
ever
y8–
12 h
ours
ora
lly)
Ther
apy
given
on
inpa
tient
or o
utpa
tient
basis
, ini
tiate
d by
eith
eri.v
. or o
ral r
oute
and
coul
d sw
itch
from
i.v.
toor
al at
the
inve
stiga
tor’s
disc
retio
n. T
reat
men
t for
at le
ast 7
but f
or n
om
ore
than
28
days
Vanc
omyc
in (1
g ev
ery
12ho
urs i
.v., a
djus
ted
for
rena
l dys
func
tion,
adva
nced
age
or o
besit
y)ad
ded
to th
eam
inop
enici
llin/�
-lac
tam
ase
inhi
bito
rre
gimen
if in
fect
ion
with
MRS
A su
spec
ted
orco
nfirm
ed.
Inve
stiga
tor c
ould
choo
se to
give
aztr
eona
m (1
–2g
i.v.
ever
y 8–
12ho
urs)
for
patie
nts s
uspe
cted
or
docu
men
ted
to h
ave
Gra
m-n
egat
ivepa
thog
ens r
esist
ant t
ost
udy
med
icatio
n
Stat
istica
l met
hods
: In
tent
ion-
to-tr
eat;
one-
way
AN
OVA
;W
ilcox
on ra
nk su
m te
st; �
2 ; Fi
sher
’s ex
act t
est;
CIs;
frequ
encie
s/per
cent
ages
Def
initi
ons o
f clin
ical r
espo
nse
totr
eatm
ent:
Cur
ed: r
esol
utio
n of
all
clini
cal s
igns
and
sym
ptom
s of i
nfec
tion
and
ahe
aling
wou
nd a
fter ≥
5da
ys o
fth
erap
y. Im
prov
ed: r
esol
utio
n of
at
leas
t tw
o, b
ut n
ot a
ll, c
linica
l sign
s or
sym
ptom
s of i
nfec
tion
afte
r ≥5
days
of th
erap
y (o
nly
used
at e
nd o
ftr
eatm
ent).
Fail
ed: p
ersis
tenc
e or
prog
ress
ion
of b
asel
ine
clini
cal s
igns
and
sym
ptom
s of i
nfec
tion
afte
r≥2
days
of t
hera
py. M
issin
g: p
atie
nts
rece
ived
<2
days
of t
hera
pyIn
dete
rmin
ate:
circ
umst
ance
spr
eclu
ded
class
ifica
tion
Clin
ically
eva
luab
le p
atie
nts (
met
entr
y cr
iteria
, too
k 80
% o
fpr
escr
ibed
med
icatio
n, h
ad a
dequ
ate
follo
w-u
p):
I1: 2
03/2
41 (8
4%)
I2: 1
03/1
20 (8
6%)
Ove
rall
clini
cal c
ure:
I1: 1
65/2
03 (8
1%)
I2: 7
7/10
8 (7
1%)
I1: 1
8I2
: 4D
iscon
tinua
tion
due
to a
dver
seev
ent
Stud
y sp
onso
rshi
p:Ph
aram
acia
Cor
pora
tion;
Dep
artm
ent o
fVe
tera
ns A
ffairs
.
They
des
crib
e th
eIT
T po
pulat
ion
asall
peo
ple
who
had
rece
ived
at le
ast
one
dose
of s
tudy
med
icatio
n. It
shou
ld in
clude
all
who
wer
era
ndom
ised,
rega
rdle
ss o
fw
heth
er th
eyre
ceive
d th
e st
udy
med
icatio
ns
Issue
s wor
thy
ofno
te re
gard
ing
bioa
vaila
bilit
y of
A/B
(i.v./
oral)
and
the
pote
ntial
for
early
out
patie
nttr
eatm
ent i
f apo
tent
, ora
l age
ntis
avail
able
, e.g
.flu
oroq
uino
lone
s/lin
ezol
id
cont
inue
d
Appendix 4
164
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
toe
bloo
d pr
essu
re<
45m
mH
g), u
nles
sap
prov
ed b
y a
vasc
ular
surg
eon.
Aw
ound
with
pros
thet
ic m
ater
ials
or d
evice
s; an
infe
ctio
n re
quiri
ngm
ore
than
28
days
of a
ntib
iotic
trea
tmen
t; a
wou
ndw
ith e
xten
sive
gang
rene
. Pat
ient
sals
o ex
clude
d if
they
had
rece
ived
>72
hour
s of
pote
ntial
ly ef
fect
ivean
tibio
tic th
erap
y in
wee
k pr
ior t
oen
rolm
ent;
need
edad
ditio
nal n
on-s
tudy
antib
iotic
; abs
olut
ene
utro
phil
coun
t<
500
cells
/mm
3 ;pr
egna
ncy
orlac
tatin
g; h
istor
y of
hype
rsen
sitivi
ty to
linez
olid
, pen
icillin
or v
anco
myc
in
Use
of t
opica
lan
timicr
obial
age
nts n
otpe
rmitt
ed
Patie
nts r
ecei
ved
twice
-da
ily d
ress
ing
chan
ges
(any
ster
ile n
on-a
dher
ent
type
sele
cted
by
the
inve
stiga
tor)
and
per
iodi
cde
brid
emen
t as r
equi
red.
Pres
sure
on
the
wou
ndav
oide
d by
a m
etho
dse
lect
ed b
y th
ein
vest
igato
r
Resu
lts fo
r inf
ecte
d ul
cers
:(c
linica
l cur
e)I1
: 131
/190
(69%
)I2
: 57/
93 (6
1%)
Mea
n du
ratio
n of
ther
apy
(day
s ±SD
)I1
: 17.
2 ±
7.9
I2: 1
6.5
±7.
9
Clin
ical c
ure
rate
s for
mos
t fre
quen
tlyiso
lated
bas
elin
e pa
thog
ens (
base
d on
am
odifi
ed in
tent
ion-
to-tr
eat p
opul
atio
n, i.
e.th
ose
patie
nts w
ith a
Gra
m-p
ositi
veba
selin
e pa
thog
en):
I1 (%
)I2
(%)
Stap
hylo
cocc
us a
ureu
s:M
ethi
cillin
sens
itive
50/6
7 (7
5)28
/39
(72)
Met
hicil
lin re
sista
nt13
/18
(72)
4/7
(57)
Coa
gulas
e-ne
gativ
eSt
aphy
loco
cci:
31/3
5 (8
9)17
/19
(90)
Stre
ptoc
occu
sag
alac
tiae
26/3
1 (8
4)9/
18 (5
0)En
tero
cocc
ussp
p.23
/34
(68)
13/1
7 (7
6)Ps
eudo
mon
assp
p.13
/16
(81)
7/11
(64)
Ente
roba
cter
iacea
52/6
5 (8
0)16
/23
(70)
Adve
rse
even
ts n
(%):
I1I2
Any
even
ta64
(26.
6)12
(10)
Diar
rhoe
a18
(7.5
)4
(3.3
)N
ause
a14
(5.8
)0
(0)
Anae
mia
11 (4
.6)
0 (0
)Th
rom
bocy
tope
nia
9 (3
.7)
0 (0
)Vo
miti
ng4
(1.7
)1
(0.8
)D
ecre
ased
app
etite
3 (1
.2)
0 (0
)D
yspe
psia
3 (1
.2)
1 (0
.8)
a (Sta
tistic
ally
signi
fican
t mor
e ev
ents
with
I1).
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
165
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Disc
ontin
uatio
n du
e to
adv
erse
eve
nt:
I1: 1
8I2
: 4
Use
of v
anco
myc
in:
I1: 1
I2
: 5
Use
of a
ztre
onam
:I1
: 12
I2: 3
Appendix 4
166
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Lips
ky (u
npub
lishe
d)B,
114
USA
Stud
y 30
4Fu
ll pa
pers
not
ava
ilabl
e.D
ata
extr
acte
d fro
mab
stra
ct p
rese
nted
at
37th
ICAA
C
(Sep
t. 28
–Oct
. 1 1
997)
and
CD
-Rom
slid
espr
esen
ted
at th
e FD
AAd
visor
y C
omm
ittee
(Mar
ch 1
999)
Stud
y de
sign:
RC
T(d
oubl
e-bl
ind)
I1: P
exiga
nan
I2: O
floxa
cin
Met
hod
ofra
ndom
isatio
n:
Not
stat
ed
Uni
t of a
lloca
tion:
Pa
tient
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
stat
ed
Out
com
e as
sess
men
t:Pr
imar
y: (1
) clin
ical
outc
ome
(cur
ed: n
ofu
rthe
r sign
s or
sym
ptom
s of i
nfec
tion;
impr
oved
: sign
ifica
ntim
prov
emen
t but
inco
mpl
etel
y re
solve
d;fa
iled:
no
appa
rent
resp
onse
to th
erap
y);
(2) m
icrob
iolo
gical
outc
ome,
(3) t
hera
peut
icre
spon
se
Popu
latio
n:
39 c
entr
es, 3
42 (I
117
1; I2
171
) DFU
outp
atie
nts
Inclu
sion
crite
ria:
Clin
ical d
iagno
sisof
DFU
with
out
exte
nsive
cel
lulit
is,os
teom
yelit
is,ex
posu
re o
f bon
eor
tend
on o
r fev
er
Exclu
sion
crite
ria:
Ost
eom
yelit
is,ex
tens
ive c
ellu
litis,
gang
rene
, sys
tem
icto
xicit
y, in
patie
nttr
eatm
ent
Gen
der:
(M/F
)I1
: 118
/53
(69/
31%
)I2
: 109
/62
(64/
36%
)
Ethn
icity
:W
hite
I1: 1
42 (8
3%)
I2: 1
38 (8
1%)
Afric
an/A
mer
ican
I1:
20 (1
2%)
I2:
24 (1
4%)
Oth
erI1
: 9
(5%
)I2
: 9
(5%
)
Mea
n ±
SDag
e (y
ears
):I1
: 60.
8 (1
1.8)
I2: 5
9.5
(12.
4)
Trea
ted
with
ora
l ant
idiab
etic
med
icatio
n/in
sulin
dep
ende
nt:
I1:
Any
med
icatio
n:17
0 (9
9%)
Insu
lin:
118
(69%
)O
ral a
gent
s:56
(33%
)I2
:An
y m
edica
tion:
169
(99%
)In
sulin
:11
2 (6
5%)
Ora
l age
nts:
66 (3
9%)
Body
wei
ght m
ean
±SD
(lb)
:
I1: 2
07.1
(46.
0)I2
: 209
.2 (4
7.0)
Evid
ence
of n
euro
path
y an
d ty
pe:
Non
-palp
able
pul
ses i
n af
fect
ed fo
ot:
I1I2
Dor
sal p
edis:
22 (1
3%)
17 (1
0%)
Post
erial
tibi
al:
29 (1
7%)
22 (1
3%)
Dop
pler
pul
ses:
1 (<
1%)
2 (<
1%)
<40
mm
Hg
Neu
ropa
thy:
I1I2
Righ
t:13
7 (8
0%)1
42 (8
3%)
Left:
40 (8
2%)
138
(81%
)
I1: 1
71 p
atie
nts
rece
ived
twice
a d
ayap
plica
tion
of p
exiga
nan
crea
m (1
%) –
a b
road
-sp
ectr
um to
pica
lan
timicr
obial
age
nt
I2: 1
71 p
atie
nts
rece
ived
twice
dail
ydo
se o
f oflo
xacin
(400
mg
b.d.
)
Deb
ridem
ent a
nd o
ff-lo
adin
g of
ulce
rspe
rform
ed in
add
ition
to a
ntim
icrob
ialth
erap
y. St
anda
rddr
essin
gs u
sed
Stat
istica
l met
hods
:
For c
linica
l out
com
e:
Inte
ntio
n-to
-trea
t (IT
T): a
ll ra
ndom
ised
patie
nts;
per-
prot
ocol
2 (P
P2):
ITT
patie
nts w
ith n
one
ofth
e ni
ne p
roto
col v
iolat
ions
For m
icrob
iolo
gical
outc
ome
and
ther
apeu
ticre
spon
se:
Inte
ntio
n-to
-trea
t micr
obio
logic
al (IT
TM):
ITT
patie
nts w
ith a
t lea
st o
ne b
asel
ine
path
ogen
; per
-pr
otoc
ol m
icrob
iolo
gical
(PP2
M):
PP2
patie
nts
with
at l
east
one
bas
elin
e pa
thog
en
Deb
ridem
ent p
erfo
rmed
:I1
I2Ba
selin
e93
.694
.2D
ay 3
81.9
77.6
Day
10
79.7
75.6
EOT
65.8
63.0
Follo
w-u
p59
.854
.2
Clin
ical o
utco
meb
Ove
rall
clini
cal o
utco
me
at d
ay 1
0:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
T15
2/17
189
151/
171
88–6
.16
to 7
.33
PP2
96/1
0889
106/
120
88–7
.71
to 8
.82
Ove
rall
clini
cal o
utco
me
at e
nd o
f tre
atm
ent:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
T15
3/17
189
153/
171
89–6
.51
to 6
.51
PP
298
/108
9110
9/12
091
–7.6
2 to
7.4
4
Ove
rall
clini
cal o
utco
me
at fo
llow
-up:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
T13
4/16
3 82
137/
163
84–9
.97
to 6
.29
PP2
87/1
05 8
310
1/11
786
–13.
00 to
6.0
7
Num
bers
of
with
draw
als p
ertr
eatm
ent
grou
p:I1
: 16
I2: 1
5
Reas
ons f
orw
ithdr
awal:
Dat
a no
tav
ailab
le b
yst
udy
303/
304
Relat
edst
udie
s:Li
psky
(unp
ublis
hed
B) –
see
sepa
rate
dat
aex
trac
tion)
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
167
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Seco
ndar
y: (1
) wou
ndsc
ores
and
mea
sure
men
ts;
(2)b
asel
ine
path
ogen
erad
icatio
n
Setti
ng: O
utpa
tient
s
Leng
th o
f tre
atm
ent:
14–2
8 da
ysAs
sess
men
t: Ba
selin
eda
ys 3
, 10a , 1
4, 2
1, e
ndof
trea
tmen
t (EO
T)a
(14–
28 d
ays)
, fol
low
-up
(FU
)a(2
wee
ks a
fter e
ndof
trea
tmen
t visi
t)a
Prin
cipal
time
poin
ts o
fin
tere
st
Foot
ulce
r, os
teom
yelit
is an
dam
puta
tion/
foot
surg
ery
hist
ory:
I1I2
Foot
ulce
rs11
3 (6
6%)1
09 (6
4%)
Ost
eom
yelit
is34
(20%
)40
(23%
)Am
puta
tion/
78 (4
6%)
64 (3
7%)
foot
surg
ery
Ampu
tatio
n49
(29%
)49
(29%
)
Base
line
wou
nd a
rea
(med
ian, m
m2 )
(min
.–m
ax.): I1
I214
6.9
160.
8(6
.2–2
628.
0)(3
2.9–
1738
.0)
Base
line
wou
nd d
epth
(med
ian, m
m2 )
(min
.–m
ax.) I1
I23.
03.
0(0
–14)
(0–2
0)
b %
resp
onse
= %
cur
ed +
% im
prov
edD
iffer
ence
(Diff
) = p
exiga
nan
% –
oflo
xacin
%
Cur
ed a
t day
10
(%):
I1I2
ITT
2020
ITTM
1919
PP2
2219
PP2M
2120
Cur
ed a
t end
of t
reat
men
t (%
):IT
T49
47IT
TM49
46PP
253
51PP
2M52
51
Cur
ed a
t fol
low
-up
(%):
ITT
5153
ITTM
5151
PP2
5055
PP2M
4954
Micr
obio
logic
al ou
tcom
ec
Ove
rall
micr
obio
logic
al ou
tcom
e at
day
10:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
TM44
/138
3230
/140
210.
12 to
20.
79PP
2M31
/89
3520
/96
211.
18 to
26.
81
Ove
rall
micr
obio
logic
al ou
tcom
e at
end
of
trea
tmen
t:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
TM63
/138
4666
/140
47–1
3.22
to 1
0.24
PP2M
45/8
951
50/9
652
–15.
95 to
12.
90
Ove
rall
micr
obio
logic
al ou
tcom
e at
follo
w-u
p:
I1I2
95%
CI
n/N
%n/
N%
Diff
.TT
M63
/138
4666
/140
47–1
3.22
to 1
0.24
PP2M
45/8
951
50/9
652
–15.
95 to
12.
90
cont
inue
d
Appendix 4
168
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
c %
resp
onse
= %
reso
lved
+ %
impr
oved
Diff
.= p
exiga
nan%
– o
floxa
cin%
Micr
obio
logic
al ou
tcom
e ‘re
solve
d’ a
t end
of
trea
tmen
t:I1
I2IT
TM53
(38%
)59
(42%
)
Micr
obio
logic
al ou
tcom
e ‘re
solve
d’ a
t fol
low
-up:
I1I2
ITTM
50 (3
8%)
61 (4
6%)
Ther
apeu
tic re
spon
sed
Ther
apeu
tic re
spon
se a
t end
of t
reat
men
t:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
TM46
/138
3853
/140
38–1
5.77
to 6
.73
PP2M
32/8
936
36
/96
41–1
8.68
to 9
.34
Ther
apeu
tic re
spon
se a
t fol
low
-up:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
TM48
/130
3760
/134
45–1
9.68
to 3
.97
PP2M
32/8
637
44/9
447
–23.
97 to
4.7
7d
% re
spon
se =
% c
linica
lly c
ured
+m
icrob
iolo
gicall
y re
solve
dD
iffer
ence
= p
exiga
nan
% –
oflo
xacin
%Re
duct
ion
in w
ound
are
a (m
m2 ) f
rom
bas
elin
e by
EOT
(FU
) clin
ical r
espo
nse
(ITT)
:
EOT
FUI1
I2I1
I2C
ured
:M
edian
–72.
8–1
13.6
–91.
8–1
23.7
Mea
n–9
0.3
–183
.6–1
09.2
–184
.4M
edian
(%)
–67.
1–7
7.8
–78.
9–9
3.9
Mea
n (%
)–5
6.0
–65.
8–5
7.1
–76.
5
Impr
oved
:M
edian
–69.
4–6
9.2
–60.
7–6
0.5
Mea
n–1
20.6
–80.
9–9
8.6
–109
.6
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
169
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Med
ian (%
)–4
6.5
–45.
1–3
7.9
–38.
8M
ean
(%)
–38.
8–3
5.7
–14.
3–3
2.6
Faile
d:M
edian
22.1
–38.
3–0
.9–4
4.3
Mea
n39
.9–8
3.4
24.4
–90.
0M
edian
(%)
10.8
–20.
8–1
.3–4
9.4
Mea
n (%
)21
.0–1
8.3
19.9
–22.
7
Mos
t fre
quen
t bas
elin
e pa
thog
ens e
radi
cate
d at
follo
w-u
p (IT
TM):
I1I2
n/N
%n/
N%
Stap
hylo
cocc
us a
ureu
s29
/55
5342
/70
60En
tero
cocc
us fa
ecal
is25
/49
5132
/47
68St
rept
ococ
cus a
gala
ctia
e13
/25
5213
/23
57St
aphy
loco
ccus
epi
derm
is8/
1362
7/11
64Ps
eudo
mon
as a
erug
inos
a7/
1164
11/1
669
Ente
roco
ccus
spec
ies
4/9
441/
425
Stre
ptoc
occu
s can
is3/
933
5/10
50Es
cher
ichia
col
i7/
710
07/
888
Prev
otel
la b
ivia
7/7
100
4/4
100
Prot
eus m
irabl
is3/
743
6/10
60
Ampu
tatio
n (in
ciden
ce a
nd ty
pe, e
.g. m
ajor/m
inor
)I1
: 7I2
: 3
Num
ber/d
urat
ion
of h
ospi
tal a
dmiss
ions
for D
FUpr
oble
ms (
by E
OT
and
FU fa
ilure
s):
EOT
failu
res
FU fa
ilure
sI1
:3
4I2
:6
7
Adve
rse
even
ts le
adin
g to
pat
ient
with
draw
al:
I1I2
n%
n%
At le
ast o
ne a
dver
se e
vent
lead
ing
to w
ithdr
awal
169
159
cont
inue
d
Appendix 4
170
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Mos
t fre
quen
t adv
erse
eve
nt (c
ombi
ned
stud
ies
303/
304)
:D
iarrh
oea
Nau
sea
Pain
Serio
us a
dver
se e
vent
s:I1
: 22
(13%
)I2
: 19
(11%
)
Health Technology Assessment 2006; Vol. 10: No. 12
171
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Lips
ky (
unpu
blish
ed)
A,11
4U
SA
Stud
y 30
3Fu
ll pa
pers
not
ava
ilabl
e.D
ata
extr
acte
d fro
mab
stra
ct p
rese
nted
at
37th
ICAA
C (S
ept.
28–O
ct. 1
, 199
7) a
ndC
D-R
om sl
ides
pres
ente
d at
the
FDA
Advis
ory
Com
mitt
ee(M
arch
199
9)
Stud
y de
sign:
RC
T(d
oubl
e-bl
ind)
I1: P
exiga
nan
I2: O
floxa
cin
Met
hod
ofra
ndom
isatio
n:
Not
stat
ed
Uni
t of a
lloca
tion:
Pa
tient
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
stat
ed
Out
com
e as
sess
men
t:Pr
imar
y: (1
) clin
ical
outc
ome
(cur
ed: n
ofu
rthe
r sign
s or
sym
ptom
s of i
nfec
tion;
impr
oved
: sign
ifica
ntim
prov
emen
t but
inco
mpl
etel
y re
solve
d;fa
iled:
no
appa
rent
resp
onse
to th
erap
y);
(2) m
icrob
iolo
gical
outc
ome;
(3) t
hera
peut
icre
spon
se
Popu
latio
n:
42 c
ente
rs, 4
93(I1
247
; I2
246)
DFU
out
patie
nts
Inclu
sion
crite
ria:
Clin
ical d
iagno
sisof
diab
etic
foot
ulce
r with
out
exte
nsive
cellu
litis,
oste
omye
litis,
expo
sure
of b
one
or te
ndon
or
feve
r
Exclu
sion
crite
ria:
Ost
eom
yelit
is,ex
tens
ivece
llulit
is,ga
ngre
ne,
syst
emic
toxi
city,
inpa
tient
trea
tmen
t
Gen
der:
(M/F
)I1
: 185
/62
(75/
25%
)I2
: 180
/66
(73/
27%
)
Ethn
icity
:W
hite
I1: 1
84 (7
4%)
I2: 1
92 (7
8%)
Afric
an/A
mer
ican
I1:
22 (9
%)
I2:
20 (8
%)
Oth
erI1
: 41
(17%
)I2
: 34
(14%
)
Mea
n ±
SDag
e (y
ears
):I1
: 58.
3 (1
2.2)
I2: 5
8.7
(12.
1)
Trea
ted
with
ora
l ant
idiab
etic
med
icatio
n/in
sulin
dep
ende
nt:
I1:
Any
med
icatio
n:24
6 (1
00%
)In
sulin
:17
1 (6
9%)
Ora
l age
nts:
82 (3
3%)
I2:
Any
med
icatio
n:24
3 (9
9%)
Insu
lin:
151
(61%
)O
ral a
gent
s:97
(39%
)
Body
wei
ght m
ean
±SD
(lb):
I1: 2
07.8
(48.
5)I2
: 211
.3 (4
4.7)
Evid
ence
of n
euro
path
y, an
d ty
pe:
Non
-palp
able
pul
ses i
n af
fect
ed fo
ot:
I1I2
Dor
sal p
edis:
23 (9
%)
24 (1
0%)
Post
erial
tibi
al:31
(13%
)30
(12%
)D
oppl
er p
ulse
s:5
(2%
)3
(1%
)<
40m
mH
g
Neu
ropa
thy:
I1I2
Righ
t:21
4 (8
7%)
216
(88%
)Le
ft:21
9 (8
9%)
213
(87%
)
I1: 2
47 p
atie
nts
rece
ived
twice
a d
ayap
plica
tion
ofpe
xiga
nan
crea
m (1
%)
– a
broa
d-sp
ectr
umto
pica
l ant
imicr
obial
agen
t
I2: 2
46 p
atie
nts
rece
ived
twice
dail
ydo
se o
f oflo
xacin
(400
mg
b.d.
)
Deb
ridem
ent a
nd o
ff-lo
adin
g of
ulce
rspe
rform
ed in
add
ition
to a
ntim
icrob
ialth
erap
y. St
anda
rddr
essin
gs u
sed
Stat
istica
l met
hods
:
For c
linica
l out
com
e:
Inte
ntio
n-to
-trea
t (IT
T): a
ll ra
ndom
ised
patie
nts;
per p
roto
col 2
(PP2
) (ju
dged
to h
ave
com
plet
ed a
tle
ast 7
5% o
f dos
es):
ITT
patie
nts w
ith n
one
of th
eni
ne p
roto
col v
iolat
ions
For m
icrob
iolo
gical
outc
ome
and
ther
apeu
ticre
spon
se:
Inte
ntio
n-to
-trea
t micr
obio
logic
al (IT
TM):
ITT
patie
nts w
ith a
t lea
st o
ne b
asel
ine
path
ogen
; per
prot
ocol
micr
obio
logic
al (P
P2M
): PP
2 pa
tient
s with
at le
ast o
ne b
asel
ine
path
ogen
Deb
ridem
ent p
erfo
rmed
(ITT
):I1
I2Ba
selin
e96
.893
.1D
ay 3
82.5
79.7
Day
10
86.1
83.9
End
of tr
eatm
ent
71.7
63.9
Follo
w-u
p68
.463
.1
Clin
ical o
utco
meb
Ove
rall
clini
cal o
utco
me
at d
ay 1
0:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
T20
8/24
784
220/
246
89–1
1.18
to 0
.74
PP2
105/
125
8412
7/14
190
–14.
18 to
2.0
4
Ove
rall
clini
cal o
utco
me
at e
nd o
f tre
atm
ent:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
T21
0/24
785
224/
246
91–1
1.74
to –
0.33
PP2
106/
125
8512
9/14
191
–14.
50 to
1.1
2
Ove
rall
clini
cal o
utco
me
at fo
llow
-up:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
T18
6/24
377
201/
240
84–1
4.29
to –
0.12
PP
292
/123
7511
8/14
084
–19.
25 to
0.2
8
Num
bers
of
with
draw
als p
ertr
eatm
ent
grou
p:
I1: 2
8I2
: 23
Reas
ons f
orw
ithdr
awal:
Dat
a no
tav
ailab
le b
yst
udy
303/
304
Ove
rall:
I1
I2C
ellu
litis
157
Infe
ctio
n4
4O
steo
M4
31+
AE
4438
Relat
edst
udie
s:Li
psky
et a
l.(u
npub
lishe
d)A
see
sepa
rate
dat
aex
trac
tion)
cont
inue
d
Appendix 4
172
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Seco
ndar
y: (1
) wou
ndsc
ores
and
mea
sure
men
ts,
(2) b
asel
ine
path
ogen
erad
icatio
n
Setti
ng: O
utpa
tient
s
Leng
th o
f tre
atm
ent:
14–2
8 da
ysAs
sess
men
t: Ba
selin
e,da
ys 3
, 10a , 1
4, 2
1, e
ndof
trea
tmen
t (EO
T)a
(14–
28 d
ays)
, Fol
low
-up
(FU
)a(2
wee
ks a
fter e
ndof
trea
tmen
t visi
t)a
Prin
cipal
time
poin
ts o
fin
tere
st
Foot
ulce
r, os
teom
yelit
is an
dam
puta
tion/
foot
surg
ery
hist
ory:
I1I2
Foot
ulce
rs16
4 (6
6%)
145
(59%
)O
steo
mye
litis
80 (3
2%)
59 (2
4%)
Ampu
tatio
n/12
1 (4
9%)
85 (3
5%)
foot
surg
ery
Ampu
tatio
n94
(38%
)64
(26%
)
Base
line
wou
nd a
rea
(med
ian m
m2 ):
(min
–max
.)I1
I213
1.5
117.
3(0
–223
7.0)
(6.2
–199
1.0)
Base
line
wou
nd d
epth
(med
ian m
m)
(min
.–m
ax.)
I1I2
3.0
(0.1
–13)
3.0
(0–1
4)
b %
resp
onse
= %
cur
ed +
% im
prov
edD
iffer
ence
= p
exiga
nan
% –
oflo
xacin
%
Cur
ed a
t day
10
(%):
I1I2
ITT
2628
ITTM
2226
PP2
2428
PP2M
2224
Cur
ed a
t end
of t
reat
men
t (%
):IT
T54
61IT
TM52
56PP
253
62PP
2M55
55
Cur
ed a
t fol
low
-up
(%):
ITT
5665
ITTM
5560
PP2
5663
PP2M
5559
Micr
obio
logic
al ou
tcom
ec
Ove
rall
micr
obio
logic
al ou
tcom
e at
day
10:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
TM73
/189
3966
/198
33–4
.27
to 1
4.85
PP2M
40/9
542
45/1
2137
–8.2
4 to
18.
07
Ove
rall
micr
obio
logic
al ou
tcom
e at
end
of
trea
tmen
t:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
TM91
/189
4894
/198
47–9
.29
to 1
0.63
PP2M
50/9
553
58/1
2148
–8.7
3 to
18.
13
Ove
rall
micr
obio
logic
al ou
tcom
e at
follo
w-u
p:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
TM78
/185
4290
/194
46–1
4.23
to 5
.77
PP2M
42/9
345
55/1
2145
–13.
76 to
13.
17
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
173
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
c %
resp
onse
= %
reso
lved
+ %
impr
oved
Diff
. = p
exiga
nan
% –
oflo
xacin
%
Micr
obio
logic
al ou
tcom
e ‘re
solve
d’ a
t end
of
trea
tmen
t:I1
I2IT
TM74
(39%
)82
(41%
)
Micr
obio
logic
al ‘re
solve
d’ a
t fol
low
-up:
ITTM
75 (4
1%)
84 (4
3%)
Ther
apeu
tic re
spon
sed
Ther
apeu
tic re
spon
se a
t end
of t
reat
men
t:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
TM67
/189
3575
/198
38–1
2.03
to 7
.18
PP2M
38/9
540
48/1
2140
–12.
83 to
13.
49
Ther
apeu
tic re
spon
se a
t fol
low
-up:
I1I2
95%
CI
n/N
%n/
N%
Diff
.IT
TM73
/185
3982
/193
42–1
2.94
to 6
.89
PP2M
38/9
341
50/1
2042
–14.
14 to
12.
53
d %
resp
onse
= %
clin
ically
cur
ed +
micr
obio
logic
ally
reso
lved
Diff
. = p
exiga
nan
% –
oflo
xacin
%
Redu
ctio
n in
wou
nd a
rea
(mm
2 ) fro
m b
asel
ine
byEO
T (F
U) c
linica
l res
pons
e (IT
T):
EOT
FUI1
I2I1
I2C
ured
:M
edian
–67.
7–6
4.6
–74.
9–6
9.2
Mea
n–1
23.2
–99.
6–1
20.0
–114
.4M
edian
(%)
–75.
2–7
6.5
–84.
6–8
7.1
Mea
n (%
)–6
2.8
–63.
2–6
2.0
–68.
9
Impr
oved
:M
edian
–54.
3–4
7.9
–51.
8–5
0.9
Mea
n–7
0.2
–81.
3–8
6.2
–87.
9M
edian
(%)
–35.
7–3
7.8
–26.
1–3
5.2
Mea
n(%
)–2
9.6
–25.
2–3
0.9
–28.
4co
ntin
ued
Appendix 4
174
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Faile
d:M
edian
2.6
–30.
1–4
3.1
–59.
7M
ean
36.4
–117
.8–3
3.8
–168
.3M
edian
(%)
0.9
–24.
1–2
9.7
–27.
2M
ean(
%)
21.3
–19.
0–1
3.4
–30.
2
Mos
t fre
quen
t bas
elin
e pa
thog
ens e
radi
cate
d at
follo
w-u
p (IT
TM):
I1I2
n/N
%n/
N%
Stap
hylo
cocc
us a
ureu
s43
/87
4955
/91
60En
tero
cocc
us fa
ecal
is33
/56
5935
/58
60St
rept
ococ
cus a
gala
ctia
e18
/34
5326
/43
60En
tero
cocc
us sp
ecie
s12
/17
716/
875
Prot
eus m
irabl
is9/
1369
9/11
82St
rept
ococ
cuss
pecie
s11
/13
856/
967
Eche
richi
a co
li8/
1267
7/8
88Ps
eudo
mon
as a
erug
inos
a4/
1136
10/2
050
Stap
hylo
cocc
us e
pide
rmid
is7/
1164
9/12
75
Ampu
tatio
n:
I1: 4
I2: 6
Num
ber/d
urat
ion
of h
ospi
tal a
dmiss
ions
for D
FUpr
oble
ms (
by E
OT
and
FU fa
ilure
s):
EOT
failu
res
FU fa
ilure
sI1
:11
14I2
:4
9
Adve
rse
even
ts le
adin
g to
pat
ient
with
draw
al:
I1I2
n%
n%
At le
ast o
ne a
dver
se e
vent
lead
ing
to w
ithdr
awal
2811
239
Mos
t fre
quen
t adv
erse
eve
nt (c
ombi
ned
stud
ies
303/
304)
:I1
I2D
iarrh
oea
42
Nau
sea
22
Pain
21
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
175
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Prob
ably
relat
ed a
dver
se e
vent
s:41
841
7
Serio
us a
dver
se e
vent
s: (n=
28)
(n=
20)
11%
8%
Appendix 4
176
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Lips
ky (1
990)
,75U
SA
Stud
y de
sign:
RC
T
Met
hod
ofra
ndom
isatio
n:N
ot sp
ecifi
ed
Uni
t of a
lloca
tion:
Pa
tient
Calc
ulat
ion
of st
atist
ical
pow
er:
See
Com
men
ts se
ctio
n
Out
com
e as
sess
men
t(b
linde
d):
Wou
nd h
ealin
g/siz
e of
ulce
r (cli
nica
lcla
ssifi
catio
n); p
atho
gen
prof
ile (m
icrob
iolo
gical
class
ifica
tion)
Setti
ng a
nd le
ngth
of
trea
tmen
t: O
utpa
tient
clini
c/2
wee
ks
(+ 3
mon
ths f
ollo
w-u
p)
Recr
uitm
ent:
Oct
ober
1985
–Mar
ch 1
988
Writ
ten
info
rmed
cons
ent:
Loca
l Com
mitt
ee e
thica
lap
prov
al
Popu
latio
n:
Diab
etic
outp
atie
nts –
Seat
tle (W
A)Ve
tera
ns A
ffairs
Med
ical C
ente
r
Inclu
sion
crite
ria:
Patie
nts w
ithcli
nica
lly in
fect
edle
sion
(low
erex
trem
ity).
No
antim
icrob
ialth
erap
y pr
eced
ing
2w
eeks
(les
ions
wer
e ±
brea
k in
skin
)
Exclu
sion
crite
ria:
Pres
ence
of
syst
emic
toxi
city
(e.g
. high
feve
r,hy
pote
nsio
n),
pres
ence
of
imm
ediat
e lif
e or
limb
thre
at,
inab
ility
tope
rform
dail
yw
ound
car
e,hi
stor
y of
pat
ient
non-
com
plian
cew
ith o
utpa
tient
trea
tmen
t,un
willi
ngne
ss to
retu
rn fo
rou
tpat
ient
visi
ts,
aller
gy to
stud
ydr
ugs
Def
initi
on o
fin
fect
ion:
rece
ntde
velo
pmen
t of
All m
ale (n
= 6
0)I1
: n=
27
I2: n
= 2
9
Mea
n ±
SEM
age
(yea
rs):
I1: 5
9.4
±2.
3I2
: 62.
7 ±
2.4
Non
-insu
lin-d
epen
dent
diab
etes
:I1
: 23
(85%
)I2
: 28
(97%
)
Insu
lin-tr
eate
d:I1
: 19
(70%
)I2
: 18
(62%
)
Lesio
n ul
cera
ted:
I1: 2
4 (8
9%)
I2: 2
7 (9
3%)
Infe
ctio
n pr
esen
t <1
mon
th:
I1: 2
6 (9
6%)
I2: 2
8 (9
7%)
Lesio
n fo
ul sm
ellin
g:I1
: 2 (7
%)
I2: 2
(7%
)
Anae
robe
s iso
lated
:I1
: 4 (1
5%)
I2: 3
(10%
)
Aero
bic
Gra
m-n
egat
ive b
acilli
isol
ated
:I1
: 7 (2
6%)
I2: 5
(17%
)
No
use
of a
ntim
icrob
ial a
gent
s in
prec
edin
g 2
wee
ks
Auth
ors r
epor
t no
stat
istica
llysig
nific
ant d
iffer
ence
s bet
wee
n gr
oups
on d
emog
raph
ic, c
linica
l or
micr
obio
logic
al ch
arac
teris
tics
60 p
atie
nts r
ando
mise
d, b
ut d
ata
on
I1: n
= 2
7 re
ceive
d or
alcli
ndam
ycin
hyd
roch
lorid
e(C
leoc
in) 3
00m
g,
4×da
ily fo
r 2w
eeks
I2: n
= 2
9 re
ceive
d or
alce
phale
xin
(Kef
lex)
50
0 m
g, 4
×da
ily fo
r2
wee
ks
Patie
nts w
ere
seen
inou
tpat
ient
clin
ic ev
ery
3–7
days
, dep
endi
ng o
nse
verit
y of
infe
ctio
n
Wou
nd c
are:
Al
l les
ions
cle
anse
d,dr
esse
d an
d de
brid
emen
tad
min
ister
ed (w
here
nece
ssar
y) a
t ini
tial
evalu
atio
n. P
atie
nts
advis
ed to
per
form
twice
-da
ily c
lean
sing
and
dres
sing
regim
en, a
void
unne
cess
ary
ambu
latio
n,se
lf-ev
aluat
ion/
call
rese
arch
nur
se if
nece
ssar
y
Thos
e w
hose
infe
ctio
nsfa
iled
to im
prov
e, o
rw
orse
ned,
wer
ew
ithdr
awn
from
the
stud
yan
d ho
spita
lised
. Tho
sew
hose
cul
ture
s yie
lded
one
or m
ore
isolat
esre
sista
nt to
the
stud
yan
tibio
tic w
ere
asse
ssed
.Th
erap
y co
ntin
ued
ifin
fect
ion
impr
ovin
g,ot
herw
ise o
ther
appr
opria
te tr
eatm
ent
Infe
ctio
n re
spon
se: (
n=
56) I1
I2C
ured
21 (7
8%)
21 (7
2%)
Impr
oved
5 (1
9%)
4 (1
4%)
Faile
d1
(4%
)4
(14%
)
Bact
erio
logic
al re
spon
se: (
n=
52)
I1 (n
= 2
6)I2
(n=
26)
Cur
ed20
(77%
)20
(77%
)Im
prov
ed4
(15%
)2
(8%
)Fa
iled
2 (8
%)
2 (8
%)
Supe
rinfe
ctio
n3
(12%
)1
(4%
)
Wou
nd h
ealin
g: (n
= 5
2) I1 (n
= 2
5)I2
(n=
27)
Hea
led
10 (4
0%)
9 (3
3%)
Prog
ress
14 (5
6%)
18 (6
7%)
Uni
mpr
oved
1 (4
%)
0 (0
%)
Recu
rren
ce a
t fol
low
-up
(15
±9
mon
ths)
:8/
51 (1
6%) o
f pat
ient
s with
cur
ed o
rim
prov
ed in
fect
ion
at 2
wee
ks re
quire
dth
erap
y fo
r sub
sequ
ent i
nfec
tion
at sa
me
site
4 pa
tient
s req
uire
d tr
eatm
ent (
>2
wee
ks) (
I2)
Acqu
isitio
n of
resis
tant
org
anism
s: no
ted
in1
patie
nt (I
1) a
nd 4
pat
ient
s (I2
)
Adve
rse
even
ts:
I1:1
pat
ient
with
mild
diar
rhoe
a –
reso
lved
I2:2
pat
ient
s with
mild
nau
sea
and
diar
rhoe
a –
reso
lved
Num
bers
of
with
draw
als: 2
Reas
ons f
orw
ithdr
awal:
hosp
italis
atio
n(1
was
due
tore
ason
sun
relat
ed to
the
infe
ctio
n)
Que
ry th
ese
as‘w
ithdr
awals
’ –th
ere
was
no
crite
ria fo
rde
finin
g a
with
draw
al
Lim
itatio
ns o
fth
e st
udy
(as
note
d by
auth
ors)
:D
iffer
ence
inov
erall
infe
ctio
nre
spon
se ra
tebe
twee
n I1
and
I2 w
asno
tst
atist
ically
signi
fican
t due
to lo
w p
ower
All m
ale
Stud
ysp
onso
rshi
p:Au
thor
sac
know
ledg
e‘g
rant
-in-a
id’
from
Upj
ohn,
Kalam
azoo
,M
I, U
SA
Def
initi
on o
fou
tcom
es:
Cur
ed =
all
signs
and
sym
ptom
s of
infe
ctio
n ha
dre
solve
d
Impr
oved
=m
ost s
igns
and
sym
ptom
sha
d re
solve
d
Faile
d =
no
subs
tant
ial
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
177
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
puru
lenc
e or
atle
ast 2
of t
hefo
llow
ing:
eryt
hem
a,w
arm
th,
tend
erne
ss,
indu
ratio
n,flu
ctua
nce,
drain
age
56 re
port
ed a
s 4 w
ere
exclu
ded
as:
dete
ctio
n of
ost
eom
yelit
is af
ter
rand
omisa
tion
(n=
2);
patie
ntin
siste
nce
on b
eing
hos
pita
lised
(n
= 1
); pa
tient
failu
re to
take
A/B
(n
= 1
)
adm
inist
ered
. Afte
r2
wee
ks o
f the
rapy
, tho
sesh
owin
g im
prov
emen
t but
pers
istin
g cli
nica
l sign
s of
infe
ctio
n w
ere
inst
ruct
edto
con
tinue
pre
scrib
edre
gimen
. On
each
retu
rnvis
it, m
edica
tion
com
plian
ce re
view
ed a
ndad
vers
e dr
ug e
ffect
sas
sess
ed
Loca
l car
e of
ulce
rsin
clude
d co
vera
ge w
ithfin
e m
esh,
non
-adh
eren
tdr
essin
g an
d dr
y ga
uze
onto
p of
that
. Cle
ansin
g of
ulce
r (by
pat
ient
) was
with
hyd
roge
n pe
roxi
de(tw
ice/d
aily)
impr
ovem
ent
in in
fect
ion
AND
ach
ange
in A
/Btr
eatm
ent O
Rsu
rgica
lin
terv
entio
nbe
lieve
dne
cess
ary
Appendix 4
178
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Mar
chin
a (1
997)
,123
Italy
Stud
y de
sign:
RCT
(sin
gle-b
lind)
Met
hod
ofra
ndom
isatio
n:N
ot st
ated
Uni
t of a
lloca
tion:
Patie
nts
Calc
ulat
ion
of st
atist
ical
pow
er:
No
a pr
iori
pow
erca
lculat
ion
repo
rted
Out
com
e as
sess
men
t:H
ealin
g pr
ogre
ssas
sess
ed a
t 5, 1
0 an
d15
days
. Wou
nds w
ere
grad
ed a
s one
of t
hefo
llow
ing:
3: c
ompl
ete
heali
ng2:
>50
% w
ound
are
ahe
aled,
relat
ive to
base
line
1: 2
5–50
% h
eale
dU
nsat
isfac
tory
<25
%he
aled
No
info
rmat
ion
given
abou
t met
hods
of
mea
sure
men
t or h
owm
any
asse
ssor
s inv
olve
d
Trea
tmen
t dur
atio
n:
15-d
ay tr
ial. S
ettin
g no
tst
ated
Inclu
sion
crite
ria:
Patie
nts a
ged
65ye
ars a
nd o
ver,
with
DFU
s, ve
nous
leg
ulce
rs a
ndpr
essu
re so
res.
Wou
nds h
ad to
be
class
ified
as 1
st o
r2n
d de
gree
(not
defin
ed)
Exclu
sion
crite
ria:
Sens
itivit
y to
test
med
icatio
n,re
ceivi
ng o
ther
trea
tmen
t
Gen
der (
M/F
):I 6
/14
C 8
/12
Mea
n ±
SD(r
ange
) age
(yea
rs):
I 76.
7 ±
5.2
(66–
86)
C 7
9.1
±6.
4 (6
7–89
)
Wou
nd ty
pe:
Pres
sure
ulce
r/diab
etic
foot
I 9/1
1C
10/
10
Wou
nd c
ondi
tion:
Goo
d/m
oder
ate/
poor
Pres
sure
ulce
rsI 0
/3/6
C 0
/3/7
DFU
sI 4
/6/1
C 3
/7/0
No
info
rmat
ion
given
on
base
line
wou
nd a
rea
38 p
atie
nts p
rese
nted
oth
er c
o-m
orbi
ditie
s (e.
g. d
iabet
es m
ellit
us,
hype
rten
sion)
and
con
tinue
d w
ithus
ual m
edica
tion
durin
g th
e st
udy
perio
d
I: W
ound
s wer
e cle
aned
with
norm
al sa
line
and
drie
d w
ithga
uze.
An
antis
eptic
spra
y (2
%eo
sin a
nd 0
.3%
chl
orox
yleno
lin
hyd
rogly
colic
solu
tion)
was
appl
ied
to th
e w
ound
surfa
ceus
ing
gauz
e. W
ound
was
then
cove
red
with
gau
ze. T
hedr
essin
g w
as c
hang
ed2–
3tim
es p
er d
ay. T
here
wer
eno
det
ails o
f the
use
of o
ther
inte
rven
tions
(e.g
. pre
ssur
ere
lief)
Patie
nts w
ho w
ere
bein
gtr
eate
d w
ith a
n an
tisep
tic p
rior
to th
e st
udy
had
a 1
day
‘was
h-ou
t’ pe
riod,
dur
ing
whi
ch th
ew
ound
was
cle
aned
2–3
tim
esw
ith n
orm
al sa
line.
Dur
ing
the
stud
y pe
riod,
trea
tmen
t with
othe
r ant
isept
ics, h
ealin
gm
edica
tions
, ant
ibio
tics,
analg
esics
, abs
orbi
ng a
gent
san
d an
ti-in
flam
mat
ory
agen
tsw
as d
iscon
tinue
d.(n
= 2
0)
C: A
s abo
ve, e
xcep
t tha
t an
alter
nativ
e sp
ray
was
use
d (n
otde
scrib
ed).
(n=
20)
At 1
5da
ys
Hea
ling
(3/2
/1/u
nsat
isfac
tory
)Al
l wou
nds
I 58%
/12%
/30%
/0C
30%
/40%
/18%
/12%
Figu
res t
aken
from
gra
ph
Hea
ling
(3/2
/1/u
nsat
isfac
tory
)Fo
r DFU
s onl
yI 8
2%/1
8%/0
/0C
50%
/50%
/0/0
Figu
res t
aken
from
gra
ph
Hea
ling
(3/2
/1/u
nsat
isfac
tory
)Fo
r pre
ssur
e ul
cers
onl
yI 2
0%/1
0%/7
0%/0
C 1
0%/3
0%/3
0%/3
0%Fi
gure
s tak
en fr
om g
raph
Adve
rse
effe
cts (
loca
l bur
ning
sens
atio
n)I 3
pat
ient
sC
1 p
atie
nt
No
with
draw
alsTh
is is
a sm
allst
udy.
Larg
ernu
mbe
rs m
ay b
ere
quire
d to
det
ect
the
true
trea
tmen
tef
fect
The
base
line
and
end-
poin
tas
sess
men
ts o
fw
ound
con
ditio
nap
pear
to b
e ba
sed
on a
subj
ectiv
eas
sess
men
t. Th
ere
are
no d
etail
s of
inde
pend
ent
asse
ssm
ents
by
mor
e th
an o
neex
amin
er, a
ndbl
indi
ng p
roce
dure
sar
e als
o un
clear
.Th
e re
liabi
lity
ofth
e re
sults
may
ther
efor
e be
ques
tiona
ble
C, c
ontr
ol g
roup
; I, i
nter
vent
ion
grou
p.
Health Technology Assessment 2006; Vol. 10: No. 12
179
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Mar
kevic
h (2
000)
,105
Ukr
aine
RCT
Met
hod
of ra
ndom
isatio
nN
ot st
ated
Uni
t of a
lloca
tion:
Patie
nt
No
pres
enta
tion
ofpo
wer
calc
ulat
ion
Out
com
e as
sess
men
t:N
umbe
r of u
lcers
heale
d, p
ropo
rtio
n of
ulce
rs w
ith a
t lea
st 5
0%gr
anul
atio
n tis
sue,
prop
ortio
n of
pat
ient
sw
ith a
t lea
st 5
0%re
duct
ion
in w
ound
are
a,w
ound
dep
th a
ndvo
lum
e, e
valu
atio
n of
surr
ound
ing
skin
, tiss
uequ
ality
(nec
rotic
, slo
ugh,
fibro
tic o
r gra
nulat
ion)
,ex
udat
e, o
dour
and
gluco
se le
vels
Setti
ng:
Inpa
tient
s in
Lviv
Med
ical
Uni
vers
ity H
ospi
tal
Popu
latio
n:
140
peop
le w
ithne
urop
athi
c fo
otw
ound
s req
uirin
gde
brid
emen
t
Inclu
sion
crite
ria:
Non
e st
ated
insh
ort a
bstr
act b
utan
othe
r con
fere
nce
repo
rt st
ates
diab
etes
mel
litus
,ne
urop
athy
, gra
de 2
or 3
ulce
rs w
ithslo
ugh,
palp
able
foot
pulse
s
Exclu
sion
crite
ria:
Non
e st
ated
insh
ort a
bstr
act b
utan
othe
r con
fere
nce
repo
rt st
ates
perip
hera
l vas
cular
dise
ase,
isch
aem
iche
art d
iseas
e, re
nal
failu
re, h
epat
icdi
seas
e, rh
eum
atoi
dar
thrit
is, im
mun
o-co
mpr
omise
d an
dco
ncur
rent
ster
oid
ther
apy
Mea
n ag
e: 5
3.6
year
s (±
15.4
year
s)(u
ncle
ar w
hat f
igure
±re
pres
ents
)
Mea
n du
ratio
n of
diab
etes
: 15.
8±
10.7
year
s (un
clear
if ±
is SD
/SE
or ra
nge)
Mea
n ±
SDul
cer a
rea:
I1: L
arva
l the
rapy
gro
up –
14.
9cm
2
I2: H
ydro
gel g
roup
– 1
5.14
cm2
Auth
ors s
tate
: “w
ound
surfa
ce a
rea,
dept
h an
d vo
lum
e, e
valu
atio
n of
surr
ound
ing
skin
, tiss
ue q
ualit
y(n
ecro
tic, s
loug
h, fi
brot
ic or
gran
ulat
ion)
and
hea
ling
rate
s,ex
udat
e, o
dour
and
glu
cose
leve
lsw
ere
com
para
ble
at b
asel
ine”
but
no d
ata
prov
ided
oth
er th
an o
nw
ound
are
a
No
data
on
gend
er, e
thni
city
or ty
peof
diab
etes
for a
ll 14
0 pa
rtici
pant
s,bu
t dat
a av
ailab
le fo
r 22
patie
nts
repo
rted
at a
con
fere
nce:
Male
/fem
ale: 4
5%/5
5%Ty
pe I/
II di
abet
es: 2
7%/7
3%U
lcer g
rade
2/3
: 86%
/14%
I1: L
arva
l the
rapy
(ste
rile
larva
eof
the
gree
n bo
ttle
fly, L
ucilia
serri
cata
) 6–1
0 lar
vae
per
1cm
2w
ound
are
a, re
mov
edaf
ter 7
2 ho
urs.
Dre
ssin
gs ly
ing
abov
e lar
vae
wer
e ch
ange
d as
requ
ired.
Up
to th
ree
appl
icatio
ns o
f lar
vae
wer
eus
ed. n
= 7
0
I2: H
ydro
gel d
ress
ing
(unn
amed
). D
ress
ing
rem
oved
at le
ast e
very
thre
e da
ys.
n=
70
No
info
rmat
ion
on c
oncu
rren
ttr
eatm
ents
(suc
h as
bed
rest
).Al
l par
ticip
ants
wer
e ho
spita
lin
patie
nts
Stat
istica
l met
hods
: 3-
way
AN
OVA
, ind
epen
dent
t-
test
, �2
test
Prop
ortio
n of
pat
ient
s ach
ievin
gco
mpl
ete
heali
ng in
10
days
: I1
: 5/7
0 (7
.1%
)I2
: 2/7
0 (2
.9%
)
Prop
ortio
n of
pat
ient
s with
at
leas
t 50%
gra
nulat
ion
tissu
e in
wou
nd:
I1: 6
0% (?
42/7
0)I2
: 34.
3% (?
24/7
0)p
< 0
.001
Prop
ortio
n of
pat
ient
s with
at
leas
t 50%
redu
ctio
n in
are
a of
wou
nd:
I1. 5
1.1%
(?36
/70)
I2. 2
7.1%
(?19
/70)
p<
0.0
5
Num
bers
of
with
draw
als p
ertr
eatm
ent
grou
p: n
otst
ated
Abst
ract
ava
ilabl
e on
full
stud
y (n
= 1
40),
but p
rese
ntat
ion
ofre
sults
from
52
patie
nts (
? an
inte
riman
alysis
) obt
ained
from
con
fere
nce
proc
eedi
ngs
No
info
rmat
ion
onfu
ndin
g/sp
onso
rshi
p
10-d
ay fo
llow
-up
isto
o sh
ort t
o ca
ptur
eul
cer h
ealin
g
The
repo
rt d
oes n
otre
port
the
prop
ortio
n of
peo
ple
who
se u
lcer b
ecam
eco
mpl
etel
y de
brid
edin
the
10-d
ay p
erio
din
the
two
grou
ps,
the
num
ber o
f lar
val
ther
apy
trea
tmen
tsre
quire
d or
the
med
ian ti
me
toco
mpl
ete
debr
idem
ent
The
ulce
rs in
this
stud
y ar
e lar
ge (a
rea
of 1
5cm
2 ) in
com
paris
on w
ithot
her D
FU st
udie
san
d th
is m
ay a
ffect
its g
ener
alisa
bilit
y
Appendix 4
180
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Pete
rson
(198
9),10
1U
SA
Stud
y de
sign:
RC
T
Met
hod
ofra
ndom
isatio
n: P
harm
acy
Serv
ice ra
ndom
lyas
signe
d pa
tient
scip
roflo
xacin
at a
dos
e of
eith
er 7
50 o
r 100
0m
gor
ally
twice
dail
y. Al
lot
hers
wer
e bl
inde
d to
the
rand
omisa
tion
by th
eus
e of
plac
ebo
to m
ake
the
num
ber o
f dail
ydo
ses i
dent
ical i
n bo
thgr
oups
Uni
t of a
lloca
tion:
Pa
tient
Out
com
e as
sess
men
t:Re
spon
se to
two
diffe
rent
dos
es o
fcip
roflo
xacin
(I1,
750
mg
twice
dail
y; I2
, 100
0m
gtw
ice d
aily)
: ful
lysu
cces
sful o
utco
me
defin
ed a
s not
requ
iring
eith
er re
peat
antim
icrob
ial th
erap
y fo
rin
itial
infe
ctio
n or
ampu
tatio
n of
the
invo
lved
extr
emity
Popu
latio
n:
Adul
ts w
ithpe
riphe
ral v
ascu
lardi
seas
e(b
ut u
ncle
arw
heth
er w
ound
sar
e di
abet
ic or
vasc
ular
in o
rigin
)
Inclu
sion
crite
ria:
(1) H
istor
y of
clini
cal e
viden
ce o
fpe
riphe
ral v
ascu
lardi
seas
e or
diab
etes
mel
litus
; (2)
puru
lent
-app
earin
glo
wer
ext
rem
ityle
sion
of su
fficie
ntse
verit
y to
requ
ireho
spita
lisat
ion
for
intr
aven
ous
antim
icrob
ialth
erap
y; (3
) had
two
or m
ore
signs
of
infe
ctio
n in
cludi
nglo
cal h
eat,
oede
ma,
drain
age,
ery
them
a,pa
in, o
rte
mpe
ratu
re g
reat
erth
an 3
7.8°
C
48 p
atie
nts
Gen
der:
M 4
7, F
1
Mea
n ±
SDag
e: 6
4ye
ars
No.
with
diab
etes
mel
litus
: 46/
48(9
6%)
No.
with
ost
eom
yelit
is: 3
1/48
(65%
)N
o. w
ith c
ellu
litis:
16/
48 (3
3%)
I1: (
n= 2
4) re
ceive
dcip
roflo
xacin
at 7
50 m
g or
ally
twice
dail
y. Pa
tient
s diag
nose
das
hav
ing
oste
omye
litis
whe
n co
mpa
tible
cha
nges
wer
eob
serv
ed, e
ither
radi
ogra
phica
lly o
r on
thre
e-ph
ase
bone
scan
. The
sepa
tient
s give
n 3
mon
ths o
fth
erap
y. Pa
tient
s who
had
no
evid
ence
of o
steo
mye
litis
wer
egiv
en 3
wee
ks o
f tre
atm
ent.
No
othe
r ant
imicr
obial
s wer
egiv
en to
pat
ient
s (co
ncur
rent
lyor
follo
win
g cip
roflo
xacin
ther
apy)
unl
ess i
t was
dete
rmin
ed th
at th
e qu
inol
one
trea
tmen
t was
a fa
ilure
I2 (n
= 2
4): A
s abo
ve, b
ut10
00m
g or
al cip
roflo
xacin
given
twice
dail
y
Loca
l wou
nd c
are:
bot
hgr
oups
. (1)
deb
ridem
ent o
fw
ound
to re
mov
e su
rface
esch
ars a
nd n
ecro
tic m
ater
ial;
(2) m
ainte
nanc
e of
a c
lean
wou
nd b
y fo
ot so
akin
g an
d w
etor
dry
gau
ze d
ress
ings
; (3
) avo
idan
ce o
f any
pre
ssur
eon
the
wou
nd it
self;
(4)
ther
apy
of th
e in
fect
ed le
sion
with
syst
emic
rath
er th
anto
pica
l ant
imicr
obial
age
nts
Fully
eva
luab
le p
atie
nts:
I1: 2
3 pa
tient
sI2
: 22
patie
nts
Ampu
tatio
n: (i
n th
ose
for w
hom
ther
apy
faile
d)
I1: 6
/11
(55%
)I2
: 3/7
(43%
)
Long
-term
out
com
e (d
efin
edea
rlier
) in
patie
nts t
reat
ed fo
r (a
) ost
eom
yelit
is an
d (b
) cel
lulit
is(%
):
Tota
l (a)
19
(65)
; (b)
8 (5
0)I1
I2(a
)(b
)(a
)(b
)10
(67)
2 (2
5)9
(64)
6 (7
5)
Adve
rse
even
ts:
I2: 2
pat
ient
s req
uire
d ce
ssat
ion
of tr
eatm
ent.
One
was
due
tona
usea
and
vom
iting
, whi
chbe
gan
follo
win
g ho
spita
ldi
scha
rge
at 2
days
. The
oth
erpa
tient
disc
ontin
ued
at 3
4da
ysdu
e to
seve
re a
nxie
ty, s
imila
r to
that
pre
vious
ly ex
perie
nced
with
othe
r med
icatio
ns
6 pa
tient
s (I2
), 2
patie
nts (
I1)
expe
rienc
ed c
hem
ical
abno
rmali
ties
(incr
ease
d bl
ood
urea
nitr
ogen
or
seru
m c
reat
inin
e le
vels)
Num
bers
of
with
draw
als(a
lthou
ghw
ithdr
awal
not
defin
ed) p
ertr
eatm
ent g
roup
:
I1: 1
rece
ived
ampu
tatio
n w
ithin
24ho
urs o
fen
rolm
ent
I2: 2
pat
ient
s due
to a
dver
se e
vent
s(s
ee p
revio
usno
te)
Stud
y sp
onso
rshi
p:M
iles
Phar
mac
eutic
als,
Wes
t Hav
en, C
T,U
SA
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
181
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Setti
ng a
nd le
ngth
of
trea
tmen
t: in
patie
nts a
tth
e M
inne
apol
is Ve
tera
nsAd
min
istra
tion
Med
ical
Cen
ter.
Trea
tmen
t ove
r72
hour
s/fol
low
-up
at12
mon
ths
Exclu
sion
crite
ria:
(1) F
ailur
e to
give
info
rmed
con
sent
;(2
) alle
rgy
toqu
inol
one
antib
iotic
s; (3
) prio
ran
tibio
tic th
erap
ygiv
en w
ithin
the
prev
ious
72
hour
sth
at w
as e
ffect
ive, i
nviv
oor
invit
ro,
again
st th
eir
path
ogen
ic ba
cter
ialiso
lates
. No
patie
ntw
as e
xclu
ded
for
the
first
two
indi
catio
ns
Swab
cul
ture
s obt
ained
afte
rth
e su
rface
of t
he w
ound
has
been
thor
ough
ly cle
anse
d to
min
imise
surfa
ce c
onta
min
atio
n
Appendix 4
182
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Rhaie
m (1
998)
,124
Tuni
sia
Stud
y de
sign:
RC
T
Met
hod
ofra
ndom
isatio
n:
Not
stat
ed
Uni
t of a
lloca
tion:
Patie
nt
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
des
crib
ed
Out
com
e as
sess
men
t:Th
e m
ain o
utco
mes
repo
rted
per
stud
ygr
oup
wer
e he
aling
rate
and
time
to h
ealin
g.W
here
hea
ling
rate
sw
ere
repo
rted
acc
ordi
ngto
socio
-eco
nom
ic le
vel,
a sc
ore
was
calc
ulat
edac
cord
ing
to th
efo
llow
ing:
leve
l of
educ
atio
n (0
illit
erat
e,
1 pr
imar
y sc
hool
leve
l, 2
seco
ndar
y sc
hool
, 3
furt
her e
duca
tion)
;pr
ofes
sion
(0 u
nem
ploy
ed, 1
low
inco
me,
2 m
oder
ate
inco
me,
3 h
igh in
com
e);
type
of h
ousin
g an
dnu
mbe
r of d
epen
dant
s
Setti
ng a
nd le
ngth
of
trea
tmen
t:H
ospi
tal;
mea
n±sd
(?)
leng
th o
f hos
pita
l sta
y:40
±13
days
Popu
latio
n:D
iabet
ic pa
tient
sw
ith c
utan
eous
wou
nds,
hosp
italis
ed a
t Rab
taH
ospi
tal,
Tuni
sia,
betw
een
1992
and
1995
Inclu
sion
crite
ria:
As a
bove
Exclu
sion
crite
ria:
Not
stat
ed
Base
line
char
acte
ristic
s wer
ere
port
ed fo
r the
sam
ple
over
all,
and
not p
er st
udy
grou
p
Num
ber m
ale/fe
male
:59
/21
Mea
n ±
SD (?
) (ra
nge)
age
(yea
rs):
56 ±
32 (2
6–89
)
Num
ber w
ith in
sulin
-de
pend
ent/n
on-in
sulin
dep
ende
ntdi
abet
es:
61/1
9
Mea
n ±
SD(?)
(ran
ge) d
urat
ion
of d
iabet
es (y
ears
):13
±10
.6 (1
–26)
Num
ber o
f pat
ient
s with
diab
etes
for l
ess t
han/
at le
ast 1
0ye
ars:
22/5
8
Num
ber o
f pat
ient
s with
out
occu
patio
n/illi
tera
te:
61/5
3
Prop
ortio
ns o
f pat
ient
s with
risk
fact
ors:
body
mas
s ind
ex o
f at l
east
25kg
/m2 : 4
0%D
yslip
idae
mia:
28%
Smok
ers:
55%
Alco
hol u
se: 2
1%Pe
riphe
ral n
euro
path
y: 7
4.6%
Vege
tativ
e ne
urop
athy
: 18.
6%Ar
terit
is of
low
er li
mbs
: 46.
6%Ar
teria
l hyp
erte
nsio
n: 3
0.6%
Cor
onar
y in
suffi
cienc
y: 9
.3%
Prop
ortio
n of
pat
ient
s with
diab
etes
-rel
ated
co-
mor
bidi
ty:
Nep
hrop
athy
: 17.
3%
I1: T
he w
ound
was
debr
ided
, cle
aned
with
3%
hydr
ogen
per
oxid
e so
lutio
nan
d dr
ied
with
a c
ompr
ess.
Suga
r was
then
pou
red
into
the
wou
nd c
avity
, tak
ing
care
to e
nsur
e th
at th
e de
epes
tpa
rts o
f the
wou
nd w
ere
fille
d. A
n oc
clusiv
e dr
essin
gan
d ba
ndag
e w
ere
appl
ied
and
chan
ged
daily
(n=
16)
I2: A
s abo
ve, w
ith th
ead
ditio
n of
syst
emic
antib
iotic
s. Th
e ch
oice
of
antib
iotic
was
det
erm
ined
thro
ugh
the
bact
erial
pro
file
of w
ound
sam
ples
and
was
mod
ified
as i
ndica
ted
byfu
rthe
r cul
ture
s (n
= 2
4)
I3: T
he w
ound
was
debr
ided
, cle
aned
with
3%
hydr
ogen
per
oxid
e so
lutio
nan
d dr
ied
with
a c
ompr
ess.
Syst
emic
antib
iotic
s wer
ead
min
ister
ed. A
n oc
clusiv
edr
essin
g an
d ba
ndag
e w
ere
appl
ied
(n=
40)
Stat
istica
l met
hods
:N
ot d
escr
ibed
Hea
ling
rate
(ove
rall)
:I1
: 49.
9%I2
: 45.
8%I1
and
I2 c
ombi
ned:
47.
5%I3
: 40.
0%ns M
ean
time
to h
ealin
g (o
vera
ll):
I1 &
I2: 6
wee
ksI3
: 9 w
eeks
ns Hea
ling
rate
acc
ordi
ng to
site
of
wou
nd:
Foot
:I1
and
I2 c
ombi
ned
30.7
%I3
: 36.
1%ns Si
tes o
ther
than
foot
:I1
and
I2 c
ombi
ned:
100
%I3
: 75%
p<
0.0
01
Ove
rall
heali
ng ra
te fo
rin
fect
ed/n
euro
path
ic/isc
haem
icle
sions
:66
%/3
8.7%
/37.
5%p
< 0
.001
Hea
ling
rate
for
infe
cted
/neu
ropa
thic/
ischa
emic
lesio
ns tr
eate
d w
ith su
gar (
grou
psI1
and
I2 c
ombi
ned)
:66
.6%
/38.
7%/3
1.5%
p<
0.0
01 fo
r inf
ecte
d ve
rsus
neur
opat
hic
wou
nds a
nd fo
rin
fect
ed v
ersu
s isc
haem
ic w
ound
s
Not
repo
rted
Ratio
nale
for u
se o
fsu
gar a
s an
antim
icrob
ial:
in th
eir d
iscus
sion,
the
auth
ors c
ite o
ther
stud
ies t
hat h
ave
used
suga
r as a
topi
cal
antim
icrob
ial a
gent
with
wou
nds,
and
they
also
desc
ribe
the
poss
ible
phys
iolo
gical
mec
hani
sms i
nvol
ved
The
auth
ors p
ropo
sed
that
bet
wee
n-gr
oup
diffe
renc
es m
ay n
ot h
ave
been
det
ecte
d fo
r foo
tw
ound
s bec
ause
of t
hedi
fficu
lty o
f app
lying
suga
r to
the
foot
and
beca
use
of li
kely
conc
urre
nt n
euro
logic
alan
d va
scul
ar c
o-m
orbi
ditie
s
Lim
itatio
ns o
f the
stud
yas
not
ed b
y th
ere
view
er: t
his i
s a w
eak
stud
y in
seve
ral
impo
rtan
t res
pect
s.Ba
selin
e da
ta a
re n
otre
port
ed p
er g
roup
,th
eref
ore
grou
pco
mpa
rabi
lity
cann
ot b
eas
sess
ed. T
here
are
no
base
line
data
on
wou
ndsiz
e or
seve
rity.
Som
ede
tails
of i
nter
vent
ions
are
lacki
ng (e
.g. t
he ty
peof
deb
ridem
ent u
sed,
and
the
type
of s
ugar
).U
neve
n nu
mbe
rs w
ere
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
183
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Diab
etic
retin
opat
hy: 5
3.3%
Prop
ortio
n of
pat
ient
s with
wou
nd o
n fo
ot/le
g/ot
her s
ite:
81.2
5%/5
.00%
/13.
75%
Prop
ortio
n of
pat
ient
s with
infe
cted
/neu
ropa
thic/
ischa
emic
wou
nds:
51.7
%/4
4.6%
/33.
00%
In p
atie
nts w
ith fo
ot w
ound
s,nu
mbe
r (%
) with
mal
perfo
rant
plan
tar l
esio
ns/is
chae
mic
lesio
ns/le
sions
invo
lving
bon
e:55
(68.
75%
)/25
(31.
25%
)/31
(38.
75%
)
Prop
ortio
n of
pat
ient
s with
wou
nds p
rece
ded
by tr
aum
a, n
otim
med
iatel
y no
ticed
due
tose
nsor
y ne
urop
athy
:82
%
Hea
ling
rate
acc
ordi
ng to
dur
atio
nof
diab
etes
:Le
ss th
an 1
0ye
ars:
54.4
%At
leas
t 10
year
s: 36
.6%
p<
0.0
5
Mea
n ±
SD(?)
tim
e to
hea
ling
acco
rdin
g to
dur
atio
n of
diab
etes
:Le
ss th
an 1
0ye
ars:
6.4
±2.
2 w
eeks
At le
ast 1
0ye
ars:
10.7
5 ±
3.1
wee
ksp
< 0
.05
Hea
ling
rate
acc
ordi
ng to
glyc
aem
icco
ntro
l:Bl
ood
suga
r <2
g/l:
48.5
0%Bl
ood
suga
r 2–2
.5g/
l: 31
.25
Bloo
d su
gar >
2.5
g/l:
25.0
0%p
< 0
.05
Hea
ling
rate
acc
ordi
ng to
socio
-ec
onom
ic le
vel:
Goo
d sc
ore
>6:
44.
4%M
oder
ate
3–6:
31.
2%Po
or <
3: 2
3.3%
p<
0.0
5
Mea
n ±
SD(?)
tim
e to
hea
ling
acco
rdin
g to
socio
-eco
nom
ic le
vel:
Goo
d sc
ore
>6:
6 ±
1.6
wee
ksM
oder
ate
3-6:
8.4
±2
wee
ksPo
or <
3: 1
0 ±
3w
eeks
p<
0.0
5
Cos
t of h
ospi
talis
atio
n, n
ot in
cludi
ngtr
eatm
ent (
over
all):
Aver
age
was
800
din
ars (
20 d
inar
spe
r day
)
Cos
t of t
reat
men
t (ov
erall
):Av
erag
e w
as 1
94 d
inar
s per
pat
ient
(sur
gical
proc
edur
es n
ot in
clude
d)
recr
uite
d to
the
stud
ygr
oups
and
this
was
not
expl
ained
in th
e m
etho
dsse
ctio
n. T
he st
udy
perio
d is
not c
lear
. The
mea
n ±
SD(?)
leng
th o
fho
spita
l sta
y w
asre
port
ed a
s 40
±13
days
; how
ever
, an
aver
age
leng
th o
f sta
y of
15–3
0 da
ys is
also
repo
rted
. Pat
ient
s wer
efo
llow
ed u
p fo
r up
to9
wee
ks b
ut it
is n
otst
ated
whe
ther
this
occu
rred
afte
r disc
harg
e,an
d if
so, w
hat
trea
tmen
t was
pro
vided
in th
e in
terim
per
iod.
The
stat
istica
l met
hods
used
are
not
des
crib
ed,
and
it is
not c
lear
whe
ther
the
repo
rted
varia
nces
are
stan
dard
devia
tion
or st
anda
rder
ror.
Hea
ling
rate
s are
repo
rted
, but
hea
ling
isno
t def
ined
. The
re a
refe
w d
etail
s abo
ut h
owou
tcom
es w
ere
asse
ssed
. It i
s not
cle
arin
eve
ry c
ase
exac
tlyw
hat c
ompa
rison
s the
repo
rted
p-v
alues
are
refe
rrin
g to
. Gro
ups 1
and
2 (th
ose
invo
lving
use
of su
gar)
are
som
etim
es c
ombi
ned
for
analy
sis b
ut th
is is
not
expl
ained
in th
e m
etho
ds
cont
inue
d
Appendix 4
184
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
The
auth
ors e
stim
ated
that
by
usin
gsu
gar,
the
aver
age
cost
per
pat
ient
coul
d be
redu
ced
to 2
1 di
nars
as
muc
h of
the
care
cou
ld b
e ca
rrie
dou
t by
the
patie
nt o
r his/
her f
amily
at h
ome.
The
met
hods
of e
stim
atio
nus
ed w
ere
not d
escr
ibed
sect
ion.
Man
y of
the
resu
lts a
re n
ot re
port
edpe
r tre
atm
ent g
roup
. In
thei
r con
clusio
n th
eau
thor
s sta
te th
at u
se o
fsu
gar d
oes n
ot p
rodu
cead
vers
e ef
fect
s, bu
t thi
sw
as n
ot a
sses
sed
durin
gth
e st
udy.
Stud
y sp
onso
rshi
p:N
ot st
ated
Health Technology Assessment 2006; Vol. 10: No. 12
185
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Seid
el (1
991)
,110
Ger
man
y
Stud
y de
sign:
CC
T
Met
hod
of a
lloca
tion:
Patie
nts c
hose
thei
r ow
nth
erap
y
Uni
t of a
lloca
tion:
Pa
tient
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
stat
ed
Out
com
e as
sess
men
t:C
linica
l sta
tus o
f ulce
r:(1
) pur
ulen
tm
embr
anes
/no
impr
ovem
ent –
scor
e 0
poin
ts; (
2) p
artia
lva
scul
ar g
ranu
latio
n –
scor
e 1
poin
t; (3
) ful
lva
scul
ar g
ranu
latio
n –
scor
e 2
poin
ts;
(4) d
imin
utio
n of
ulce
r –sc
ore
3 po
ints
; (5)
cur
e –
scor
e 4
poin
ts.
Plan
imet
ric m
easu
res
(pho
togr
aphi
c/X
-ray
).Ba
cter
ial a
nalys
is (n
oda
ta a
vaila
ble)
.Ps
ycho
logic
al ou
tcom
e(q
uest
ionn
aire:
pat
ient
opin
ion
of e
ffect
of
trea
tmen
t)
Setti
ng:
Inpa
tient
s
Leng
th o
f tre
atm
ent:
10da
ys
Popu
latio
n: m
alein
patie
nts w
ithD
NPU
All m
ale (n
= 4
0)
I1: n
= 2
0I2
: n=
20
Age:
45–
70ye
ars
Mea
n ag
e of
initi
al D
NPU
man
ifest
atio
n: 6
2 (±
5 ye
ars)
Type
of d
iabet
es:
Type
I: 8
/40
(20%
)Ty
pe II
a: 1
4/40
(35%
)Ty
pe II
b: 1
8/40
(45%
)
Bact
erio
logy
: N
o da
ta
Clin
ical s
tatu
s of u
lcer (
scor
e):
I1I2
Puru
lent
mem
bran
es9
10Pa
rtial
vas
cular
gran
ulat
ion
98
Full
vasc
ular
gran
ulat
ion
22
Patie
nts w
ith o
steo
mye
litis:
I1: 5
/20
(25%
)I2
: 7/2
0 (3
5%)
I1: (
n=
20)
Pat
ient
s rec
eive
d a
perfu
sion
(onc
e da
ily) o
f RVP
(com
prisi
ng 1
20m
gge
ntam
icin,
50
mg
buflo
med
il,4
mg
dexa
met
haso
ne, 4
mg
ligno
cain
e an
d 25
00IU
of
hepa
rin d
issol
ved
in 1
20m
lsa
line
solu
tion)
. Afte
r ase
ptic
punc
ture
of a
foot
vei
n, th
e le
gis
drain
ed b
y hi
gh e
leva
tion
for
2m
inut
es a
nd th
en m
id/u
pper
leg
com
pres
sed
at 3
0m
m/H
gab
ove
the
syst
olic
arte
rial
pres
sure
. The
‘coc
ktail
’ is t
hen
inje
cted
as a
bol
us. A
dditi
onal
even
ing
med
icatio
n of
60
mg
gent
amici
n i.m
. and
one
reta
rdta
blet
of b
uflo
med
il. F
orre
ason
s of c
ompa
rabi
lity
anad
ditio
nal i
nfus
ion
ther
apy
with
3 ×
4g
pipe
racil
line
also
given
I2: (
n=
20)
Tre
ated
conv
entio
nally
with
3 ×
4g
pipe
racil
lin, 3
×60
mg
gent
amici
n, 3
x 5
0m
gbu
flom
edil,
3 ×
500
ml d
extr
an40
and
3 ×
5000
IU h
epar
inda
ily
Both
gro
ups r
ecei
ved
sam
ere
gimen
of l
ocal
antib
acte
rial
ther
apy
Ulce
r hea
led:
I1: 6
/20
(30%
)I2
: 0/
20 (0
%)
Ulce
r dim
inish
ed in
size
:I1
: 10/
20 (5
0%)
I2:
3/20
(15
%)
% D
imin
utio
n of
ulce
rous
pain
(not
cle
ar w
heth
er th
is is
pain
or
area
?):I1
: 55%
±8
I2:
7.5%
±3.
6
Deb
ridem
ent o
f exu
dativ
ede
tritu
s:I1
: 93%
±3
I2: 4
2% ±
8
Redu
ctio
n in
infe
ctio
us u
lcer
cove
r:I1
: 86%
±3.
7I2
: 38%
±8
Hos
pita
lisat
ion
(ave
rage
day
s):
I1: 1
2 ±
2I2
: 19
±3
Ampu
tatio
n:I1
: 0/2
0 (0
%)
I2: 4
/20
(20%
) (du
e to
unde
rlyin
g os
teom
yelit
is)
Cur
e of
ost
eom
yelit
is (%
):I1
: 4/5
(80%
)I2
: 0/7
(0%
)
HbA
1c (%
):I1
: 8.1
±1.
0I2
: 8.9
±1.
0
Que
stio
nnair
e re
sults
:
Dist
inct
diff
eren
ce b
etw
een
grou
ps w
ith I1
gro
up sh
owin
g
Not
stat
edLi
mita
tions
of t
he st
udy:
Patie
nts c
hose
thei
r ow
nth
erap
y
10%
mor
e ca
ses o
fos
teom
yelit
is in
I2 g
roup
at b
asel
ine?
No
dem
ogra
phic
com
para
bilit
y of
gro
ups
repo
rted
, e.g
. age
data
/type
of d
iabet
es,
area
of u
lcera
tion
Auth
ors s
ay th
eim
prov
emen
t in
patie
ntkn
owle
dge
was
bec
ause
the
30-m
inut
e tr
eatm
ent
time
allow
ed p
atie
nt to
ask
doct
or q
uest
ions
,pa
tient
train
ing
coul
d be
deliv
ered
cont
inue
d
Appendix 4
186
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
grea
ter p
erce
ptio
n of
phys
ical/e
mot
iona
l im
prov
emen
t.C
ompl
iance
and
indi
vidua
lkn
owle
dge
abou
t the
dise
ase
also
high
er in
this
grou
p
Bact
erial
pro
file:
no
resu
lts g
iven
Adve
rse
even
ts (R
VP):
Pete
chiae
: 6/2
0 (3
0%)
Pain
(fro
m a
rter
ial o
cclu
sion)
:5/
20 (2
5%)
Hae
mor
rhag
e: 4
/20
(20%
)St
asis
derm
atiti
s: 3/
20 (1
5%)
Nau
sea:
2/2
0 (8
%)
Reve
rsib
le N
VIII
affe
ctio
n: 1
(5%
)(te
mpo
rary
dec
reas
e in
hea
ring
capa
city)
Health Technology Assessment 2006; Vol. 10: No. 12
187
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Seid
el (1
993,
1994
),111,
112
Ger
man
y(G
erm
an tr
ansla
tion
ofpa
per)
Stud
y de
sign:
CC
T
Met
hod
ofra
ndom
isatio
n:
Patie
nts c
hose
thei
r ow
nth
erap
y
Uni
t of a
lloca
tion:
Pa
tient
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
stat
ed
Out
com
e as
sess
men
t:(a
s Sei
del e
t al.,
1991
110 )
Setti
ng a
nd le
ngth
of
trea
tmen
t (in
patie
nts a
sSe
idel
et a
l.,19
9111
0 ).Tr
eatm
ent o
ver 1
0da
ys.
Dat
e of
recr
uitm
ent:
Dec
embe
r 198
9
Popu
latio
n:m
ale in
patie
nts w
ithD
NPU
Male
s: 45
Age:
35–
70 y
ears
Mea
n ±
SDag
e (y
ears
): 60
±4
Type
of d
iabet
es:
Type
I:8
(17%
)Ty
pe II
a:14
(35%
)Ty
pe II
b:23
(48%
)
Clin
ical s
tatu
s of u
lcer: I1
I2Pu
s10
9Pa
rtial
119
Full
33
I1: (
n=
24)
RVP
net
ilmyc
in
Patie
nts g
iven
(10
a.m
.) 20
0m
gne
tilm
ycin
; 50
mg
bufe
dil;
200
IU h
epar
in; 4
mg
dexa
met
haso
ne; 2
mg
lidoc
aine
(all
in 1
00m
l 0.9
% sa
line)
. At
6p.
m.:
100
mg
netil
myc
in(i.
m.);
600
mg
bufe
dil r
etar
d(o
ral);
4g
pipe
racil
lin tw
ice a
day
(i.v.)
I2: (
n=
21)
SVI
– n
etilm
ycin
Patie
nts g
iven
(at 9
a.m
.,3
p.m
., 9
p.m
.) 10
0m
gne
tilm
ycin
; 50
mg
bufe
dil;
2500
I.U. h
epar
in a
ll in
rheo
mac
rode
x. A
t 9 a
.m. –
4m
g D
exam
etha
sone
. 4 g
pipe
racil
lin tw
ice a
day
(i.v.
).
Con
curr
ent t
reat
men
t i.v.
:C
lean
sed
with
hyd
roge
npe
roxi
de, p
ovid
one
iodi
ne p
ad,
ster
ile b
anda
ge. D
ieta
ry a
ndm
edica
l tre
atm
ents
for
diab
etes
I1I2
Ulce
r hea
led:
8 (3
3%)
3 (1
4%)
At le
ast 3
0%
10 (4
2%)
4 (1
9%)
redu
ctio
n in
are
aRe
duct
ion
in
93 ±
642
±8
puru
lent
are
aAm
puta
tion
3 (1
3%)
4 (1
9%)
Appendix 4
188
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Tan
(199
3),10
8U
SA
Stud
y de
sign:
RC
T (d
oubl
e-bl
ind)
Met
hod
of ra
ndom
isatio
n:
Com
pute
r-ge
nera
ted
sche
dule
. 3:2
ratio
I1:I2
to a
llow
larg
er sa
fety
data
base
for r
egist
ratio
nof
I1 d
rug
Uni
t of a
lloca
tion:
Pa
tient
Calc
ulat
ion
of st
atist
ical
pow
er: E
stim
ated
appr
oxim
atel
y 50
% o
fra
ndom
ised
patie
nts
(sam
ple
size
I1 n
= 1
50an
d I2
n=
100
) wou
ldbe
eva
luab
le fo
r prim
ary
analy
ses.
Proj
ecte
dev
aluab
le p
atie
nts
prov
ided
a p
ower
of
70%
for o
bser
ved
trea
tmen
t diff
eren
ce(s
ignifi
canc
e: �
= 0
.05,
two-
taile
d) if
the
true
trea
tmen
t diff
eren
ce in
unde
rlyin
g po
pulat
ion
not
mor
e th
an 2
0%. A
llpa
tient
s qua
lifie
d fo
rin
tent
ion
to tr
eat
analy
sis. P
roje
cted
num
bers
pro
vided
pow
erof
82%
for o
bser
ved
trea
tmen
t diff
eren
ce(s
ignifi
canc
e, �
= 0
.05,
two
taile
d) if
true
trea
tmen
t diff
eren
ce w
asno
mor
e th
an 1
5%
Popu
latio
n:
251
hosp
italis
edpa
tient
s with
com
plica
ted
skin
/skin
stru
ctur
ein
fect
ions
(a
ge 1
6+ y
ears
)
Inclu
sion
crite
ria:
Puru
lent
dra
inag
e or
colle
ctio
n pl
us a
tle
ast 3
of t
hefo
llow
ing:
tem
pera
ture
>38
°C, p
erip
hera
lle
ukoc
yte
coun
t>
10,0
00/m
m3
(with
>5%
imm
atur
ene
utro
phils
), lo
cal
eryt
hem
a, lo
cal
swel
ling,
tend
erne
ss, p
ain, o
rflu
ctua
nce.
Sev
erity
asse
ssed
by
inve
stiga
tor a
s mild
,m
oder
ate
or se
vere
at b
asel
ine
Exclu
sion
crite
ria:
Know
n or
susp
ecte
dhy
pers
ensit
ivity
tobe
ta-la
ctam
antib
iotic
s or
�-la
ctam
ase
inhi
bito
rs; m
oder
ate
to se
vere
rena
ldy
sfunc
tion;
evid
ence
of a
ctive
liver
dise
ase;
perip
hera
lgr
anul
ocyt
e co
unts
Tota
l no.
of p
artic
ipan
ts:
I1: (
all) 1
53, (
evalu
able
) 67
I2: (
all) 9
8, (e
valu
able
) 44
Male
/fem
ale (n
umbe
rs):
I1: (
all) 1
15/3
8, (e
valu
able
) 53/
14I2
: (all
) 69/
29, (
evalu
able
) 32/
12
Ethn
icity
(num
bers
): All
Evalu
able
I1:
Cau
casia
n11
143
Blac
k29
12O
ther
race
1312
I2:
Cau
casia
n69
29Bl
ack
208
Oth
er ra
ce9
7
Age:
mea
n ±
SD(y
ears
):I1
: (all
) 53,
(eva
luab
le) 5
3I2
: (all
) 52,
(eva
luab
le) 5
5
Num
ber/%
with
diab
etic
foot
ulce
rs (c
lasse
d as
‘wou
ndin
fect
ion’
by
auth
or):
I1: (
all) 3
1 (2
0), (
evalu
able
) 16
(24)
I2: (
all) 1
8 (1
8), (
evalu
able
) 7 (1
6)
Prio
r/cur
rent
use
of a
ntim
icrob
ialag
ents
: see
Exc
lusio
n cr
iteria
I1: (
n =
153
) Pat
ient
s dos
edev
ery
6 ho
urs w
ithpi
pera
cillin
–taz
obac
tam
, 3 g
and
375
mg,
resp
ectiv
ely
for a
min
imum
of 5
days
and
for a
tle
ast 4
8ho
urs a
fter t
here
solu
tion
of si
gns a
ndsy
mpt
oms.
I2: (
n =
98)
Pat
ient
s dos
edev
ery
6ho
urs w
ithtic
arcil
lin–c
lavul
anat
e, 3
g an
d10
0m
g, re
spec
tivel
y, fo
r am
inim
um o
f 5 fu
ll da
ys a
nd fo
rat
leas
t 48
hour
s afte
r the
reso
lutio
n of
sign
s and
sym
ptom
s
Surg
ical d
ebrid
emen
t or
drain
age
allow
ed a
nd a
ccep
ted
as p
art o
f pat
ient
man
agem
ent.
Nee
d fo
r sur
gery
or o
ther
adju
nctiv
e th
erap
y w
asde
term
ined
by
the
inve
stiga
tor
and
the
colla
bora
ting
surg
eon
Stat
istica
l met
hods
: num
bers
(%);
Wilc
oxon
, �2
test
s.[s
ignifi
canc
e te
stin
g –
�(tw
o-ta
iled)
= 0
.05]
Mea
n du
ratio
n of
trea
tmen
t(d
ays)
I1: (
all) 8
.2, (
evalu
able
) 10.
2I2
: (all
) 9.1
, (ev
aluab
le) 1
0.5
Evalu
able
pat
ient
s divi
ded
bydi
agno
sis:
1st:
Cel
lulit
is2n
d: C
utan
eous
abs
cess
3rd:
Diab
etic
or is
chae
mic
foot
infe
ctio
n4t
h: in
fect
ed w
ound
s and
ulce
rs–
inclu
des p
ress
ure
ulce
rs o
n th
efo
ot.
Clin
ical r
espo
nse
(no.
gro
up a
nd%
gro
up) f
or w
ound
or u
lcer
infe
ctio
n [th
ese
wer
e ev
aluab
lepa
tient
s with
diab
etic
foot
ulce
rs,
as c
onfir
med
by
auth
or]:
I1:
Cur
ed9/
16 (5
6)Im
prov
ed1/
16 (6
)Fa
vour
able
10/1
6 (6
3)
I2:
Cur
ed6/
7 (8
6)Im
prov
ed1/
7 (1
4)Fa
vour
able
7/7
(100
)
(p =
0.1
7)
Clin
ical f
ailur
es (w
ound
/ulce
rpa
tient
s):
I1: 2
(sw
itche
d to
ano
ther
antib
iotic
)
Clin
ical f
ailur
es:
I1: 5
I2: 4
3 pa
tient
s in
each
trea
tmen
tar
m d
ue to
ampu
tatio
n of
infe
cted
lim
b. 2
patie
nts i
n I1
and
1 in
I2 sw
itche
dto
ano
ther
antib
iotic
Que
ry w
heth
er th
ose
with
wou
nd in
fect
ion
(aut
hors
say
thes
e w
ere
foot
ulce
r pat
ient
s) w
ere
also
diab
etic?
Shar
p re
duct
ion
innu
mbe
rs a
vaila
ble
for
final
evalu
atio
n
Evalu
abilit
y cr
iteria
:
Failu
re to
mee
t crit
eria
for d
iagno
sis; n
o ba
selin
epa
thog
en, i
nade
quat
ecli
nica
l fol
low
-up;
pre
-st
udy
antib
iotic
;co
ncom
itant
infe
ctio
n;re
sista
nt p
atho
gen
atba
selin
e; o
ther
(inco
rrec
t diag
nosis
,in
adeq
uate
dru
gsu
scep
tibilit
y da
ta,
inad
equa
teba
cter
iolo
gical
follo
w-u
p,in
adeq
uate
trea
tmen
tre
gimen
)
Stud
y sp
onso
rshi
p:In
fect
ions
Lim
ited?
Mul
ti-ce
ntre
(20
sites
)
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
189
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Out
com
e as
sess
men
t:C
linica
l:(1
) Cur
ed: r
ecov
ery
from
infe
ctio
n;
(2) i
mpr
oved
– sh
owed
impr
ovem
ent i
n at
leas
t3
of th
e fo
llow
ing
para
met
ers c
ompa
red
with
valu
es o
btain
ed a
tpr
e-en
rolm
ent
evalu
atio
n: q
uant
ity o
fdr
ainag
e, e
ryth
ema,
seve
rity
of sw
ellin
g,te
nder
ness
, pain
,flu
ctua
nce,
lym
phan
gitis,
rigor
s, te
mpe
ratu
re,
perip
hera
l leu
cocy
teco
unt;
(and
no
new
antim
icrob
ial th
erap
yne
cess
ary)
(1) a
nd (2
) C
lasse
d as
favo
urab
lecli
nica
l res
pons
e.
(3)
Unf
avou
rabl
e: re
lapse
from
initi
al im
prov
emen
tan
d w
orse
ning
of
para
met
ers a
bove
, or
failu
re, r
equi
ring
chan
gein
ant
imicr
obial
ther
apy.
They
use
d 2
sets
of
outc
ome
crite
ria –
regis
trat
ion
crite
ria (u
sed
for d
rug
regis
trat
ion
purp
oses
) and
revis
edou
tcom
e de
term
inat
ions
Clin
ical f
ailur
es: c
riter
ia(1
) am
puta
tion
atin
fect
ion
site,
eve
n if
of <
1000
/mm
3or
plat
elet
cou
nts o
f<
50,0
00/m
m3 ;
rece
ipt o
f mor
eth
an 2
dos
es o
fan
othe
r ant
ibac
teria
lag
ent w
ithin
72ho
urs p
rior t
oen
rolm
ent;
rece
ipt
of a
noth
erin
vest
igatio
nal d
rug
with
in 1
mon
thpr
ior t
o en
rolm
ent;
activ
e or
trea
ted
leuk
aem
ia; A
IDS;
need
for
haem
odial
ysis,
perit
onea
l dial
ysis,
plas
map
here
sis o
rhe
mop
erfu
sion,
oste
omye
litis
cont
iguou
s with
ask
in/sk
in st
ruct
ure
infe
ctio
n; p
oten
tial
requ
irem
ent f
oram
puta
tion
ofin
fect
ed a
rea;
pres
sure
ulce
rin
fect
ions
of
>2
wee
ks d
urat
ion;
conc
omita
ntin
fect
ion
othe
r tha
nsk
in/sk
in st
ruct
ure
infe
ctio
n
Endp
oint
era
dica
tion
of b
acte
rial
path
ogen
s (iso
lated
from
the
infe
cted
site
in e
valu
able
pat
ient
s):
Tota
l no.
of i
solat
eser
adica
ted/
no. o
f iso
lates
reco
vere
d (%
)I1
I2To
tal1
03/1
35 (7
6)82
/99
(82.
8)
Adve
rse
even
ts (a
ll pa
tient
sex
perie
ncin
g at
leas
t one
adv
erse
even
t):
I1: 6
5 (4
2%)
I2: 4
1 (4
2%)
Of w
hich
:I1
: 11%
gas
troi
ntes
tinal
trac
t6.
5% d
iarrh
oea
I2: 1
1% g
astr
oint
estin
al tr
act
4.1%
diar
rhoe
a
(ns)
bet
wee
n gr
oups
cont
inue
d
Appendix 4
190
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
non-
infe
ctio
n-re
lated
of
impr
ovem
ents
obs
erve
d,or
(2) p
atie
nt sw
itche
dto
ora
l ant
ibio
tics e
ven
ifth
ey h
ad li
ttle
or n
oin
fect
ion
at th
at ti
me,
esta
blish
ed to
ass
ess
effic
acie
s of d
rugs
for
regis
trat
ion
purp
oses
Bact
erio
logic
alou
tcom
es: O
rgan
isms
isolat
ed fr
om e
valu
able
patie
nts a
nd fr
eque
ncy
with
whi
ch th
ey w
ere
erad
icate
d. E
radi
catio
n:ba
selin
e pa
thog
ens
erad
icate
d. E
radi
catio
npr
esum
ed: i
mpr
ovem
ent
but n
o m
ater
ial a
vaila
ble
for a
nalys
is. P
ersis
tenc
e:at
leas
t one
pat
hoge
nfro
m in
itial
sam
ple
still
pres
ent a
t fol
low
up.
Pers
isten
ce p
resu
med
:un
favo
urab
le re
spon
sebu
t no
mat
erial
ava
ilabl
efo
r ana
lysis
Setti
ng a
nd le
ngth
of
trea
tmen
t: M
ulti-
cent
re (2
0)ho
spita
l set
ting.
Min
imum
5da
ytr
eatm
ent p
lus a
t lea
st48
hour
s afte
r res
olut
ion
of si
gns a
nd sy
mpt
oms.
Early
follo
w-u
p:
24–7
2 ho
urs a
fter
ther
apy
com
plet
ion.
Lat
efo
llow
-up:
10–
14 d
ays
afte
r the
rapy
com
plet
ion
Health Technology Assessment 2006; Vol. 10: No. 12
191
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Vand
eput
te (1
996)
125
Belgi
um
Stud
y de
sign:
RC
T
Met
hod
ofra
ndom
isatio
n:
Pre-
prep
ared
rand
omise
d lis
ting
Uni
t of a
lloca
tion:
Patie
nt
Calc
ulat
ion
of st
atist
ical
pow
er:
Not
stat
ed
Out
com
e as
sess
men
t: W
ound
hea
ling
time
(by
phot
ogra
phic
mea
sure
ever
y 4
wee
ks);
pres
sure
relie
f, m
obilit
y, dr
essin
gdu
rabi
lity,
infe
ctio
ndu
ring
trial
, call
usfo
rmat
ion,
nee
d fo
rsy
stem
ic lo
cal a
ntib
iotic
sor
ant
isept
ic cr
eam
s,am
puta
tion.
Pat
ient
inte
rvie
wed
dur
ing
trial
abou
t com
fort
and
pain
Setti
ng:
Not
stat
ed
Leng
th o
f tre
atm
ent:
3m
onth
s
Writ
ten
cons
ent
Inclu
sion
crite
ria:
29 d
iabet
ic pa
tient
sw
ith fo
ot u
lcers
(neu
ropa
thic
or n
ot)
Exclu
sion
crite
ria:
Patie
nts t
akin
gsy
stem
ic an
tibio
tics
Num
bers
in st
udy:
I1: 1
5I2
: 14
Male
/fem
ale:
I1: 7
/8I2
: 6/8
Mea
n ±
SDag
e (y
ears
):I1
: 62.
6 (1
4.7)
I2: 6
5.3
(14.
3)
Com
plet
ely
mob
ile:
I1:
12/1
5 (8
0%)
I2: 1
1/14
(79%
)
Trea
ted
with
ora
l ant
idiab
etic
med
icatio
n/in
sulin
dep
ende
nt:
All p
atie
nts r
ecei
ved
optim
alin
sulin
trea
tmen
t and
die
tre
gulat
ion
(acc
ordi
ng to
inte
rnat
iona
l rec
ogni
sed
diab
etic
regu
latio
n pr
otoc
ols)
Evid
ence
of n
euro
path
y:
I1: 9
/15
(60%
)I2
: 9/1
4 (6
4%)
Infe
ctio
n pr
esen
t bef
ore
trial
:I1
: 1/1
5 (7
%)
I2: 1
/14
(7%
)
I1: P
atie
nts (
n=
15)
trea
ted
with
hyd
roge
ldr
essin
g an
d de
rmal
wou
nd c
lean
ser (
Flam
i-C
lens
= sa
line
wat
er +
0.8%
vin
egar
acid
as
buffe
r). (
From
pre
vious
data
ext
ract
ion:
wou
ndca
vitie
s wer
e fil
led
with
an a
lgina
te d
ress
ing)
I2: P
atie
nts (
n=
14)
trea
ted
with
a d
ry g
auze
(twice
a d
ay) a
ndirr
igate
d w
ithch
lorh
exid
ine
(0.0
5%so
lutio
n).
[Fro
m p
revio
us d
ata
extr
actio
n: a
ll pa
tient
sre
ceive
d sy
stem
ic or
topi
cal a
ntib
iotic
s or
topi
cal a
ntise
ptic
crea
ms.
6 pa
tient
sre
ceive
d sy
stem
ican
tibio
tics.
The
mos
tfre
quen
tly u
sed
topi
cal
prep
arat
ion
was
povid
one-
iodi
ne c
ream
]
Mor
talit
y:
I2: 2
pat
ient
s die
d du
ring
trial
Ampu
tatio
n (o
ne o
r mor
e to
es):
I1: 1
/15
(7%
)I2
: 5/1
4 (3
6%)
(p<
0.0
53)
Patie
nt c
ould
walk
with
dre
ssin
g on
:I1
: 12/
15 (8
0%)
I2: 9
/14
(64%
)(p
< 0
.01)
Aver
age
time
dres
sing
stay
ed o
n w
ound
:I1
5 d
ays
I2: 1
day
(p<
0.0
01)
Infe
ctio
n du
ring
trial
:I1
: 1/
15 (7
%)
I2: 7
/14
(50%
)(p
< 0
.01)
Form
atio
n of
call
us:
I1 7
/15
(47%
)I2
: 14/
14 (1
00%
)(p
< 0
.05)
Nee
d fo
r sys
tem
ic/lo
cal a
ntib
iotic
s or
loca
l ant
isept
ic cr
eam
s:I1
: 1/
15 (7
%)
I2:
14/1
4 (1
00%
)(p
< 0
.000
1)
Com
plet
e he
aling
at 3
mon
ths:
I1: 1
4/15
(93%
)I2
: 5/1
4 (3
6%)
(p<
0.0
5)
Impr
oved
sligh
tly:
I1: 0
/15
(0%
)I2
: 1/1
4 (7
%)
(p<
0.0
5)
Not
impr
oved
:I1
: 1/1
5 (7
%)
I2: 4
/14
(29%
)(p
< 0
.05)
2 pa
tient
s die
d(I2
gro
up) d
urin
gtr
ial
Rele
vanc
e to
DAS
IDU
are
findi
ngs f
or c
ontr
olgr
oup
(chl
orhe
xidi
ne).
Com
pare
d w
ith u
se o
fhy
drog
el, c
ontr
ol g
roup
requ
ired
addi
tiona
l loc
alan
tibio
tics/a
ntise
ptics
,ha
d hi
gher
incid
ence
of
ampu
tatio
ns, a
nd g
reat
erhe
aling
tim
e re
quire
d.Po
ssib
ly/pr
obab
ly no
tin
tent
ion-
to-tr
eat
analy
sis a
s the
y ex
clude
dth
e pa
tient
who
die
dfro
m th
e an
alysis
Appendix 4
192
Stud
y an
d de
sign
Part
icip
ants
Bas
elin
e ch
arac
teri
stic
sIn
terv
entio
n de
tails
Resu
ltsW
ithdr
awal
sC
omm
ents
Yone
m (2
001)
,120
Turk
ey
Stud
y de
sign:
RC
T
Met
hod
ofra
ndom
isatio
n:
Not
spec
ified
Uni
t of a
lloca
tion:
pat
ient
Calc
ulat
ion
of st
atist
ical
pow
er: N
ot sp
ecifi
ed
Out
com
e as
sess
men
t:Pr
imar
y: ti
me
tore
solu
tion
of in
fect
ion,
time
to h
ospi
tal
disc
harg
eSe
cond
ary:
nee
d fo
rsu
rgica
l int
erve
ntio
n,ef
fect
s of G
-CSF
on n
eutr
ophi
l fun
ctio
n
Setti
ng a
nd le
ngth
of
trea
tmen
t: N
ot sp
ecifi
ed/n
ot c
lear
Inclu
sion
crite
ria:
30 d
iabet
ic pa
tient
sw
ith p
edal
cellu
litis
or W
agne
r’scla
ssifi
catio
n gr
ade
2or
less
foot
lesio
n
Exclu
sion
crite
ria:
Pres
ence
of
haem
atol
ogica
ldi
seas
e, h
istor
y or
prev
ious
or c
urre
ntm
align
ancy
, ren
al or
hepa
tic fa
ilure
,pr
egna
nt o
rlac
tatin
g, se
vere
leg
ischa
emia,
dee
p or
seve
re in
fect
ions
,re
ceivi
ngim
mun
osup
pres
sive
ther
apy.
Abso
lute
neut
roph
il co
unt
<1.
5 ×
10 (9
)/l o
r>
20 ×
10 (9
)/l
Male
/fem
ale:
I1: 9
/6I2
: 8/7
Mea
n ±
SDag
e (y
ears
):I1
: 61
±1.
4I2
: 60.
3 ±
1.3
Mea
n ±
SDdu
ratio
n of
diab
etes
(yea
rs):
I1: 1
2.7
±0.
9I2
: 13.
5 ±
1.2
Neu
trop
hil c
ount
/mm
3 :I1
: 570
0 ±
600
I2: 5
200
±50
0
Phag
ocyt
osis
test
(%):
I1: 6
8.1
±2.
2I2
: 70.
4 ±
2.0
Resp
irato
ry b
urst
(mV)
:I1
: 2.0
±0.
4I2
: 1.6
±0.
3
No
signi
fican
t diff
eren
ces
repo
rted
bet
wee
n gr
oups
on
abov
e cr
iteria
Cul
ture
s for
aer
obes
and
anae
robe
s tak
en fr
om th
eul
cers
with
an
appr
opria
tete
chni
que.
The
n:
I1: 1
5 pa
tient
s in
the
‘stan
dard
gro
up’ r
ecei
ved
class
ical t
reat
men
tco
mpr
ising
a c
ombi
natio
n of
loca
l wou
nd c
are
and
antib
ioth
erap
y (in
trav
enou
scip
roflo
xacin
and
met
roni
dazo
le)
I2: 1
5 pa
tient
s in
the
‘G-C
SFgr
oup’
rece
ived
the
abov
ecla
ssica
l tre
atm
ent,
plus
reco
mbi
nant
hum
an G
-CSF
[Filg
rast
im (N
eupo
gen)
]. G
-CSF
(5�
g/kg
) adm
inist
ered
subc
utan
eous
ly on
ce d
aily.
Ifth
e ab
solu
te n
eutr
ophi
lco
unt w
as >
30 ×
10 (9
)/laf
ter 3
con
secu
tive
dose
s,th
e do
se w
as c
hang
ed to
2.5
µg/k
g da
ily o
n alt
erna
teda
ys. I
f tot
al w
hite
blo
odce
ll co
unt w
as
>70
×10
(9)/l
or t
heab
solu
te n
eutr
ophi
l cou
ntw
as >
45 ×
10 (9
)/l, G
-CSF
trea
tmen
t was
stop
ped
All p
atie
nts p
laced
on
daily
mul
tiple
-dos
e in
ject
ion
ofsh
ort-a
ctin
g in
sulin
Stat
istica
l met
hods
:M
ann–
Whi
tney
U-te
st, W
ilcox
onm
atch
ed p
airs,
signe
d ra
nks a
nd �
2
test
s. Sp
earm
an c
orre
latio
n an
alyse
s.M
eans
±SD
. Sign
ifica
nce
betw
een
stud
y gr
oups
Tim
e to
reso
lutio
n of
infe
ctio
n (d
ays)
:I1
: 22.
3 ±
1.7
I2: 2
3.6
±1.
8ns D
urat
ion
of h
ospi
talis
atio
n (d
ays)
I1: 2
8.3
±2.
2I2
: 26.
9 ±
2.0
ns Nee
d fo
r sur
gical
inte
rven
tion
(am
puta
tion)
:I1
: 3 (2
0%)
I2: 2
(13.
3%)
ns Effe
ct o
n ne
utro
phils
(pos
t-tr
eatm
ent):
Neu
trop
hil c
ount
(mea
n ±
SD):
I1: 4
800
±30
0/m
m3
I2: 4
8700
±10
00/m
m3
p<
0.0
01
Phag
ocyt
osis
test
(%):
I1: 6
9.4
±1.
9I2
: 74.
5 ±
1.9
ns Resp
irato
ry b
urst
(mV)
:I1
: 2.3
±0.
4I2
: 2.3
±0.
5ns D
urat
ion
of p
aren
tera
l A/B
:
I1: 2
3.3
±1.
9I2
: 22.
9 ±
2.0
Adve
rse
even
ts: n
one
Not
stat
edAu
thor
s dra
w a
ttent
ion
to v
ery
limite
def
fect
ivene
ss o
f G-C
SF in
the
trea
tmen
t of d
iabet
icfo
ot in
fect
ion.
How
ever
,st
udy
lacks
pow
er
Writ
ten
info
rmed
cons
ent.
Loca
l eth
icsap
prov
al ob
tain
ed
High
whi
te b
lood
cel
lco
unts
may
pre
disp
ose
to c
oron
ary/
cere
brov
ascu
lar e
vent
s
Health Technology Assessment 2006; Vol. 10: No. 12
193
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Cos
t-ef
fect
iven
ess
data
ext
ract
ion
tabl
es
Stud
y id
entif
ier
and
Key
ele
men
ts o
f C
linic
al e
ffect
iven
ess
data
Econ
omic
ana
lysis
Resu
ltsC
omm
ents
obje
ctiv
eth
e st
udy
Apel
qvist
(199
6),12
2,12
6
Swed
en
Stud
y ob
ject
ive:
To c
ompa
re th
e cli
nica
lef
fect
and
eco
nom
ic co
stof
cad
exom
er io
dine
with
that
of s
tand
ard
trea
tmen
t in
diab
etic
patie
nts w
ith c
avity
foot
ulce
rs
Type
of e
cono
mic
evalu
atio
n:C
EASi
nce
no d
iffer
ence
sin
clin
ical r
esul
tsw
ere
obse
rved
, aco
st-m
inim
isatio
nan
alysis
was
perfo
rmed
Pers
pect
ive:
Hea
lth se
rvice
Setti
ng:
Lund
, Sw
eden
Dat
es to
whi
ch d
ata
relat
e:Th
e da
tes t
o w
hich
the
effe
ctive
ness
analy
sis a
ndre
sour
ce u
se d
ata
refe
rred
wer
e no
tre
port
ed. P
rice
year
was
199
3
Cur
renc
y: S
wed
ishKr
oner
(SEK
). A
conv
ersio
n to
UK
poun
ds w
aspe
rform
ed u
sing
a19
93 e
xcha
nge
rate
of £
1= S
EK12
.10.
A co
nver
sion
to U
Sdo
llars
was
perfo
rmed
usin
g a
1993
exc
hang
e ra
teof
US$
1= S
EK8.
10
Sour
ce:
Sing
le R
CT
Det
ails o
f par
ticip
ants
,in
terv
entio
ns, o
utco
mes
and
resu
lts o
f the
clin
ical t
rial a
resu
mm
arise
d ab
ove
(clin
ical
effe
ctive
ness
tabl
e)
Link
bet
wee
n cli
nica
l effe
ctive
ness
and
cost
dat
a:Th
e da
ta fo
r the
eco
nom
icev
aluat
ion
wer
e co
llect
ed d
urin
gth
e cli
nica
l tria
l
35 p
atie
nts w
ere
inclu
ded
in th
eec
onom
ic an
alysis
Mea
sure
of h
ealth
ben
efits
use
d:N
o su
mm
ary
bene
fit m
easu
re w
asus
ed, a
nd o
nly
sepa
rate
clin
ical
outc
omes
wer
e re
port
ed
Reso
urce
use
:Fr
eque
ncy
of d
ress
ing
chan
ges,
drug
pres
crip
tion,
mat
erial
con
sum
ptio
nan
d tim
e in
volve
d w
ere
reco
rded
.Ty
pe o
f dre
ssin
gs/d
rugs
, per
son
who
chan
ged
dres
sings
, tim
e in
volve
d, a
ndlo
catio
n of
dre
ssin
g ch
ange
wer
edo
cum
ente
d
Des
crip
tion
of c
osts
:D
irect
cos
ts w
ere
estim
ated
for
dres
sing
mat
erial
s, dr
ugs,
staf
f and
tran
spor
t. Th
e au
thor
s sta
ted
that
,sin
ce m
ost p
atie
nts i
n th
e st
udy
wer
eab
ove
wor
king
age
, no
indi
rect
cos
tsfo
r los
t pro
duct
ion
wer
e es
timat
ed.
Cos
ts a
nd q
uant
ities
wer
e re
port
edse
para
tely.
The
ope
ratin
g co
sts
(mat
erial
s and
dru
gs, s
taff
and
tran
spor
t) an
d co
st o
f com
plica
tions
wer
e m
easu
red.
The
est
imat
ion
ofqu
antit
ies a
nd u
nit c
osts
was
bas
ed o
nac
tual
data
apa
rt fr
om th
ose
for
tran
spor
t. Th
e av
erag
e va
lues
for
tran
spor
t for
the
patie
nt to
visi
t an
outp
atie
nt c
are
unit
or fo
r the
staf
f to
visit
the
patie
nt a
t hom
e w
ere
estim
ated
in te
rms o
f dist
ance
/pric
e at
10 k
m/S
EK24
.50.
If th
e pa
tient
or a
relat
ive li
ving
in th
e sa
me
hous
ehol
dpe
rform
ed th
e dr
essin
g ch
ange
, no
Estim
ated
hea
lth b
enef
its u
sed
in th
eec
onom
ic an
alysis
:N
ot a
pplic
able
Reso
urce
use
:M
ean
(ran
ge) d
ress
ing
chan
ges p
er w
eek,
and
adhe
renc
e:C
: 9.9
(3.1
–13.
9)Lo
wer
mea
n th
an e
xpec
ted
– pr
escr
ibed
once
or t
wice
dail
y:I:
4.7
(3.2
–6.9
)H
igher
mea
n th
an e
xpec
ted
– pr
escr
ibed
daily
dur
ing
wee
k 1
and
daily
or e
very
2or
3 d
ays t
here
afte
r
Num
ber (
%) d
ress
ing
chan
ges p
erfo
rmed
by:
Nur
seC
: 591
(30.
0%)
I: 21
0 (2
6.8%
)Au
xilia
ry n
urse
C: 1
,095
(55.
6%)
I: 35
0 (4
4.6%
)Pa
tient
or s
pous
eC
: 7 (0
.4%
)I:
113
(14.
4%)
Oth
erC
: 276
(14.
0%)
I: 11
2 (1
4.3%
)
Mea
n (r
ange
) min
utes
per
dre
ssin
gch
ange
:C
: 11
(5–2
3)I:
13 (8
–24)
Type
of d
ress
ing
(num
ber o
f pat
ient
str
eate
d C
/I):
Cad
exom
er io
dine
0/1
7G
enta
mici
n so
lutio
n 14
/0
Not
es a
bout
dup
licat
epu
blica
tion:
See
clini
cal e
ffect
ivene
ssta
ble
(pp.
134
–5)
Lim
itatio
ns o
f the
stud
y, as
note
d by
the
stud
y au
thor
s:1.
Pat
ient
s sho
uld
befo
llow
ed u
p un
til fi
nal
outc
ome
(com
plet
ehe
aling
or d
eath
).H
owev
er, i
t may
be
diffi
cult
to c
olle
ct a
ccur
ate
data
on
reso
urce
use
ifda
ta a
re c
olle
cted
ove
r alo
nger
per
iod
of ti
me
2. N
o tim
e co
sts w
ere
calcu
lated
for p
atie
nts o
rre
lative
s who
cha
nged
dres
sings
with
out h
elp
from
the
healt
hcar
esy
stem
3. P
atie
nts i
n a
clini
cal t
rial
may
be
mor
e clo
sely
mon
itore
d an
d tr
eatm
ent
patte
rns m
ay d
iffer
from
norm
al cli
nica
l pra
ctice
.M
ore
reso
urce
s may
ther
efor
e be
con
sum
edAd
here
nce
with
ther
apy
may
be lo
wer
in re
gular
pra
ctice
than
in a
trial
. In
the
futu
re,
it m
ay b
e ad
visab
le to
mak
ead
just
men
ts to
the
econ
omic
evalu
atio
n in
ord
er to
refle
ctcli
nica
l pra
ctice
cont
inue
d
Appendix 4
194
Stud
y id
entif
ier
and
Key
ele
men
ts o
f C
linic
al e
ffect
iven
ess
data
Econ
omic
ana
lysis
Resu
ltsC
omm
ents
obje
ctiv
eth
e st
udy
trav
ellin
g co
sts a
nd n
o lab
our c
osts
wer
e es
timat
ed. T
he so
urce
of
quan
titie
s was
the
stud
y re
cord
s. Th
eda
tes d
urin
g w
hich
the
quan
titie
sw
ere
mea
sure
d w
ere
not r
epor
ted
Info
rmat
ion
on p
rices
for d
rugs
and
mat
erial
s was
obt
ained
from
FAS
S(1
995)
: Läk
emed
el i
Sver
ige.
Stoc
khol
m, S
wed
en(L
äkem
edel
sinfo
rmat
ion
AB, 1
995)
and
curr
ent m
arke
t pric
es. T
heav
erag
e w
ages
for n
ursin
g st
aff i
n19
91, w
ith n
on-w
age
labou
r cos
tsad
ded
(taxe
s, na
tiona
l ins
uran
ce),
wer
e ad
just
ed to
199
3 pr
ices.
Labo
urco
sts i
nclu
ded
the
time
requ
ired
topr
epar
e fo
r the
dre
ssin
g ch
ange
, to
redr
ess t
he w
ound
and
to ti
dy u
paf
ter t
he p
roce
dure
. If t
rave
lling
was
invo
lved,
an
extr
a 30
min
utes
was
adde
d to
the
trea
tmen
t tim
e.
The
cost
s of o
utpa
tient
visi
ts, w
hich
wer
e th
ough
t not
to d
iffer
infre
quen
cy b
etw
een
trea
tmen
top
tions
, wer
e ex
clude
d
Met
hods
use
d fo
r sta
tistic
al an
alysis
of
quan
titie
s and
cos
ts:
The
Man
n–W
hitn
ey U
-test
(tw
o-ta
iled)
was
use
d th
e co
mpa
re c
osts
betw
een
the
two
grou
ps
Assu
mpt
ions
use
d:1.
Wee
kly
reso
urce
cos
ts w
ill re
main
cons
tant
unt
il co
mpl
ete
heali
ng.
2. T
he h
ealin
g ra
te in
pat
ient
s in
grou
p I w
ill be
at l
east
as g
ood
as in
patie
nts i
n gr
oup
C u
ntil
com
plet
ehe
aling
occ
urs
Stre
ptod
orna
se/st
rept
okin
ase
2/0
Dry
salin
e ga
uze
9/1
Vase
line
gauz
e 6/
8
Mea
n (r
ange
) wee
ks o
f tre
atm
ent:
C: 1
1 (5
–12)
I: 10
(1–1
2)
Cos
t res
ults
:M
ean
(ran
ge) w
eekl
y st
aff (
SEK)
:C
: 884
(315
–149
2)I:
380
(96–
570)
p<
0.0
01
Mea
n (r
ange
) wee
kly
tran
spor
t cos
ts(S
EK):
C: 2
43 (7
6–34
1)I:
100
(29–
156)
p<
0.0
01
Mea
n (r
ange
) wee
kly
cost
for m
ater
ials
and
drug
s SEK
:C
: 294
(37–
981)
I: 42
3 (1
66–1
113)
ns Mea
n (r
ange
) tot
al w
eekl
y (S
EK):
C: 1
421
(428
–267
9)I:
903
(524
–169
7)p
< 0
.01
Synt
hesis
of c
osts
and
ben
efits
Wee
kly
cost
per
pat
ient
hea
led:
C: S
EK12
,790
I: S
EK30
70ns Se
nsiti
vity
analy
ses:
1. T
he re
sults
wer
e se
nsiti
ve to
the
assu
mpt
ions
abo
ut tr
avel
ling
dist
ance
and
time.
If a
trav
ellin
g di
stan
ce o
f 5in
stea
d of
10
km w
as a
ssum
ed, t
he
Stud
y sp
onso
rshi
p:Pe
rsto
rp P
harm
a, L
und,
Swed
en, a
nd th
e Sw
edish
Diab
etes
Ass
ociat
ion co
ntin
ued
Health Technology Assessment 2006; Vol. 10: No. 12
195
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y id
entif
ier
and
Key
ele
men
ts o
f C
linic
al e
ffect
iven
ess
data
Econ
omic
ana
lysis
Resu
ltsC
omm
ents
obje
ctiv
eth
e st
udy
Met
hods
use
d fo
r sen
sitivi
ty a
nalys
es:
The
para
met
ers u
sed
wer
e tr
ansp
ort
cost
s, ty
pe o
f sta
ff pe
rform
ing
the
dres
sing,
the
abilit
y of
pat
ient
s to
chan
ge th
eir u
lcer d
ress
ings
with
out
help
from
the
healt
h ca
re st
aff a
ndst
rict a
dher
ence
with
phy
sician
s'pr
escr
iptio
ns. A
lso, o
ne (o
rigin
ally
exclu
ded)
hos
pita
lisat
ion
was
inclu
ded
in th
e an
alysis
and
the
corr
espo
ndin
gre
sults
wer
e co
mpa
red
Synt
hesis
of c
osts
and
ben
efits
:Al
thou
gh a
synt
hesis
of c
osts
and
bene
fits w
as n
ot re
quire
d du
e to
the
inte
rven
tion
bein
g a
dom
inan
tst
rate
gy, t
he w
eekl
y co
st p
er p
atie
nthe
aled
was
calc
ulat
ed
estim
ated
tim
e fo
r tra
vellin
g w
asas
sum
ed to
be
redu
ced
by 1
5m
inut
es,
resu
lting
in a
redu
ctio
n of
the
tota
lw
eekl
y co
st o
f 20%
for p
atie
nts
trea
ted
with
cad
exom
er io
dine
and
31%
for p
atie
nts t
reat
ed w
ith th
eco
ntro
l reg
imen
. Tra
vellin
g co
sts w
ould
be 5
0% lo
wer
in b
oth
grou
ps, w
here
asst
aff c
osts
wou
ld b
e 35
and
36%
low
er,
resp
ectiv
ely.
2. If
pat
ient
s or r
elat
ives l
iving
in th
e sa
me
hous
ehol
d co
uld
perfo
rm 5
0% o
f the
dres
sing
chan
ges,
tota
l wee
kly
cost
sw
ould
dec
reas
e by
27%
in I
and
by40
% in
C.
3. S
taff
cate
gory
: the
redu
ctio
n in
tota
lw
eekl
y co
sts i
f all
dres
sing
chan
ges
wer
e pe
rform
ed b
y au
xilia
ry n
urse
sco
mpa
red
with
if n
urse
s per
form
all
the
chan
ges i
s 7%
for I
pat
ient
s and
9%
for
C p
atie
nts.
4. A
dher
ence
: if p
atie
nts w
ere
trea
ted
exac
tly a
ccor
ding
to p
resc
riptio
n, th
eto
tal w
eekl
y co
st w
ould
be
SEK8
36 fo
rpa
tient
s tre
ated
with
cad
exom
er io
dine
and
SEK1
914
for p
atie
nts t
reat
ed w
ithth
e co
ntro
l reg
imen
(ass
umin
g th
at st
aff
prop
ortio
n an
d av
erag
e tr
eatm
ent t
ime
wer
e th
e sa
me
as in
this
stud
y).
5. R
esul
ts w
ere
also
sens
itive
to a
pos
sible
adve
rse
reac
tion
resu
lting
inho
spita
lisat
ion.
Bas
ed o
n da
ta fr
om o
nepa
tient
who
was
hos
pita
lised
due
tofe
ver,
the
tota
l cos
ts w
ere
estim
ated
as
SEK9
916
for g
roup
I an
d SE
K891
0 fo
rgr
oup
C, a
nd w
eekl
y co
sts w
ere
estim
ated
as S
EK 1
040
for g
roup
I an
dSE
K903
for g
roup
C
CEA
, cos
t-effe
ctive
ness
ana
lysis.
Appendix 4
196
Stud
y id
entif
ier
and
Key
ele
men
ts o
f C
linic
al e
ffect
iven
ess
data
Econ
omic
ana
lysis
Resu
ltsC
omm
ents
obje
ctiv
eth
e st
udy
McK
inno
n (1
997)
,113
USA
To c
ompa
re th
e co
st-
effe
ctive
ness
of A
/S
(I1 g
roup
) ver
sus
I/C
(I2 g
roup
) in
the
trea
tmen
t of d
iabet
icfo
ot in
fect
ions
. See
Gra
yson
et a
l.(1
994)
44
for e
ffect
ivene
ss d
ata
extr
actio
n
Pers
on in
vest
igatin
g w
asun
awar
e w
hich
regim
enw
as u
sed
for e
ach
patie
nt
Type
of e
cono
mic
evalu
atio
n: C
EA
Pers
pect
ive:
Inst
itutio
n (h
ospi
tal)
Setti
ngs o
f clin
ical
effe
ctive
ness
stud
yan
d ec
onom
icev
aluat
ion:
Dea
cone
ss H
ospi
tal
Podi
atry
Ser
vices
,Bo
ston
, MA,
USA
Clin
ical t
rial w
asov
er 1
year
; 199
4pr
ices (
US
$) u
sed.
No
spec
ific
date
s,bu
t eco
nom
icev
aluat
ion
star
ted
on d
ay st
udy-
drug
trea
tmen
t ini
tiate
dan
d ce
ased
whe
nan
tibio
ticad
min
istra
tion
stop
ped
(unl
ess
trea
tmen
t not
succ
essfu
l, in
whi
chca
se su
bseq
uent
cost
s wer
eca
lculat
ed)
Sour
ce:
Sing
le st
udy
(dou
ble-
blin
d, R
CT)
.
Det
ails o
f par
ticip
ants
,in
terv
entio
ns a
nd re
sults
of
clini
cal e
ffect
ivene
ss g
iven
inG
rays
on e
t al.
(199
4).44
Econ
omic
data
ava
ilabl
e fo
r 90/
93 o
f the
origi
nal s
ampl
e. (I
1, n
= 4
5, I2
, n
= 4
5)
Econ
omica
lly si
gnifi
cant
adv
erse
even
ts(i.
e. re
quiri
ng tr
eatm
ent a
ndre
latin
g to
stud
y dr
ug o
r of
unkn
own
origi
n)
I1: 7
(16%
)I2
: 9 (2
0%)
Due
to:
Diar
rhoe
a: I1
: 1 I2
: 4Se
izure
: I1:
0 I2
: 1O
ther
a : I1:
6 I2
: 4a
Rash
, nau
sea/
vom
iting
or f
unga
lsu
perin
fect
ion
Mea
sure
of h
ealth
ben
efits
use
d:
No
clini
cally
sign
ifica
nt d
iffer
ence
sw
ere
foun
d be
twee
n th
e tw
otr
eatm
ent r
egim
ens,
ther
efor
eec
onom
ic an
alysis
com
pare
d co
sts
only
Cos
ting
unde
rtak
en re
tros
pect
ively
Des
crip
tion
of c
osts
:
Thre
e le
vels
of a
nalys
is:
Leve
l I: a
cqui
sitio
n pr
ice o
f med
icatio
n(b
ased
on
natio
nally
pub
lishe
d di
rect
drug
pric
es in
199
4)Le
vel I
I: le
vel I
cos
ts, p
lus a
ll co
sts
dire
ctly
relat
ed to
ant
ibio
tic u
se a
ndin
fect
ion
trea
tmen
t, ex
cludi
ng c
ost o
fa
hosp
ital b
ed. A
ntib
iotic
-rel
ated
item
s inc
lude
acq
uisit
ion
cost
,m
edica
tion
prep
arat
ion
(ave
rage
$4
per i
ntra
veno
us d
ose)
and
adm
inist
ratio
n, tr
eatm
ent o
f adv
erse
even
ts, s
econ
dary
trea
tmen
t of
failu
res
Leve
l III:
all
leve
l II c
osts
plu
s hos
pita
lbe
d co
sts.
Aver
age
valu
e fo
r hos
pita
lbe
d us
e in
US
($85
2/da
y) w
as a
pplie
d
ALO
S (a
ntib
iotic
-rel
ated
leng
th o
fst
ay) u
sed
to c
alcul
ate
the
cost
s of
hosp
ital s
tay
dire
ctly
relat
ed to
the
trea
tmen
t. Ra
w L
OS
(leng
th o
f sta
y)da
ta w
ere
also
calcu
lated
No
disc
ount
ing
nece
ssar
y as
cos
ts a
ndou
tcom
es o
ccur
red
durin
g sa
me
time
perio
d
Cur
renc
y: U
S$
Estim
ated
hea
lth b
enef
its u
sed
in th
eec
onom
ic an
alysis
: not
app
licab
le
Cos
t res
ults
:
Mea
n le
vel I
cos
ts p
er p
atie
nt ($
):I1
: $60
3 (S
D 3
13)
I2: $
1307
(SD
816
)(p
< 0
.001
)
Mea
n le
vel I
I cos
ts p
er p
atie
nt ($
):I1
: $98
2 (S
D 6
50)
I2: $
1654
(SD
913
)(p
< 0
.001
)
Mea
n le
vel I
II co
sts p
er p
atie
nt ($
):I1
: 14,
084
(SD
826
2)I2
: 17,
008
(SD
906
4)(p
= 0
.05)
Mea
n to
tal t
reat
men
t cos
t was
$30
00 le
sspe
r pat
ient
in I1
than
in I2
. Give
n th
at n
osig
nific
ant d
iffer
ence
s wer
e fo
und
betw
een
trea
tmen
ts in
effe
ctive
ness
stud
y, co
st-e
ffect
ivene
ss w
as m
ainta
ined
for I
1
Sens
itivit
y an
alysis
resu
lts:
I2 (I
/C) w
ould
nee
d to
be
30%
mor
eef
fect
ive th
an I1
(A/S
) in
orde
r to
beco
me
cost
-effe
ctive
as d
efin
ed in
the
para
met
ers o
f thi
s stu
dy
Lim
itatio
ns o
f the
stud
y (a
sno
ted
by th
e au
thor
s):
Retr
ospe
ctive
ana
lysis
cann
otsa
tisfy
crit
eria
for
com
preh
ensiv
e ev
aluat
ion
asno
t all
desir
ed d
ata
wer
eco
llect
ed (e
.g.,
pote
ntial
diffe
renc
es in
LO
S in
inte
nsive
car
e un
its) a
t the
time
of th
e tr
ial
Resu
lts li
mite
d to
mod
erat
ese
verit
y in
fect
ions
. Aut
hors
advis
e ca
utio
us a
ppro
ach
inge
nera
lisin
g to
seve
re/li
fe-
thre
aten
ing
infe
ctio
ns
Dat
a no
t col
lect
ed o
nlab
orat
ory
test
s, su
rger
y,ph
ysica
l the
rapy
,ra
diot
hera
py, e
tc.
Not
gen
erali
sabl
e to
mor
ese
vere
infe
ctio
ns
Uni
vers
ity o
f Yor
k, C
entr
efo
r Rev
iew
s and
Diss
emin
atio
n (C
RD)
com
men
tary
:
1. S
elec
tion
of c
ompa
rato
rs:
clear
2. V
alidi
ty o
f est
imat
e of
mea
sure
of b
enef
its: l
ikel
yto
be
inte
rnall
y va
lid,
altho
ugh
som
e de
tails
with
rega
rd to
the
adeq
uacy
of
stud
y siz
e ar
e m
issin
g3.
Vali
dity
of e
stim
ate
ofco
sts:
met
hods
of c
ost
estim
atio
n cle
arly
cont
inue
d
Health Technology Assessment 2006; Vol. 10: No. 12
197
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Stud
y id
entif
ier
and
Key
ele
men
ts o
f C
linic
al e
ffect
iven
ess
data
Econ
omic
ana
lysis
Resu
ltsC
omm
ents
obje
ctiv
eth
e st
udy
Met
hods
use
d fo
r sta
tistic
al an
alysis
of
quan
titie
s and
cos
ts: M
eans
, SD
and
Krus
kal–
Wall
is on
e-w
ay A
NO
VA u
sed
to c
ompa
re L
OS,
ALO
S an
d co
sts
asso
ciate
d w
ith th
e tw
o re
gimen
s
Met
hod
used
for s
ensit
ivity
ana
lyses
:D
ecisi
on tr
eeD
rug
acqu
isitio
n pr
ice te
sted
25%
abov
e an
d be
low
dire
ct p
rice
for e
ach
antib
iotic
($9–
15 fo
r 3g
of A
/S a
nd$1
7–30
for 5
00m
g of
I/C
)
Hos
pita
l bed
cos
t $85
2 ±
$250
,va
ried
for a
rang
e of
$60
0–11
00
Prob
abilit
y of
trea
tmen
t suc
cess
varie
d in
depe
nden
tly b
etw
een
50%
and
95%
to e
ncom
pass
pos
sible
outc
omes
expl
ained
. Aut
hors
felt
that
dire
ct m
easu
rem
ent
of re
sour
ces a
nd p
rices
wou
ld h
ave
been
pref
erab
le, b
ut th
ey h
ave
prod
uced
a g
ener
al co
stes
timat
e. A
lthou
gh so
me
cost
s wer
e om
itted
(e.g
.di
ffere
nces
in le
ngth
of
inte
nsive
car
e un
it st
ay),
all th
e m
ost i
mpo
rtan
tco
st e
lem
ents
wer
ein
clude
d in
the
analy
sis
Stud
y sp
onso
rshi
p:Pa
rtly
supp
orte
d by
Pfiz
erPh
arm
aceu
ticals
ANO
VA, a
nalys
is of
var
iance
; C, c
ontr
ol g
roup
; CEA
, cos
t-effe
ctive
ness
ana
lysis;
I, in
terv
entio
n gr
oup;
I1, f
irst i
nter
vent
ion
grou
p; I2
, sec
ond
inte
rven
tion
grou
p.
Health Technology Assessment 2006; Vol. 10: No. 12
199
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Appendix 5
Quality assessment
Quality assessment of diagnostic studies
Study
Item Gardner Bill Ratliff and et al. (2001)90 et al. (2001)91 Rodeheaver (2002)92
1. Was the spectrum of patients representative of the No Yes Yespatients who will receive the test in practice?
2. Were selection criteria clearly described? Yes Yes Yes
3. Is the reference standard likely to classify the target Unclear Unclear Unclearcondition correctly?
4. Is the time period between reference standard and Yes for 3 out of Yes Unclearindex test short enough to be reasonably sure that 4 study centres the target condition did not change between the that participated two tests? in the evaluation
5. Did the whole sample or a random selection of Yes Yes Yesthe sample receive verification using a reference standard of diagnosis?
6. Did patients receive the same reference standard Yes Yes Yesregardless of the index test result?
7. Was the reference standard independent of the Yes Yes Yesindex test (i.e. the index test did not form part of the reference standard)?
8a. Was the execution of the index test described in Yes Yes Yessufficient detail to permit replication of the test?
8b. Was the execution of the reference standard Yes Yes Yesdescribed in sufficient detail to permit its replication?
9a. Were the index test results interpreted without Unclear Unclear Unclearknowledge of the results of the reference standard?
9b. Were the reference standard results interpreted Unclear Unclear Unclearwithout knowledge of the results of the index test?
10. Were the same clinical data available when test Unclear Unclear Unclearresults were interpreted as would be available when the test is used in practice?
11. Were uninterpretable/intermediate test results Noa Noa Noa
reported?
12. Were withdrawals from the study explained? Noa Noa Noa
a No, not applicable as there did not appear to be any uninterpretable results or withdrawals.
Appendix 5
200
Quality assessment for RCTs and CCTs
Study Score for Score for double Score for Score for randomisationa blindingb reporting of allocation
withdrawalsc concealmentd
Apelqvist (1996)122 2 0 0 C
Bouter (1996)106 2 0 1 C
Bradsher (1984)43 2 0 1 B
Chantelau (1996)74 2 1 0 B
de Lalla (2001)119 1 0 1 B
Dwivedi (2000)127 1 0 0 B
Erstad (1997)107 1 1 1 B
Gough (1997)100 2 2 1 A
Grayson (1994)44 2 1 1 B
Kastenbauer (2003)118 1 0 1 B
Lipsky A114 1 2 1 B
Lipsky B114 1 2 1 B
Lipsky (2004)109 1 0 0 B
Lipsky (1990)75 1 0 1 B
Marchina (1997)123 1 0 NA B
Markevich (2000)105 1 0 0 B
Peterson (1989)101 2 1 1 A
Rhaiem (1998) 124 1 0 0 B
Seidel (1991)110 (CCT)e
NA Patients chose therapy. 0 CBaseline comparability: unclear.Adjustments: none
Seidel (1993,1994)111, 112 NA Patients chose therapy. 0 C(CCT)e Baseline comparability:
unclear.
Adjustments: none
Tan (1993)108 2 1 1 B
Vandeputte (1996)125 2 0 1 B
Yonem (2001)120 1 0 0 B
NA, not applicablea Randomisation. score: 0 or 1 or 2. One point was given if the study described using words such as random or
randomisation. One extra point was given if the method of randomisation was described and was appropriate. One pointwas deducted if the method of randomisation was described and was considered to be inappropriate.
b Double-blinding. score: 0 or 1 or 2. One point was given if the study was described as double-blind. One extra point wasgiven if the method of double-blinding was described and was appropriate. One point was taken away if the method ofdouble-blinding was described and was inappropriate.
c Withdrawals. score: 0 or 1. One point was given if the number and reasons for withdrawals in each group were stated.d Allocation concealment. score: A or B or C. A, Adequate: if adequate measures were taken to conceal allocation. B, Unclear:
if report of allocation concealment was not reported or did not fit in category A or C. C, Inadequate: trials in whichallocation concealment was inadequate.
e The critical appraisal of CCTs included the points above, with the exception of the first (randomisation). In CCTs thefollowing additional items were assessed: method of allocation to treatment groups; degree of baseline comparabilitybetween treatment groups; and appropriateness of adjustment during data analysis for observed imbalances betweentreatment groups.
Health Technology Assessment 2006; Vol. 10: No. 12
201
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Quality assessment of economic evaluations
Study
Criterion Apelqvist et al. McKinnon et al. (1996)122 (1997)113
1. Was a well-defined question posed in answerable form?� Study examined both costs and effects? Y Y� Study involved a comparison of alternatives? Y Y� Viewpoint for analysis stated? Y Y
2. Was a comprehensive description of the competing alternatives given?� Any important alternative omitted? N Unclear� Was a ‘do nothing’ alternative considered? N NA
3. Was the effectiveness of the programmes or services established?� Was it via an RCT? If so did the protocol reflect real practice? Y Y� Was it via an overview of clinical studies? N N� Were observational data or assumptions used to establish effectiveness. N N
If so what are the potential biases?
4. Were all the important and relevant costs and consequences for each alternative identified?� Was the range wide enough for the research question? Y Y� Did it cover all relevant viewpoints? Y Y� Were capital and operating costs included? N N
5. Were costs and consequences measured accurately in appropriate physical units?� Were any items omitted from the measurement? If so, does this mean N N
they carried no weight in the subsequent analysis?� Were there any circumstances that made measurement difficult? If so, N N
were these handled appropriately?
6. Were costs and consequences valued credibly?� Were the sources of values clearly identified? Y Y� Were market values employed for changes involving resources Y Y
gained or depleted?� Where market values were absent, or market values did not reflect Y NA
actual values, were adjustments made?� Was the valuation of consequences appropriate for the question? Y Y
7. Were costs and consequences adjusted for differential timing?� Were costs and consequences that occur in the future discounted? N NA� Was any justification of the discount rate used given? N
8. Was an incremental analysis of costs and consequences of alternatives performed?� Were the incremental costs generated by one alternative over another Y NA
compared with the additional benefits?
9. Was allowance made for uncertainty in the estimates of costs and consequences?� If data on costs or consequences were stochastic, were appropriate Y Y
statistical analyses performed?� If a sensitivity analysis was employed, was justification provided for N N
the range of values?� Were study results sensitive to changes in values? Y Y
10. Did the presentation and discussion of study results include all issues of concern to users?� Were the conclusions of the analysis based on an overall index or ratio N NA
of costs to consequences? If so, was the index interpreted intelligently?� Were the results compared with those of others who have studied the N N
same question?� Did the study discuss the generalisability of the results? N Y� Did the study take account of other important factors in the choice Y N
or decision, e.g. ethics?� Did the study discuss issues of implementation, such as feasibility of N N
the preferred programme?
Health Technology Assessment 2006; Vol. 10: No. 12
203
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Appendix 6
Summary of excluded studies
Summary of excluded diagnostic studiesa
Study Description Reason for exclusion
Basak (1992)177 Evaluation of microbiology of burns, traumatic wounds No DFUs or venous leg ulcers in the sampleand pressures sores using wound swab and tissue biopsy
Bessman (1992)178 Comparison of prevalence of diphtheroids in reliable Unclear how many patients had ulceration; (derived from deep tissue intra-operatively) and 2 × 2 diagnostic data not reportednon-reliable cultures (specimen taken at bedside) in patients with diabetic foot infection
Buntinx (1996)179 Assessment of several different types of wound Assessment of inter-observer variation, not classification systems, including one for assessing diagnostic performanceclinical signs of infection, in wounds of various aetiologies including venous leg ulcers
Cooper (1995)180 Assessment of the association between clinical Swabs were processed exclusively for the signs of infection and the presence of Lancefield detection of streptococci, and the presence group G streptococci detected by wound swab in of other pathogens could not be excluded. venous leg ulcers There was therefore no diagnostic
verification for the presence of woundinfection
Crerand (1996)181 Description of various investigations done in a series Focus of study was diagnosis of of patients with clinically infected DFUs osteomyelitis rather than wound infection;
no diagnostic verification
Cutting (1994)93 Description of criteria for identifying wound infection Description of clinical signs and symptoms,not an evaluation
Davies (2001)38 Description of molecular techniques in analysing the Description of molecular techniques, not an microflora of chronic wounds evaluation
Edwards (2000)182 Comparison of different methods of swabbing in acute Unable to ascertain whether the sample or chronic wounds included people with DFUs or venous leg
ulcers; no outcome data available
Greenwood Pilot study of electronic aroma detection to determine No diagnostic verification(1997)183 changes in aroma of venous leg ulcers
Huovinen (1992)184 Letter to the editor reporting an evaluation of fine 2 × 2 diagnostic data not availableneedle aspiration biopsy, curettage and swab used to detect infection in leg ulcers
Johnson (1995)37 Use of needle aspiration and swab to detect anaerobic 2 × 2 diagnostic data not availablebacteria in DFUs
Kessler (2002)185 Evaluation of adverse effects and microbiological 2 × 2 diagnostic data not availableidentification of thin needle puncture compared with superficial swab for DFUs
Lee (1985)186 Evaluation of fine-needle aspiration biopsy and 2 × 2 diagnostic data not availablewound swab in patients with wounds of various aetiologies, including DFUs and venous leg ulcers
Levine (1976)187 Evaluation of swab and smear versus flamed tissue Sample did not include people with DFU or biopsy in patients with burns venous leg ulcers; 2 × 2 diagnostic data not
reported
continued
Appendix 6
204
Study Description Reason for exclusion
Lorentzen (1999)188 Evaluation of the Red–Yellow–Black wound classification Assessment of inter-observer variation, not system used with various types of chronic wounds diagnostic performance
Neil (1997)189 Comparison of swab culture and tissue culture used to Wound aetiologies unclear; no diagnostic detect bacterial counts and identification in chronic verification of wound infectionwounds
Pellizzer (2001)33 Comparison of wound swab and deep tissue biopsy No diagnostic verificationin DFUs
Sapico Evaluation of deep-tissue microbiology in people with Some patients did not have foot ulceration; (1980, 1984)190,191 diabetic foot infection using different sampling no diagnostic verification for detection of
techniques (ulcer swab pre- and post-amputation, wound infectioncurettage and needle aspiration)
Schneider (1983)192 Comparison of two methods of tissue sampling (single 2 × 2 diagnostic data not availabletissue sample divided into 4 specimens versus tissue samples taken from 4 separate areas of the wound) in pressure sores and infected surgical wounds
Sharp (1979)193 Comparison of cultures taken at the bedside with 2 × 2 diagnostic data not availablethose obtained via surgical dissection at the infection site in patients undergoing a surgical procedure for infected DFUs
a A number of other studies focusing on the prevalence and sensitivities of microorganisms, and the diagnosis ofosteomyelitis, were identified through the diagnostic search strategy, but have not been listed here.
Health Technology Assessment 2006; Vol. 10: No. 12
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© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Summary of excluded effectiveness studies
Study Description Reason for exclusion
Acevedo (1990)194 Antibiotics infused into limb with tourniquet vs Failed to meet study design inclusion criteriaconventional systemic antibiotics
Akova (1996)195 Prospective follow-up of patients treated with No comparison of interventionsparenteral S/A
Anon (1992)196 Guidelines for diabetic foot care No comparison of interventions
Anon (1996)197 Guidelines for diabetic foot care No comparison of interventions
Apelqvist (1989)198 Wound classification No comparison of interventions
Armstrong (1997)199 Risk factors associated with puncture wounds in No comparison of interventionsdiabetics vs non-diabetics
Armstrong (1997)200 Retrospective case survey of seasonal variation in No comparison of interventionslower extremity amputation
Beam (1989)201 CCT of oral vs intravenous ciprofloxacin Not DFU patients
Bendy (1965)202 RCT of standard therapy vs standard therapy plus Not DFU patientstopical gentamicin cream
Bonham ( 2001)203 Systematic review of antibiotic treatment for Focus on osteomyelitisosteomyelitis
Bose (1979)204 Case series study of surgical approach to treatment Failed to meet study design inclusioncriteria. No data by ulcer group
Bowering (2001)205 Non systematic overview of DFU aetiology, Failed to meet study design inclusion criteriaassessment and treatments
Boxer (1969)206 RCT of collagenase vs placebo in patients with venous, Not DFU patientsarterial or pressure ulcers
Brill (2000)207 CCT of HBO2 vs standard care No antimicrobial intervention
Brunner (1999)208 Overview of microbiology and antimicrobial Failed to meet study design inclusion criteriatreatments for diabetic foot infection
Calhoun (1988)209 Retrospective evaluation of Wagner classification No comparison of interventionsprotocol
Cappelli (1969)210 Uncontrolled study (Italian) Failed to meet study design inclusioncriteria. Not DFU patients
Chapuis (1964)211 Uncontrolled study (French) Failed to meet study design inclusion criteria
Close-Tweedie Povidone-iodine in podiatric wounds Failed to meet study design/intervention (2001)212 inclusion criteria
Collier (1997)213 Correspondence regarding compression and venous Failed to meet study design/intervention leg ulcers inclusion criteria
Combe (1999)214 Non-systematic overview of assessment and Failed to meet study design criteriatreatment of diabetic feet
Cunha (2000)215 Non-systematic overview of diabetic foot infection Failed to meet study design criteria
Danziger (1988)216 RCT of imipenem vs gentamicin/clindamycin Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparately
Davies (1982)217 RCT of augmentin vs co-trimoxazole No data presented for infected DFUs
Degreef (1998)218 Non-systematic overview Failed to meet study design inclusioncriteria. Not specific to DFUs
Dereume (1985)219 Survey of yeast culture from leg ulcers and risk factors Failed to meet study design/intervention for yeast infection inclusion criteria
continued
Appendix 6
206
Study Description Reason for exclusion
Dillon (1990)220 Case series study of local antibiotic injections and Failed to meet study design inclusion criteriaend-diastolic compression boot
Dominguez (1989)221RCT of intravenous/oral ciprofloxacin vs intravenous No data for DFUsceftazidime
Donaghue (1998)222 RCT of collagen–alginate dressing vs saline gauze Failed to meet intervention inclusion criteria
Draszkiewicz Report on diabetic foot care Failed to meet study design inclusion criteria(1992)223
Edmonds (2001)224 Pathophysiology of the diabetic foot Failed to meet study design inclusioncriteria. No comparison of interventions
Edmonds (2000)225 Non-systematic overview of novel treatments for DFUs Failed to meet study design inclusion criteria
Faglia (1996)226 RCT of hyperbaric oxygen therapy vs standard Failed to meet intervention inclusion criteria treatment as not an antimicrobial intervention
Fass (1989)227 RCT of intravenous/oral ciprofloxacin vs ceftadime Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparately
Fejfarova (2002)228 Microbiological resistance as risk factor for amputation Failed to meet study design/interventioninclusion criteria
Fernandez CCT of antimicrobial interventions in diabetic amputees Not DFU patientsMontequin (1991)229
File (1983)230 RCT of amdinocillin plus cefoxitin vs cefoxitin Insufficient numbers of diabetic patients.Unclear as to how many patients had footulcers
File (1991)231 Non-systematic overview of T/C therapy Failed to meet study design inclusion criteria
File (1991)232 Overview of treatments for bacterial skin/soft tissue Failed to meet study design/intervention infections inclusion criteria
File (1994)233 Overview of trials of piperacillin/tazobactam Failed to meet study design inclusion criteria
Foster (2001)234 Overview of diabetic foot management Failed to meet study design inclusioncriteria. No comparison of interventions
Foster (2001)235 Overview of diabetic foot management Failed to meet study design inclusioncriteria. No comparison of interventions
Frykberg (2000)79 Clinical guidelines No comparison of interventions
Fuentes Sermeño Evaluation of oral levofloxacin vs ciprofloxacin Not DFU patients(2001)236
Gentry (1989)237 RCT of oral ciprofloxacin vs parenteral cefotaxime Not clear whether DFU patients
Gentry (1991)238 RCT of ofloxacin vs parenteral therapy for osteomyelitis Not DFU patients
Gentry (1992)239 Overview of lactam and quinolone agents for skin/skin Failed to meet study design inclusion criteriastructure infections
Gentry (1993)240 Diagnosis and management of DFU No comparison of interventions
Gentry (1989)241 RCT of oral ofloxacin vs intravenous cefotaxime Not clear whether DFU patients
Goldenheim Correspondence Failed to meet study design inclusion criteria(1995)242
Gomez (1992)243 Risk factors for diabetic foot infection Failed to meet study design/interventioninclusion criteria
Gomis (1990)244 Uncontrolled case series study of antimicrobial therapy Failed to meet study design inclusion criteria
Grayson (1995)245 Non-systematic overview of diabetic foot infection and Failed to meet study design inclusion criteriaantimicrobial treatment
Hanft (2002)246 RCT of Dermagraft vs standard care Failed to meet intervention inclusion criteria
continued
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Study Description Reason for exclusion
Hart (1996)247 Non-systematic overview of �-lactamase inhibitors Failed to meet study design inclusion criteria
Hartemann-Heurtier Non-systematic review of antibiotics used with diabetic Failed to meet study design inclusion criteria(2000)248 foot patients
Helaly (1988)249 RCT/CCT of enzyme applications Failed to meet intervention inclusioncriteria. Unclear whether DFU patients
Henyk (1999)250 CCT of sea buckthorn ointment Failed to meet intervention inclusion criteria
Hodges (1986)251 Non-systematic overview of diabetic foot management Failed to meet study design inclusion criteria
Hughes (1987)45 RCT of cefoxitin vs ceftizoxime Not all patients diabetic and not clear howmany had a foot ulcer
Huizinga (1986)252 RCT/CCT of antibiotic prophylaxis Insufficient number of diabetic patients anddata on DFU patients not presentedseparately
Ignacio (1984)253 Uncontrolled case series study of hyberbaric Failed to meet study design/intervention oxygen therapy inclusion criteria
Jamil (2001)254,255 Uncontrolled case series on management of diabetic Failed to meet study design/intervention foot infections inclusion criteria
Jensen (1998)256 RCT of moist wound dressing protocols Failed to meet intervention inclusion criteriaas not an antimicrobial intervention. Infectedulcer patients excluded
Johnson (1985)257 Evaluation of ticarcillin plus clavulanic acid No comparison of interventions. Noseparate data for DFU patients
Joseph (1990)258 Non-systematic overview of diabetic foot infection Failed to meet study design criteria
Joseph (1987)259 Non systematic overview of physiopathology in the Failed to meet study design criteriadiabetic foot
Joseph (1987)260 Puncture wound infections Failed to meet patient inclusion criteria
Kacy (1982)261 Uncontrolled case series of amputation in Failed to meet study design/intervention diabetic/non-diabetic patients inclusion criteria
Kaltenthaler (1998)98 Systematic review of antimicrobial agents for DFU Used for reference purposes only
Karchmer (1999)262 Overview of fluroquinolones Failed to meet study design/interventioninclusion criteria
Karsegard (1995)263 Non-systematic overview of antibiotic therapy for Failed to meet study design inclusion criteriadiabetic foot infection
Kaufman (1994)264 Non-systematic review on prevention of DFUs Failed to meet study design inclusion criteria
Kerstein (1997)265 Retrospective case review of toe amputation in Failed to meet study design inclusion criteriadiabetic patients
Klepser (1997)266 RCT of piperacillin/tazobactam vs ticarcillin/clavulanate Not DFU patientsvs ampicillin/sulbactam
Koveker (2000)267 Review of growth factors in wound repair Failed to meet study design/interventioninclusion criteria
Krikava (1999)268 Survey of isolates and sensitivity to antibiotics in Not clear whether DFU patientsdiabetic feet
Laing (1994)269 Non systematic overview of DFU management Failed to meet study design inclusion criteria
Larsson (1995)270 Review of amputation rates, costs and prevention Failed to meet study inclusion/interventioninclusion criteria
Lee (1997)271 Case series study of diabetic foot patients receiving Failed to meet study inclusion/intervention hyperbaric oxygen therapy inclusion criteria
LeFrock (1983)272 Evaluation of cefoxitin in diabetic patients with Failed to meet study design criteria: as no lower extremity infections control/comparison group
continued
Appendix 6
208
Study Description Reason for exclusion
Lentino (1991)273 Evaluation of oral and intravenous ofloxacin Not clear whether DFU patients
Lipsky (1997)46 RCT of intravenous ofloxacin followed by oral ofloxacin Insufficient number of DFU patients and vs intravenous ampicillin/sulbactam followed by oral data on foot ulcer patients not presented amoxicillin/clavulanate separately
Loffler (1986)274 RCT of sulbactam plus ampicillin vs cefotaxime Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparately
Madsen RCT comparing oral and intravenous penicillin vs Insufficient number of diabetic patients and (1996,1998)275,276 no treatment data on foot ulcer patients not presented
separately
Mason (1999)99,277 Systematic review addressing different methods of For reference purposes onlytreating DFU
Mayer (1993)278 Non-systematic review of povidone-iodine wound Failed to meet study design inclusion criteriahealing products
Mizel (1989) 279 Non-systematic overview of diabetic foot infection Failed to meet study design inclusion criteria
Motarjeme (1993)280 Retrospective study of thrombolysoangioplasty as an Not clear whether DPU patientsalternative to amputation
Murphy (1981)281 Non-systematic overview of diabetic foot infections Failed to meet study design inclusion criteria
Nichols (1997)282 RCT of levofloxacin vs ciprofloxacin Unable to identify data for DFU patients
Ohsawa (2001)283 Case series study of amputation outcomes in Failed to meet study design inclusion diabetic foot patients criteria. No comparison of interventions.
Parish (1993) 284 RCT of fleroxacin vs. ceftazidime Not clear whether DFU patients
Parish (1984) 285 CCT of augmentin vs cefaclor No data on DFU infections
Parish (1984) 285 RCT of ceftizoxime vs cefamandole Not DFU patients
Parish (1987)286 RCT of cefuroxime axetil vs cefaclor Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparately
Partsch (1993)287 RCT of intravenous pressure infusions containing No comparison of antimicrobial radioactive tracers interventions
Pepe (1999)288 RCT of ASA, Ginko Biloba extract, arginine plus No comparison of antimicrobial magnesium vs ASA plus conventional interventionshaemorrheology
Perez-Ruvalcaba RCT of ciprofloxacin vs cefotaxime No data for DFU patients(1987)289
Peters (2001)290 RCT of electrical stimulation vs placebo No comparison of antimicrobialinterventions
Pien (1983)291 CCT of two dosage regimens of Cefaclor and No data for DFU patientsamoxicillin/clavulanic acid
Pinzur (1993)292 Non-systematic overview of amputation level selection Failed to meet study design inclusion in the diabetic foot patient criteria. No comparison of antimicrobial
interventions
Pinzur (1999)293 Summary of guidelines for diabetic foot care Failed to meet study design/interventioninclusion criteria
Pitkin (1995)294 Comparison of meropenem with other agents in Failed to meet study design inclusion skin/soft tissue infections criteria. No data by wound type
Powers (1993)295 RCT of oral fleroxacin vs A/C No data on DFU patients
Real (2001)296 Prospective cohort study of risk factors for Failed to meet study design inclusion hospitalisation criteria. No comparison of interventions
continued
Health Technology Assessment 2006; Vol. 10: No. 12
209
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Study Description Reason for exclusion
Rice (2001)297 RCT of biofeedback-assisted relaxation vs relaxation No comparison of antimicrobialinterventions
Rittenhouse CCT of zinc–saline wet dressings vs normal saline wet No comparison of antimicrobial (1996)298 dressings interventions
Saltzman (1999)299 Non-systematic review of diabetic foot infection Failed to meet study design inclusion criteria
Sauerwein (1994)300 Commentary on antibiotic treatments relating to DFUs Failed to meet study design inclusion criteria
Schwegler (2002)301 Overview of diabetic foot management Failed to meet study design inclusion criteria
Seewald (1999)302 Non-systematic overview of microbiological aspects Failed to meet study design inclusion criteriaof the diabetic foot
Segev (1990)303 RCT of pefloxacin vs ceftazidime Insufficient number of patients with diabetesand not clear how many had an ulcer
Self (1987)304 RCT of ciprofloxacin vs cefotaxime No data on DFU patients
Senneville (2002)305 Case series study of rifampicin and fluoroquinolone Failed to meet study design inclusion criteria
Sesin (1990)306 Case series study of oral clindamycin and ciprofloxacin Failed to meet study design inclusion criteria
Siami RCT of clinafloxacin vs piperacillin/tazobactam Not DFU patients(2001, 2002)307,308
Sibbald (2001)309 Case series study of ionised nanocrystalline silver Failed to meet study design inclusion criteriadressing in chronic wound care
Siebert (1985)310 RCT of ticarcillin plus clavulanic acid vs moxalactam Not clear whether DFU patients
Smith (1996)311 Overview of soft tissue and diabetic foot infections Failed to meet study design inclusion criteria
Smith (2001)312 Protocol description on debridement of DFUs Failed to meet study design/interventioninclusion criteria
Steed (1992)313 RCT of topical CT-102 activated platelet supernatant Failed to meet intervention inclusion criteria vs placebo as not an antimicrobial intervention
Storm (1994)314 Correspondence regarding analysis of tissue Failed to meet study design inclusion concentration of cefuroxime criteria. Not clear whether all patients had
ulcers
Stromberg (1986)315 RCT of sulbactam and ampicillin vs clindamycin and Not clear whether diabetic foot ulcer tobramycin patients
Sussman (1992)316 Non-systematic review of diabetic foot problems Failed to meet study design inclusion criteria
Tammelin (1998)317 Case series study of flora, antimicrobial resistance Failed to meet study design inclusion criteriaand treatment
Tan (1985)318 Comparison of timentin vs moxalactam Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparatelyNo outcome data
Tan (1996)319 Retrospective case review of intravenous antibiotics Failed to meet study design inclusion criteriavs surgery plus intravenous antibiotics
Tannenbaum Case series study of venous bypass grafting Failed to meet study design/intervention (1992)320 inclusion criteria
Tassler (1993)321 RCT of oral fleroxacin vs A/C Not clear whether DFU patients
Tassler (1993)322 Non-comparative study of piperacillin/tazobactam Failed to meet study design inclusion criteria
Temple (2000)323 Semi-systematic review of antibiotic treatments for Failed to meet study design inclusion criteriaDFUs
van de Meer Overview of antibiotic treatments for diabetic foot Failed to meet study design inclusion criteria(1996)324 infection
continued
Appendix 6
210
Study Description Reason for exclusion
Vanscheidt (2002)325 RCT of Butcher’s broom extract vs placebo Failed to meet intervention inclusion criteriaas not an antimicrobial intervention
Wheatley (2001)326 Audit protocol relating to diabetic foot ulcers Failed to meet study design/interventioninclusion criteria
Young (1995)327 Measurement of metatarsal pressure using plantar Failed to meet study design/intervention ultrasound inclusion criteria
Zlatkin (1987)328 Non-systematic overview of diabetic foot management Failed to meet study design inclusion criteria
Summary of excluded cost-effectiveness studies
Study Description Reason for exclusion
Bentkover (1993)329 Cost-effectiveness analysis of thrombin induced platelet Focus is not management of infection in releasate versus saline solution to treat DFUs DFUs
Apelqvist Cost analysis of primary healing and healing with No synthesis of costs and benefits (1994,1995)131,137,138 amputation in DFUs (costs only)
Eckman (1995)15 Markov model used to estimate the cost-effectiveness Focus is management of osteomyelitis rather of different aspects of the diagnosis and treatment of than wound infectiondiabetic patients with foot infections and suspected osteomyelitis
Morrison (1995)330 Evaluation of the sensitivity, specificity, clinical utility Focus is diagnosis of osteomyelitis rather and cost-effectiveness of magnetic resonance imaging than wound infection; 56% of feet studied in the diagnosis of osteomyelitis of the foot in diabetics were not diabetic; magnetic resonance
imaging was not compared directly with areference standard
Health Technology Assessment 2006; Vol. 10: No. 12
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© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Appendix 7
Experts’ views on definition and management ofclinically infected diabetic foot ulcers
Appendix 7
212
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
ref
erra
l D
: ter
tiar
y re
ferr
al
E: t
erti
ary
refe
rral
F:
ter
tiar
y re
ferr
al
refe
rral
cen
tre
cent
re in
Eng
land
cent
re in
Eng
land
cent
re, W
ales
cent
re, C
anad
ace
ntre
, Eng
land
(DG
H w
ith
(wor
ks c
lose
ly w
ith
a di
abet
es c
entr
e),
bone
infe
ctio
n te
am)
Engl
and
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
cont
inue
d
A. D
iagn
osis
of i
nfec
tion
1. In
gen
eral
, wha
t se
t of
crite
ria w
ould
you
say
is us
ed t
o di
agno
secl
inic
ally
an
infe
cted
foot
ulc
er?
Swel
ling,
red
col
our,
smel
l and
pai
n
If th
ere
are
2 of
thes
e sig
ns t
hen
she
acts
on
them
; if
ther
e is
only
1 s
ign
she
take
s a
swab
Redn
ess,
pai
n,in
dura
tion,
disc
harg
e,he
at, s
wel
ling,
sm
ell.
Ifce
llulit
is le
ss t
han
2cm
from
the
ent
ry p
oint
of
infe
ctio
n, li
kely
to
be a
min
or in
fect
ion.
Ifex
tens
ive
cellu
litis,
like
lyto
be
mod
erat
e or
seve
re in
fect
ion
The
y of
ten
do a
n X
-ray
, or
bloo
dte
st/t
empe
ratu
re t
o se
eif
pyre
xial
Surr
ound
ing
cellu
litis,
pres
ence
of
unde
rmin
ing,
oed
ema,
failu
re t
o he
al w
hen
you
thou
ght
it sh
ould
(cha
nges
in p
lain
X-r
ayov
ertim
e, M
RI –
incr
easin
g tis
sue
oede
ma)
“We
don’
t us
e sw
abs
todi
agno
se in
fect
ion,
the
clin
ical
impr
essio
n is
the
diag
nosis
, sw
abs
simpl
yco
nfirm
the
org
anism
”
Pres
ence
of u
nder
min
ing,
exce
ssiv
e or
mal
odor
ous
exud
ate,
pai
n, p
us,
spre
adin
g ce
llulit
is,bl
eedi
ng w
ound
bed
,ce
llulit
is ar
ound
the
wou
nd, p
robe
to
bone
With
the
exc
eptio
n of
prob
e to
bon
e, fo
r al
l the
othe
rs 1
fact
or =
hig
hsu
spic
ion,
pre
senc
e of
2fa
ctor
s =
def
initi
ve
Pain
in a
pai
nles
s fo
ot (a
neur
opat
hic
foot
) Sw
ellin
g ab
ove
the
foot
Incr
ease
d ex
udat
e sin
cela
st w
eek,
Pr
obe
to b
one,
X-r
ayES
R>65
C
RP >
30
Diff
eren
ce in
4–5
degr
ees
as m
easu
red
byth
erm
omet
ry
Puru
lent
disc
harg
e,er
ythe
ma,
war
mth
,sw
ellin
g. A
lso m
ore
subt
le s
igns
– c
hang
e in
both
ulc
er b
ase
and
colo
ur; i
ncre
ase
inex
udat
e vo
lum
e
B. I
ncid
ence
of c
linic
ally
dia
gnos
ed in
fect
ion
2. O
ut o
f 10
cons
ecut
ive
outp
atie
nts
with
diab
etic
foot
ulc
ers,
how
man
y of
the
m w
illfu
lfil t
he s
et o
f crit
eria
you
outli
ned
in t
hepr
evio
us q
uest
ion?
3/10
> 5
/10
Rem
arks
the
y ar
e a
spec
ialis
t ce
ntre
1/10
out
-pat
ient
s
10/1
0 in
-pat
ient
s(in
fect
ion
is a
key
reas
onfo
r ad
miss
ion)
4 or
5/1
04
wou
ld g
et o
ral A
B1
wou
ld g
et IV
AB
(ifpe
rson
is ‘u
nwel
l, if
ulce
rca
n pr
obe
to b
one,
or
ther
e is
out
of c
ontr
oldi
abet
es, s
prea
ding
infe
ctio
n’)
5 or
6/1
0T
he lo
nger
the
ulc
er h
asbe
en t
here
the
mor
elik
ely
the
ulce
r is
infe
cted
; the
dee
per
the
ulce
r, th
e hi
gher
cha
nce
of in
fect
ion.
With
poo
rdi
abet
ic c
ontr
ol, t
here
islik
ely
to b
e in
fect
ion.
Also
, poo
r co
ntro
l is
asy
mpt
om o
f inf
ectio
n
4 or
5/1
0
Health Technology Assessment 2006; Vol. 10: No. 12
213
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
D
: ter
tiar
y re
ferr
al
E: t
erti
ary
refe
rral
F:
ter
tiar
y re
ferr
al
refe
rral
cen
tre
cent
re in
Eng
land
re
ferr
al c
entr
e ce
ntre
, Wal
esce
ntre
, Can
ada
cent
re, E
ngla
nd(D
GH
wit
h (w
orks
clo
sely
wit
h a
in E
ngla
nddi
abet
es c
entr
e),
bone
infe
ctio
n te
am)
Engl
and
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
cont
inue
d
C. A
lter
nati
ve c
ours
es o
f act
ion
3. O
ut o
f 10
cons
ecut
ive
outp
atie
nts
initi
ally
diag
nose
d w
ith a
clin
ical
ly in
fect
ed D
FU(a
ccor
ding
to
the
set
ofcr
iteria
you
des
crib
edin
que
stio
n on
e), h
owm
any
of t
hese
will
com
men
ce a
cou
rse
ofor
al s
yste
mic
ant
ibio
tics
with
out
a fo
rmal
diag
nost
ic t
est
havi
ngta
ken
plac
e?
All
of t
hem
Maj
ority
go
onto
em
piric
alth
erap
yVi
rtua
lly a
ll of
the
m,
beca
use
infe
ctio
n so
easil
y be
com
es a
plan
tar
spac
ein
fect
ion.
Onc
e yo
uha
ve d
iagn
osed
infe
ctio
n, y
ou t
reat
until
oth
erw
isepr
oven
All
of t
hem
wou
ld g
etan
tibio
tics
imm
edia
tely.
The
con
sequ
ence
s of
faili
ng t
o ac
t ar
e se
rious
–so
not
left
to c
hanc
e
5 to
7/1
0H
ighe
r ris
k of
har
m if
you
wai
t
All
of t
hem
4. W
hat
patie
nt, f
oot
orul
cer
char
acte
ristic
spr
ompt
you
to
pres
crib
e or
al s
yste
mic
antib
iotic
s to
com
men
ceim
med
iate
ly?
All
patie
nts
get
antib
iotic
s so
not
rele
vant
Prac
tical
ly a
ll w
ould
get
antib
iotic
s im
med
iate
ly: o
nly
patie
nts
with
hig
h su
spic
ion
of o
steo
mye
litis
and
not a
tris
k of
sys
tem
ic in
fect
ion
wou
ld g
et a
bon
e bi
opsy
befo
re h
avin
g an
y an
tibio
tics
NB:
day
of w
eek
also
impo
rtan
t – o
n a
Frid
ay th
eygi
ve a
ntib
iotic
s fo
r a
supe
rfic
ial l
ooki
ngre
dnes
s/in
fect
ion,
whe
reas
Mon
day–
Thu
rsda
y th
eyw
ould
brin
g pa
tient
bac
kan
d se
e pr
ogre
ss b
efor
est
artin
g w
ith a
ntib
iotic
s (a
nddo
so
only
if r
edne
ssin
crea
sing)
See
abov
e –
they
all
get
antib
iotic
sSe
e ab
ove
– th
ey a
ll ge
tan
tibio
tics
Lim
b-th
reat
enin
gin
fect
ion
See
the
infe
ctio
n cr
iteria
abov
e
Appendix 7
214
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
ref
erra
l D
: ter
tiar
y re
ferr
al
E: t
erti
ary
refe
rral
F:
ter
tiar
y re
ferr
al
refe
rral
cen
tre
cent
re in
Eng
land
ce
ntre
in E
ngla
ndce
ntre
, Wal
esce
ntre
, Can
ada
cent
re, E
ngla
nd(D
GH
wit
h (w
orks
clo
sely
wit
h a
diab
etes
cen
tre)
, bo
ne in
fect
ion
team
)En
glan
d
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
cont
inue
d
5. H
ow m
any
of t
he s
ame
10 p
atie
nts
will
be
form
ally
tes
ted
usin
gon
e or
mor
e fo
rmal
diag
nost
ic t
ests
for
infe
ctio
n, i.
e. w
ound
biop
sy, w
ound
sw
ab,
X-r
ay, a
mon
g ot
hers
,an
d re
ceiv
e no
syst
emic
ant
ibio
tics
until
the
res
ults
of t
hefo
rmal
tes
t ar
eob
tain
ed?
1 or
2/1
0Pe
ople
with
sus
pect
edos
teom
yelit
isN
one
Non
e3
to 5
/10.
The
y w
ould
be d
ebrid
ed, t
reat
edw
ith lo
cal c
adex
omer
iodi
ne o
r sil
ver,
and
then
reas
sess
ed in
2w
eeks
No
repl
y
6. W
hich
dia
gnos
tic t
est
wou
ld y
ou m
ost
com
mon
ly u
se?
Swab
Dee
p tis
sue
biop
sy a
fter
debr
idem
ent
Prob
e to
bon
e
Swab
Swab
(the
ir la
bora
tory
cann
ot d
eal w
ith b
iops
ysp
ecim
ens
very
wel
l)
Swab
Neu
ropa
thic
ulc
ers
wou
ld b
e sc
rape
d fo
r a
sam
ple
Neu
ro-is
chae
mic
ulc
erw
ould
be
swab
bed.
(7/1
0 ul
cers
are
neur
opat
hic)
Health Technology Assessment 2006; Vol. 10: No. 12
215
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
ref
erra
l D
: ter
tiar
y re
ferr
al
E: t
erti
ary
refe
rral
F:
ter
tiar
y re
ferr
al
refe
rral
cen
tre
cent
re in
Eng
land
ce
ntre
in E
ngla
ndce
ntre
, Wal
esce
ntre
, Can
ada
cent
re, E
ngla
nd(D
GH
wit
h (w
orks
clo
sely
wit
h a
diab
etes
cen
tre)
, bo
ne in
fect
ion
team
)En
glan
d
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
cont
inue
d
7. If
an
initi
al d
iagn
ostic
test
pro
ved
unin
form
ativ
e an
d th
eul
cer
still
app
eare
din
fect
ed, w
ould
you
repe
at t
he s
ame
test
,O
R w
ould
you
use
adi
ffere
nt t
est
(e.g
.w
ould
you
rep
eat
aw
ound
sw
ab, o
r w
ould
you
use
a w
ound
biop
sy t
o ge
t a
bett
ersa
mpl
e?).
Plea
se li
st t
heop
tions
you
wou
ld u
sein
the
ord
er y
ou w
ould
use
them
Act
on
the
sym
ptom
s no
t th
esw
abM
ight
res
wab
Deb
ride
ulce
r ag
ain
and
take
bio
psy
agai
nD
epen
ds o
n w
ho t
ook
1st
swab
; if i
t w
as h
im,
resw
ab a
nd r
eque
st M
RIsc
an. I
f it
was
ano
ther
clin
icia
n, h
e w
ould
sw
aban
d w
ait
(bio
psy
is no
tpa
rtic
ular
ly u
sefu
l)
Mig
ht c
uret
tage
the
wou
nd. I
f the
pro
be t
obo
ne r
evea
led
a ch
unk
ofbo
ne, t
hey
wou
ld p
ick
that
out
and
sen
d it
off f
orm
icro
biol
ogy
MRI
sca
ns t
ake
too
long
to g
et in
the
ir se
ttin
g
Mig
ht t
ake
an X
-ray
if t
hepa
tient
has
not
had
one
ina
whi
le
Resw
ab, t
hen
biop
syD
eepe
r sa
mpl
ere
quire
d if
neur
opat
hic
ulce
r
8. W
hat
patie
nt, f
oot
orul
cer
char
acte
ristic
spr
ompt
ed y
ou t
o us
e a
form
al d
iagn
ostic
tes
t?
If on
ly o
ne o
f the
char
acte
ristic
s of
infe
ctio
n pr
esen
t
If I w
ere
plan
ning
to
use
a sk
in s
ubst
itute
, the
n I
wou
ld w
ant
to c
heck
the
wou
nd b
ed w
as ‘s
teril
e’be
fore
usin
g th
e re
ally
expe
nsiv
e sk
in
Appendix 7
216
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
ref
erra
l D
: ter
tiar
y re
ferr
al
E: t
erti
ary
refe
rral
F:
ter
tiar
y re
ferr
al
refe
rral
cen
tre
cent
re in
Eng
land
ce
ntre
in E
ngla
ndce
ntre
, Wal
esce
ntre
, Can
ada
cent
re, E
ngla
nd(D
GH
wit
h (w
orks
clo
sely
wit
h a
diab
etes
cen
tre)
, bo
ne in
fect
ion
team
)En
glan
d
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
cont
inue
d
9. H
ow m
any
of t
hese
sam
e 10
pat
ient
s w
illne
ither
be
trea
ted
with
sys
tem
ican
tibio
tics
orpe
rfor
med
adi
agno
stic
tes
t?
Up
to 1
/10
wou
ld b
etr
eate
d w
ith t
opic
alag
ents
Smal
l pro
port
ion
Less
tha
n 1/
10. T
here
are
patie
nts
with
infe
ctio
n bu
t th
etr
eatm
ent
they
nee
d is
surg
ery
(e.g
. isc
haem
ic).
One
app
roac
h is
tom
umm
ify t
he in
fect
ion
with
top
ical
antim
icro
bial
s an
d pu
lsedo
ses
of a
ntib
iotic
s
Non
e –
the
cons
eque
nces
too
dire
(leg
- an
d lif
eth
reat
enin
g)
Non
eN
one
10. W
hat
patie
nt, f
oot
orul
cer
char
acte
ristic
spr
ompt
you
to
cont
inue
with
cur
rent
man
agem
ent
of t
hese
DFU
s?
Prol
onge
d pr
esen
ceof
just
one
sig
n M
onda
y m
orni
ng –
patie
nt lo
oks
wel
l,no
rmal
CRP
and
ESR
Old
. Fra
il an
d ve
ry il
lan
yway
11. H
ow lo
ng w
ould
you
cont
inue
with
you
rcu
rren
t m
anag
emen
tof
the
se D
FUs
befo
rem
akin
g a
chan
ge?
D. T
he ‘u
ninf
ecte
d’, s
tati
c ul
cer
14da
ysD
epen
ds o
n th
e pa
tient
12. H
ow lo
ng w
ould
you
cont
inue
with
the
stan
dard
tre
atm
ent
befo
re m
akin
g a
chan
ge?
4w
eeks
6–8
wee
ks
Nee
d to
che
ck if
pres
sure
is r
eally
bei
ngof
fload
ed a
nd if
art
eria
lsu
pply
is r
eally
OK
If it
is slo
wly
impr
ovin
g,ne
ver
swab
. T
hey
have
a ‘p
athw
ay’ –
an
impr
essio
n of
how
an
ulce
r pr
ocee
ds, a
nd o
nly
swab
if it
dev
iate
s fr
omth
is
The
re is
no
time
guid
eU
ses
the
Mar
golis
crite
ria (t
here
sho
uld
bea
30%
red
uctio
n in
are
aby
wee
k 4)
3–4
wee
ks
Health Technology Assessment 2006; Vol. 10: No. 12
217
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
ref
erra
l D
: ter
tiar
y re
ferr
al
E: t
erti
ary
refe
rral
F:
ter
tiar
y re
ferr
al
refe
rral
cen
tre
cent
re in
Eng
land
ce
ntre
in E
ngla
ndce
ntre
, Wal
esce
ntre
, Can
ada
cent
re, E
ngla
nd(D
GH
wit
h (w
orks
clo
sely
wit
h a
diab
etes
cen
tre)
, bo
ne in
fect
ion
team
)En
glan
d
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
cont
inue
d
13. H
ow m
any
of t
hese
patie
nts
(out
of 1
0co
nsec
utiv
e) w
illco
mm
ence
a c
ours
eof
ora
l sys
tem
ican
tibio
tics
with
out
afo
rmal
dia
gnos
tic t
est
havi
ng t
aken
pla
ce?
Non
e. S
wab
firs
t an
dth
en d
epen
ding
on
the
resu
lts g
ive
antib
iotic
s
Neg
ligib
le
Oth
er t
reat
men
tsin
clud
e sil
ver/
iodi
nedr
essin
gs, r
emov
al o
fslo
ugh
Neg
ligib
le –
virt
ually
all
wou
ld b
e sa
mpl
ed. A
sth
e ch
oice
of a
ntib
iotic
sin
the
se p
eopl
e de
pend
sto
tally
on
the
bact
eria
pres
ent
0/10
(He
wou
ld s
wab
all
10 (b
efor
eus
ing
anan
tibio
tic) a
nd g
ive
topi
cal a
ntim
icro
bial
sw
hile
dec
idin
g w
hat
todo
Non
e –
he w
ould
sw
aban
d if
a ba
cter
ial r
epor
tco
mes
bac
k as
++
+,
then
he
wou
ld t
reat
14. W
hat
patie
nt, f
oot
orul
cer
char
acte
ristic
spr
ompt
ed y
ou t
opr
escr
ibe
oral
syst
emic
ant
ibio
tics
toco
mm
ence
imm
edia
tely
?
Non
eA
ver
y lo
ngst
andi
ngw
ound
See
abov
eIf
the
pers
on’s
dia
betic
cont
rol a
ppea
rs t
o be
dete
riora
ting
– th
enco
nsid
er in
fect
ion
as t
heca
use
Non
e –
he w
ould
not
15. H
ow m
any
of t
hesa
me
10 p
atie
nts
will
be fo
rmal
ly t
este
dus
ing
one
or m
ore
form
al d
iagn
ostic
tes
tsfo
r in
fect
ion,
i.e.
wou
nd b
iops
y, w
ound
swab
, X-r
ay, a
mon
got
hers
, and
rec
eive
no
syst
emic
ant
ibio
tics
until
the
res
ults
of t
hefo
rmal
tes
t ar
eob
tain
ed?
10/1
010
/10
10/1
0Re
asse
ss w
ith a
hig
her
inde
x of
sus
pici
on,
1. X
-ray
2. M
RI (a
sk lo
cal
radi
ogra
pher
for
advi
ce o
nim
agin
g)
10/1
010
/10
Neu
ropa
thic
=cu
rett
age
Neu
ro/is
chae
mic
=sw
ab
Appendix 7
218
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
ref
erra
l D
: ter
tiar
y re
ferr
al
E: t
erti
ary
refe
rral
F:
ter
tiar
y re
ferr
al
refe
rral
cen
tre
cent
re in
Eng
land
ce
ntre
in E
ngla
ndce
ntre
, Wal
esce
ntre
, Can
ada
cent
re, E
ngla
nd(D
GH
wit
h (w
orks
clo
sely
wit
h a
diab
etes
cen
tre)
, bo
ne in
fect
ion
team
)En
glan
d
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
cont
inue
d
16. W
hich
dia
gnos
tic t
est
wou
ld y
ou m
ost
com
mon
ly u
se?
Swab
Biop
sySw
ab
17. I
f an
initi
al d
iagn
ostic
test
pro
ved
unin
form
ativ
e an
d th
eul
cer
still
app
eare
din
fect
ed, w
ould
you
repe
at t
he s
ame
test
,O
R w
ould
you
use
adi
ffere
nt t
est
(e.g
.w
ould
you
rep
eat
aw
ound
sw
ab, o
rw
ould
you
use
aw
ound
bio
psy
to g
et a
bett
er s
ampl
e?).
Plea
se li
st t
he o
ptio
nsyo
u w
ould
use
in t
heor
der
you
wou
ld u
seth
em
Biop
sy (p
artic
ular
ly
if yo
u su
spec
t vi
ral
infe
ctio
n)
Bone
bio
psy
MRI
Resw
ab a
fter
a fe
ww
eeks
Mig
ht a
lso d
o an
X-r
ayan
d M
RI s
can
– pa
rtly
to
info
rm a
sses
smen
t of
prog
ress
, also
to
plan
surg
ery,
AN
D t
ope
rsua
de p
atie
nt t
hat
som
ethi
ng is
hap
peni
ngin
the
ir fo
ot (a
wal
king
time
bom
b)
Health Technology Assessment 2006; Vol. 10: No. 12
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
ref
erra
l D
: ter
tiar
y re
ferr
al
E: t
erti
ary
refe
rral
F:
ter
tiar
y re
ferr
al
refe
rral
cen
tre
cent
re in
Eng
land
ce
ntre
in E
ngla
ndce
ntre
, Wal
esce
ntre
, Can
ada
cent
re, E
ngla
nd(D
GH
wit
h (w
orks
clo
sely
wit
h a
diab
etes
cen
tre)
, bo
ne in
fect
ion
team
)En
glan
d
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
cont
inue
d
E. D
efin
itio
n of
clin
ical
infe
ctio
n
18. O
ne a
utho
r ha
s us
edth
e fo
llow
ing
defin
ition
of c
linic
alin
fect
ion
in d
iabe
ticfo
ot u
lcer
atio
n,‘e
ryth
ema,
indu
ratio
nan
d di
scha
rge’
(Cap
uto,
200
0).25
Are
ther
e an
y el
emen
ts o
fth
is de
finiti
on t
hat
you
disr
egar
d w
hen
asse
ssin
g D
FUs?
All
are
OK
Incl
ude
them
all
NB:
red
ness
and
pai
nm
ay c
ome
from
aC
harc
ot fo
ot, n
otin
fect
ion
(nee
d to
X-r
ayto
exc
lude
bon
ech
ange
s)
Indu
ratio
n: b
ecau
se o
fth
e m
odifi
ed r
espo
nse
to n
euro
path
y, t
hesy
mpa
thet
ic r
espo
nse
mea
ns t
hat
swel
ling
does
not
alw
ays
equa
lin
fect
ion.
Eryt
hem
a: im
port
ant,
but
in s
ever
ene
urop
athy
lack
of
eryt
hem
a do
es n
otm
ean
lack
of i
nfec
tion.
Disc
harg
e: n
ot u
sefu
l – if
you
alre
ady
see
pus
disc
harg
e yo
u ar
e to
ola
te! N
eed
to a
sses
sco
ntin
ually
the
vol
ume
and
char
acte
ristic
s of
disc
harg
e an
d ac
t if
ther
e is
a ch
ange
inth
ese
All
appe
ar r
elev
ant
All
appe
ar r
elev
ant.
Also
uses
ery
them
a gr
eate
rth
an 2
cm a
roun
d m
argi
nof
ulc
er.
Prob
e to
bon
e is
enou
ghon
its
own
to e
qual
infe
ctio
n, O
R th
epr
esen
ce o
f at
leas
t 2
signs
Wou
ld n
ot d
rop
any
219
Appendix 7
220
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
ref
erra
l D
: ter
tiar
y re
ferr
al
E: t
erti
ary
refe
rral
F:
ter
tiar
y re
ferr
al
refe
rral
cen
tre
cent
re in
Eng
land
ce
ntre
in E
ngla
ndce
ntre
, Wal
esce
ntre
, Can
ada
cent
re, E
ngla
nd(D
GH
wit
h (w
orks
clo
sely
wit
h a
diab
etes
cen
tre)
, bo
ne in
fect
ion
team
)En
glan
d
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
cont
inue
d
Oth
er in
form
atio
n
19.W
hat
is th
e lo
cal
choi
ce o
f firs
t lin
ean
tibio
tics
for
empi
rical
the
rapy
?
Cip
roflo
xaci
n,cl
inda
myc
in a
ndm
etro
nida
zole
(the
y al
lha
ve e
qual
tiss
uepe
netr
atio
n w
heth
ergi
ven
oral
or
i.v.)
–in
patie
nts
get
i.v.,
outp
atie
nts
get
oral
Clin
dam
ycin
and
cipr
oflo
xaci
nIn
patie
nts
get
amox
icill
in (f
or t
hest
rep.
), flu
clox
acill
in (f
orth
e st
aph.
), an
dm
etro
nida
zole
for
the
anae
robe
s an
dce
ftazi
dim
e fo
r th
eG
ram
neg
ativ
es
Out
patie
nts
get
diffe
rent
reg
imen
depe
ndin
g on
sev
erity
of in
fect
ion.
Supe
rfic
ial:
amox
icill
inan
d flu
clox
acill
inD
eep:
Am
oxic
illin
+flu
clox
acill
in +
met
roni
dazo
le +
cipr
oxin
Health Technology Assessment 2006; Vol. 10: No. 12
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
A: s
econ
dary
B
: ter
tiar
y re
ferr
al
C: s
econ
dary
ref
erra
l D
: ter
tiar
y E:
ter
tiar
y re
ferr
al
F: t
erti
ary
refe
rral
re
ferr
al c
entr
e ce
ntre
in E
ngla
nd
cent
re in
Eng
land
refe
rral
cen
tre,
ce
ntre
, Can
ada
cent
re, E
ngla
nd(D
GH
wit
h (w
orks
clo
sely
wit
h a
Wal
esdi
abet
es c
entr
e),
bone
infe
ctio
n te
am)
Engl
and
Que
stio
n↓
Podi
atri
stPo
diat
rist
Vas
cula
r su
rgeo
nN
urse
spe
cial
ist
Med
ical
doc
tor
Dia
beto
logi
st
20. O
ther
info
rmat
ion
The
y de
brid
e th
e ul
cers
dow
n to
a g
ood
base
Patie
nts
with
app
aren
tlysu
perf
icia
l inf
ectio
n ge
tflu
clox
acill
in. P
atie
nts
with
mor
eex
tens
ive/
seve
re m
ayge
t bi
opsie
s an
d ch
ange
antib
iotic
s on
tha
t ba
sis
NB:
ost
eom
yelit
is an
dso
ft tis
sue
infe
ctio
nstr
eate
d in
diff
eren
t w
ays
– yo
u m
ust
have
ade
finiti
ve c
ultu
re t
o ge
tth
e os
teom
yelit
istr
eate
d pr
oper
ly. T
oes
som
etim
es r
espo
nd t
oem
piric
al t
hera
py –
bac
kfo
ot b
ones
do
not
Onc
e as
sess
ed a
sin
fect
ed –
sw
ab a
ndst
art
loca
l ‘em
piric
alth
erap
y’ im
med
iate
ly.Re
asse
ss t
heap
prop
riate
ness
of t
hean
tibio
tic g
iven
in t
helig
ht o
f bot
h a
24 a
nd a
72-h
our
swab
res
ult
from
labo
rato
ry
Whe
n bo
ne is
infe
cted
the
cour
se o
f ant
ibio
tics
last
s fo
r 3
mon
ths
Stan
dard
car
e m
ust h
ave
vasc
ular
cor
rect
ion
whe
repo
ssib
le, c
ontr
ol o
f inf
ectio
nan
d pr
essu
re o
ff lo
adin
g
You
need
a g
ood
swab
bing
tech
niqu
e
Thi
nks
labo
rato
ry r
esul
tssh
ould
be
at le
ast s
emi-
quan
titat
ive
You
mus
t sam
ple
ever
ythi
ng a
tba
selin
e as
sess
men
t of
infe
ctio
n be
caus
e if
the
loca
l'e
mpi
rical
ther
apy'
does
not
wor
k th
en y
ou c
an ta
ilor
next
dose
A s
wab
doe
s no
t dia
gnos
ein
fect
ion
– th
e cl
inic
ian
does
that
. In
fect
ion
= d
ose/
host
resp
onse
You
do n
ot tr
eat t
he s
wab
, you
trea
t the
pat
ient
The
y su
rvey
ed 1
00 p
eopl
ew
ith n
euro
path
ic fo
ot u
lcer
s –
60%
had
had
ant
ibio
tics
in th
ela
st 6
mon
ths
Stat
ed ‘a
loca
l sw
ab m
irror
sth
e ba
cter
ia s
ampl
ed fr
om a
deep
er b
iops
y’
Men
tione
d cr
itica
l col
onisa
tion
– th
e w
ound
doe
s no
t loo
kin
fect
ed b
ut is
faili
ng to
impr
ove,
so
it m
ust b
e in
fect
ed
221
Health Technology Assessment 2006; Vol. 10: No. 12
235
Health Technology AssessmentProgramme
Prioritisation Strategy GroupMembers
Chair,Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool
Professor Bruce Campbell,Consultant Vascular & GeneralSurgeon, Royal Devon & ExeterHospital
Dr Edmund Jessop, MedicalAdvisor, National Specialist,Commissioning Advisory Group(NSCAG), Department ofHealth, London
Professor Jon Nicholl, Director,Medical Care Research Unit,University of Sheffield, Schoolof Health and Related Research
Dr John Reynolds, ClinicalDirector, Acute GeneralMedicine SDU, RadcliffeHospital, Oxford
Dr Ron Zimmern, Director,Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge
Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool
Deputy Director, Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch
HTA Commissioning BoardMembers
Programme Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool
Chair,Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch
Deputy Chair, Professor Jenny Hewison,Professor of Health CarePsychology, Academic Unit ofPsychiatry and BehaviouralSciences, University of LeedsSchool of Medicine
Dr Jeffrey AronsonReader in ClinicalPharmacology, Department ofClinical Pharmacology,Radcliffe Infirmary, Oxford
Professor Deborah Ashby,Professor of Medical Statistics,Department of Environmentaland Preventative Medicine,Queen Mary University ofLondon
Professor Ann Bowling,Professor of Health ServicesResearch, Primary Care andPopulation Studies,University College London
Dr Andrew Briggs, PublicHealth Career Scientist, HealthEconomics Research Centre,University of Oxford
Professor John Cairns, Professorof Health Economics, PublicHealth Policy, London School ofHygiene and Tropical Medicine,London
Professor Nicky Cullum,Director of Centre for EvidenceBased Nursing, Department ofHealth Sciences, University ofYork
Mr Jonathan Deeks, Senior Medical Statistician,Centre for Statistics inMedicine, University of Oxford
Dr Andrew Farmer, SeniorLecturer in General Practice,Department of Primary Health Care, University of Oxford
Professor Fiona J Gilbert,Professor of Radiology,Department of Radiology,University of Aberdeen
Professor Adrian Grant,Director, Health ServicesResearch Unit, University ofAberdeen
Professor F D Richard Hobbs,Professor of Primary Care &General Practice, Department ofPrimary Care & GeneralPractice, University ofBirmingham
Professor Peter Jones, Head ofDepartment, UniversityDepartment of Psychiatry,University of Cambridge
Professor Sallie Lamb, Professor of Rehabilitation,Centre for Primary Health Care, University of Warwick
Professor Stuart Logan,Director of Health & SocialCare Research, The Peninsula Medical School, Universities of Exeter &Plymouth
Dr Linda Patterson, Consultant Physician,Department of Medicine,Burnley General Hospital
Professor Ian Roberts, Professorof Epidemiology & PublicHealth, Intervention ResearchUnit, London School ofHygiene and Tropical Medicine
Professor Mark Sculpher,Professor of Health Economics,Centre for Health Economics,Institute for Research in theSocial Services, University of York
Dr Jonathan Shapiro, SeniorFellow, Health ServicesManagement Centre,Birmingham
Ms Kate Thomas,Deputy Director,Medical Care Research Unit,University of Sheffield
Ms Sue Ziebland,Research Director, DIPEx,Department of Primary HealthCare, University of Oxford,Institute of Health Sciences
Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)
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Health Technology Assessment Programme
236
Diagnostic Technologies & Screening PanelMembers
Chair,Dr Ron Zimmern, Director ofthe Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge
Ms Norma Armston,Lay Member, Bolton
Professor Max BachmannProfessor of Health Care Interfaces, Department of Health Policy and Practice,University of East Anglia
Professor Rudy BilousProfessor of Clinical Medicine &Consultant Physician,The Academic Centre,South Tees Hospitals NHS Trust
Dr Paul Cockcroft, Consultant MedicalMicrobiologist and ClinicalDirector of Pathology,Department of ClinicalMicrobiology, St Mary'sHospital, Portsmouth
Professor Adrian K Dixon,Professor of Radiology,University Department ofRadiology, University ofCambridge Clinical School
Dr David Elliman, Consultant Paediatrician/Hon. Senior Lecturer,Population Health Unit, Great Ormond St. Hospital,London
Professor Glyn Elwyn,Primary Medical Care Research Group,Swansea Clinical School,University of Wales Swansea
Mr Tam Fry, HonoraryChairman, Child GrowthFoundation, London
Dr Jennifer J Kurinczuk,Consultant ClinicalEpidemiologist,National PerinatalEpidemiology Unit, Oxford
Dr Susanne M Ludgate, MedicalDirector, Medicines &Healthcare Products RegulatoryAgency, London
Professor William Rosenberg,Professor of Hepatology, LiverResearch Group, University ofSouthampton
Dr Susan Schonfield, Consultantin Public Health, SpecialisedServices Commissioning NorthWest London, HillingdonPrimary Care Trust
Dr Phil Shackley, SeniorLecturer in Health Economics,School of Population andHealth Sciences, University ofNewcastle upon Tyne
Dr Margaret Somerville, PMSPublic Health Lead, PeninsulaMedical School, University ofPlymouth
Dr Graham Taylor, ScientificDirector & Senior Lecturer,Regional DNA Laboratory, TheLeeds Teaching Hospitals
Professor Lindsay WilsonTurnbull, Scientific Director,Centre for MR Investigations &YCR Professor of Radiology,University of Hull
Professor Martin J Whittle,Associate Dean for Education,Head of Department ofObstetrics and Gynaecology,University of Birmingham
Dr Dennis Wright, Consultant Biochemist &Clinical Director, Pathology & The KennedyGalton Centre, Northwick Park & St Mark’sHospitals, Harrow
Pharmaceuticals PanelMembers
Chair,Dr John Reynolds, ChairDivision A, The John RadcliffeHospital, Oxford RadcliffeHospitals NHS Trust
Professor Tony Avery, Head of Division of PrimaryCare, School of CommunityHealth Services, Division ofGeneral Practice, University ofNottingham
Ms Anne Baileff, ConsultantNurse in First Contact Care,Southampton City Primary CareTrust, University ofSouthampton
Professor Stirling Bryan,Professor of Health Economics,Health Services Management Centre,University of Birmingham
Mr Peter Cardy, ChiefExecutive, Macmillan CancerRelief, London
Professor Imti Choonara,Professor in Child Health,Academic Division of ChildHealth, University ofNottingham
Dr Robin Ferner, ConsultantPhysician and Director, WestMidlands Centre for AdverseDrug Reactions, City HospitalNHS Trust, Birmingham
Dr Karen A Fitzgerald,Consultant in PharmaceuticalPublic Health, National PublicHealth Service for Wales,Cardiff
Mrs Sharon Hart, Head of DTB Publications, Drug &Therapeutics Bulletin, London
Dr Christine Hine, Consultant inPublic Health Medicine, SouthGloucestershire Primary CareTrust
Professor Stan Kaye,Cancer Research UK Professor of Medical Oncology,Section of Medicine, The Royal Marsden Hospital,Sutton
Ms Barbara Meredith,Lay Member, Epsom
Dr Andrew Prentice, SeniorLecturer and ConsultantObstetrician & Gynaecologist,Department of Obstetrics &Gynaecology, University ofCambridge
Dr Frances Rotblat, CPMPDelegate, Medicines &Healthcare Products RegulatoryAgency, London
Professor Jan Scott, Professor of Psychological Treatments,Institute of Psychiatry,University of London
Mrs Katrina Simister, AssistantDirector New Medicines,National Prescribing Centre,Liverpool
Dr Richard Tiner, MedicalDirector, Medical Department,Association of the BritishPharmaceutical Industry,London
Dr Helen Williams,Consultant Microbiologist,Norfolk & Norwich UniversityHospital NHS Trust
Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)
Health Technology Assessment 2006; Vol. 10: No. 12
237
Therapeutic Procedures PanelMembers
Chair, Professor Bruce Campbell,Consultant Vascular andGeneral Surgeon, Departmentof Surgery, Royal Devon &Exeter Hospital
Dr Aileen Clarke,Reader in Health ServicesResearch, Public Health &Policy Research Unit, Barts &the London School of Medicine& Dentistry, London
Dr Matthew Cooke, Reader inA&E/Department of HealthAdvisor in A&E, WarwickEmergency Care andRehabilitation, University ofWarwick
Dr Carl E Counsell, ClinicalSenior Lecturer in Neurology,Department of Medicine andTherapeutics, University ofAberdeen
Ms Amelia Curwen, ExecutiveDirector of Policy, Services andResearch, Asthma UK, London
Professor Gene Feder, Professorof Primary Care R&D,Department of General Practiceand Primary Care, Barts & theLondon, Queen Mary’s Schoolof Medicine and Dentistry,London
Professor Paul Gregg,Professor of OrthopaedicSurgical Science, Department ofGeneral Practice and PrimaryCare, South Tees Hospital NHSTrust, Middlesbrough
Ms Bec Hanley, Co-Director,TwoCan Associates,Hurstpierpoint
Ms Maryann L Hardy, Lecturer, Division ofRadiography, University ofBradford
Professor Alan Horwich,Director of Clinical R&D,Academic Department ofRadiology, The Institute ofCancer Research, London
Dr Simon de Lusignan,Senior Lecturer, Primary Care Informatics,Department of CommunityHealth Sciences,St George’s Hospital MedicalSchool, London
Professor Neil McIntosh,Edward Clark Professor of Child Life & Health,Department of Child Life &Health, University of Edinburgh
Professor James Neilson,Professor of Obstetrics andGynaecology, Department ofObstetrics and Gynaecology,University of Liverpool
Dr John C Pounsford,Consultant Physician,Directorate of Medical Services,North Bristol NHS Trust
Karen Roberts, NurseConsultant, Queen ElizabethHospital, Gateshead
Dr Vimal Sharma, ConsultantPsychiatrist/Hon. Senior Lecturer,Mental Health Resource Centre,Cheshire and Wirral PartnershipNHS Trust, Wallasey
Dr L David Smith, ConsultantCardiologist, Royal Devon &Exeter Hospital
Professor Norman Waugh,Professor of Public Health,Department of Public Health,University of Aberdeen
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Health Technology Assessment Programme
238Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)
Expert Advisory NetworkMembers
Professor Douglas Altman,Director of CSM & CancerResearch UK Med Stat Gp,Centre for Statistics inMedicine, University of Oxford,Institute of Health Sciences,Headington, Oxford
Professor John Bond,Director, Centre for HealthServices Research, University ofNewcastle upon Tyne, School ofPopulation & Health Sciences,Newcastle upon Tyne
Mr Shaun Brogan, Chief Executive, RidgewayPrimary Care Group, Aylesbury
Mrs Stella Burnside OBE,Chief Executive, Office of theChief Executive. TrustHeadquarters, AltnagelvinHospitals Health & SocialServices Trust, Altnagelvin AreaHospital, Londonderry
Ms Tracy Bury, Project Manager, WorldConfederation for PhysicalTherapy, London
Professor Iain T Cameron,Professor of Obstetrics andGynaecology and Head of theSchool of Medicine,University of Southampton
Dr Christine Clark,Medical Writer & ConsultantPharmacist, Rossendale
Professor Collette Clifford,Professor of Nursing & Head ofResearch, School of HealthSciences, University ofBirmingham, Edgbaston,Birmingham
Professor Barry Cookson,Director, Laboratory ofHealthcare Associated Infection,Health Protection Agency,London
Professor Howard Cuckle,Professor of ReproductiveEpidemiology, Department ofPaediatrics, Obstetrics &Gynaecology, University ofLeeds
Dr Katherine Darton, Information Unit, MIND – The Mental Health Charity,London
Professor Carol Dezateux, Professor of PaediatricEpidemiology, London
Mr John Dunning,Consultant CardiothoracicSurgeon, CardiothoracicSurgical Unit, PapworthHospital NHS Trust, Cambridge
Mr Jonothan Earnshaw,Consultant Vascular Surgeon,Gloucestershire Royal Hospital,Gloucester
Professor Martin Eccles, Professor of ClinicalEffectiveness, Centre for HealthServices Research, University ofNewcastle upon Tyne
Professor Pam Enderby,Professor of CommunityRehabilitation, Institute ofGeneral Practice and PrimaryCare, University of Sheffield
Mr Leonard R Fenwick, Chief Executive, Newcastleupon Tyne Hospitals NHS Trust
Professor David Field, Professor of Neonatal Medicine,Child Health, The LeicesterRoyal Infirmary NHS Trust
Mrs Gillian Fletcher, Antenatal Teacher & Tutor andPresident, National ChildbirthTrust, Henfield
Professor Jayne Franklyn,Professor of Medicine,Department of Medicine,University of Birmingham,Queen Elizabeth Hospital,Edgbaston, Birmingham
Ms Grace Gibbs, Deputy Chief Executive,Director for Nursing, Midwifery& Clinical Support Services, West Middlesex UniversityHospital, Isleworth
Dr Neville Goodman, Consultant Anaesthetist,Southmead Hospital, Bristol
Professor Alastair Gray,Professor of Health Economics,Department of Public Health,University of Oxford
Professor Robert E Hawkins, CRC Professor and Director ofMedical Oncology, Christie CRCResearch Centre, ChristieHospital NHS Trust, Manchester
Professor Allen Hutchinson, Director of Public Health &Deputy Dean of ScHARR,Department of Public Health,University of Sheffield
Dr Duncan Keeley,General Practitioner (Dr Burch& Ptnrs), The Health Centre,Thame
Dr Donna Lamping,Research Degrees ProgrammeDirector & Reader in Psychology,Health Services Research Unit,London School of Hygiene andTropical Medicine, London
Mr George Levvy,Chief Executive, MotorNeurone Disease Association,Northampton
Professor James Lindesay,Professor of Psychiatry for theElderly, University of Leicester,Leicester General Hospital
Professor Julian Little,Professor of Human GenomeEpidemiology, Department ofEpidemiology & CommunityMedicine, University of Ottawa
Professor Rajan Madhok, Medical Director & Director ofPublic Health, Directorate ofClinical Strategy & PublicHealth, North & East Yorkshire& Northern Lincolnshire HealthAuthority, York
Professor David Mant, Professor of General Practice,Department of Primary Care,University of Oxford
Professor Alexander Markham, Director, Molecular MedicineUnit, St James’s UniversityHospital, Leeds
Dr Chris McCall, General Practitioner, TheHadleigh Practice, Castle Mullen
Professor Alistair McGuire,Professor of Health Economics,London School of Economics
Dr Peter Moore, Freelance Science Writer, Ashtead
Dr Sue Moss, Associate Director,Cancer Screening EvaluationUnit, Institute of CancerResearch, Sutton
Mrs Julietta Patnick, Director, NHS Cancer ScreeningProgrammes, Sheffield
Professor Tim Peters,Professor of Primary CareHealth Services Research,Academic Unit of PrimaryHealth Care, University ofBristol
Professor Chris Price, Visiting Chair – Oxford, ClinicalResearch, Bayer DiagnosticsEurope, Cirencester
Professor Peter Sandercock,Professor of Medical Neurology,Department of ClinicalNeurosciences, University ofEdinburgh
Dr Eamonn Sheridan,Consultant in Clinical Genetics,Genetics Department,St James’s University Hospital,Leeds
Dr Ken Stein,Senior Clinical Lecturer inPublic Health, Director,Peninsula TechnologyAssessment Group, University of Exeter
Professor Sarah Stewart-Brown, Professor of Public Health,University of Warwick, Division of Health in theCommunity Warwick MedicalSchool, LWMS, Coventry
Professor Ala Szczepura, Professor of Health ServiceResearch, Centre for HealthServices Studies, University ofWarwick
Dr Ross Taylor, Senior Lecturer, Department ofGeneral Practice and PrimaryCare, University of Aberdeen
Mrs Joan Webster, Consumer member, HTA –Expert Advisory Network
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HTA
Health Technology A
ssessment 2006;Vol. 10: N
o. 12A
decision analysis for sampling and treating infected diabetic foot ulcers
A series of systematic reviews toinform a decision analysis for samplingand treating infected diabetic footulcers
EA Nelson, S O’Meara, D Craig, C Iglesias, S Golder, J Dalton, K Claxton, SEM Bell-Syer, E Jude, C Dowson, R Gadsby, P O’Hareand J Powell
Health Technology Assessment 2006; Vol. 10: No. 12
HTAHealth Technology AssessmentNHS R&D HTA Programme
The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 23 8059 5639 Email: [email protected]://www.hta.ac.uk ISSN 1366-5278
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