Expert opinion on the management of infections inthe diabetic foot

B. A. Lipsky1*E. J. G. Peters2

E. Senneville3

A. R. Berendt4

J. M. Embil5

L. A. Lavery6

V. Urbančič-Rovan7

W. J. Jeffcoate8

1VA Puget Sound Health Care System,University of Washington, Seattle, WA,USA2VU University Medical Centre,Amsterdam, The Netherlands3Gustave Dron Hospital, Tourcoing,France4Bone Infection Unit, NuffieldOrthopaedic Centre, Oxford UniversityHospitals NHS Trust, Oxford, UK5University of Manitoba, Winnipeg,Manitoba, Canada6University of Texas SouthwesternMedical Center and Parkland Hospital,Dallas, TX, USA7University Medical Centre, Ljubljana,Slovenia8Nottingham University HospitalsTrust, Nottingham, UK

*Correspondence to: B. A. Lipsky,University of Washington, DirectorPrimary Care Clinic, VA Puget Sound,VA Puget Sound System, 1660 SouthColumbian Way (S-123-GMS),Seattle, WA 98108, USA.E-mail: dblipsky@hotmail.com

Summary

This update of the International Working Group on the Diabetic Foot incorpo-rates some information from a related review of diabetic foot osteomyelitis(DFO) and a systematic review of the management of infection of the diabeticfoot. The pathophysiology of these infections is now well understood, andthere is a validated system for classifying the severity of infections based ontheir clinical findings. Diagnosing osteomyelitis remains difficult, but severalrecent publications have clarified the role of clinical, laboratory and imagingtests. Magnetic resonance imaging has emerged as the most accurate meansof diagnosing bone infection, but bone biopsy for culture and histopathologyremains the criterion standard. Determining the organisms responsible for adiabetic foot infection via culture of appropriately collected tissue specimensenables clinicians to make optimal antibiotic choices based on culture and sen-sitivity results. In addition to culture-directed antibiotic therapy, most infec-tions require some surgical intervention, ranging from minor debridement tomajor resection, amputation or revascularization. Clinicians must also provideproper wound care to ensure healing of the wound. Various adjunctive thera-pies may benefit some patients, but the data supporting them are weak. Ifproperly treated, most diabetic foot infections can be cured. Providers practis-ing in developing countries, and their patients, face especially challengingsituations. Copyright © 2012 John Wiley & Sons, Ltd.

Keywords diabetes mellitus; diabetic foot; infection; osteomyelitis; antibiotics;surgery; systematic review

Introduction

This report from the expert panel on infectious diseases of the InternationalWorking Group on the Diabetic Foot (IWGDF) is an update of the one pub-lished in 2004 [1], incorporating some information from a related IWGDF2008 publication on osteomyelitis [2] and from the concurrently published‘Systematic Review of the Effectiveness of Interventions in the Managementof Infection in the Diabetic Foot’ [3]. Our intention is to present a brief over-view to assist clinicians worldwide in diagnosing and treating foot infectionsin persons with diabetes. Separately, we have proposed ‘Specific Guidelineson the Management of Diabetic Foot Infections’, also published concurrentlyin this journal.

The development of a foot infection is associated with substantial morbidity,including discomfort, healthcare provider visits, antibiotic therapy, wound careand often surgical procedures. Furthermore, foot infection is now the mostfrequent diabetic complication requiring hospitalization and the most commonprecipitating event leading to lower extremity amputation [4–6]. Managinginfection requires careful attention to properly diagnosing the condition,

REVIEW ARTICLE

Received: 12 October 2011Accepted: 12 October 2011

Copyright 2012 John Wiley & Sons, Ltd.

DIABETES/METABOLISM RESEARCH AND REVIEWSDiabetes Metab Res Rev 2012; 28(Suppl 1): 163–178.Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2248

obtaining specimens for culture, selecting empirical anddefinitive antimicrobial therapy, determining when surgi-cal interventions are needed and caring for the wound. Asystematic and, to the extent possible, evidence-basedapproach to diabetic foot infections (DFIs) should resultin better outcomes.

Pathophysiology

In persons with diabetes, foot infection is a common prob-lem. Infection is best defined as invasion and multiplicationofmicroorganisms in host tissues that induces a host inflam-matory response, usually followed by tissue destruction.DFI is defined clinically as a soft tissue or bone infectionanywhere below the malleoli. These infections usuallyoccur in a site of skin trauma or ulceration [7]. Peripheralneuropathy is the main factor leading to skin breaks andulcerations, which then become colonized with skin floraand ultimately infected. Foot ischemia, related to peripheralarterial disease, is also common in patients with a DFI;while rarely the primary cause of foot wounds, the presenceof limb ischemia increases the risk of a wound becominginfected [8] and adversely affects the outcome of infection[9]. Factors that predispose to foot infection include havingawound that is deep, long-standing or recurrent, ill-defineddiabetes-related immunological perturbations and chronicrenal failure [8,10,11].Whilemost DFIs are relatively super-ficial at presentation, microorganisms can spread contigu-ously to subcutaneous tissues, including fascia, tendons,muscle, joints and bone. The anatomy of the foot, which isdivided into several rigid but intercommunicating

compartments, fosters proximal spread of infection. Wheninfection-induced pressure in a compartment exceeds capil-lary pressure, ischemic necrosis may ensue [12,13]. Sys-temic symptoms (e.g. feverishness, chills), marked leukocy-tosis or major metabolic disturbances are uncommon inpatients with a DFI, but their presence denotes a more se-vere, potentially limb (or even life) threatening infection[14,15]. If not diagnosed and properly treated, DFIs tendto progress, sometimes rapidly.

Classification

The clinician must first diagnose the presence of a DFI andthen should classify the infection’s severity. Over the pastthree decades, investigators have proposed many classifi-cation schemes for diabetic foot wounds. Most of thesetake into account the size and depth of the ulcer and thepresence or absence of gangrene, neuropathy or arterialinsufficiency. While several include the presence or ab-sence of ‘infection’ (rarely defined), only two (nearly iden-tical) schemes proposed by the Infectious Diseases Societyof America and the IWGDF (Table 1) describe how todefine both the presence and severity of infection [16].

Diagnosis

Soft tissue infection

Because all skin wounds harbour microorganisms, theirmere presence, even if they are virulent species, cannot

Table 1. The classification systems for defining the presence and severity of an infection of the foot in a person with diabetes de-veloped by the Infectious Diseases Society of America (IDSA) and the International Working Group on the Diabetic Foot (IWGDF)

Clinical classification of infection (IDSA), with definitions IWGDF grade (IDSA classification)

Uninfected: No systemic or local symptoms or signs of infection 1 (uninfected)

Infected:– At least two of the following items are present:

•Local swelling or induration•Erythema >0.5 cm1 around the ulcer•Local tenderness or pain•Local warmth•Purulent discharge

– Other causes of an inflammatory response of the skin should be excluded (e.g. trauma,gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis, venous stasis)

– Infection involving the skin or subcutaneous tissue only (without involvement ofdeeper tissues and without systemic signs as described below)

2 (mild infection)

– Any erythema present extends <2 cm1 around the wound– No systemic signs or symptoms of infection (see below)

– Infection involving structures deeper than skin and subcutaneous tissues (e.g. bone,joint, tendon) or erythema extending >2 cm1 from the wound margin

3 (moderate infection)

– No systemic signs or symptoms of infection (see below)

– Any foot infection with the following signs of a systemic inflammatory responsesyndrome, as manifested by ≥2 of the following:

4 (severe infection)

•Temperature >38 or <36 �C•Heart rate >90beats/min•Respiratory rate >20breaths/min or PaCO2 <32mmHg•White blood cell count >12000 or <4000 cu/mm or 10% immature (band) forms

1In any direction.

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be taken as evidence of infection. Some maintain that thepresence of high numbers of bacteria (usually defined as≥105 colony forming units per gram per tissue) shouldbe the basis for diagnosing infection [17], but no convinc-ing data support this concept in the diabetic foot; further-more, quantitative microbiology is rarely available outsideof research laboratories. Thus, DFI must be diagnosedclinically (Table 1), with wound cultures reserved for de-termining the causative organisms and their antibioticsensitivities. Clinical diagnosis rests on the presence ofat least two local findings of inflammation, that is, redness(erythema or rubour), warmth (calour), pain or tender-ness (dolour), induration (swelling or tumour) or puru-lent secretions [16]. Other (sometimes called secondary)features suggestive of infection include the presence ofnecrosis, friable or discoloured granulation tissue, non-purulent secretions, foetid odour or the failure of a prop-erly treated wound to heal [18]. These may be helpfulwhen local and systemic inflammatory signs are dimin-ished because of peripheral neuropathy or ischemia[19–21]. Because infection can worsen quickly, the diag-nosis should be pursued methodically [19] and aggres-sively [22]. All wounds must be carefully inspected,palpated and probed, both at initial presentation and onfollow-up. Various imaging and laboratory studies maybe useful in some cases to define the extent of soft tissueinfection and any bone involvement.

Osteomyelitis

Accurately diagnosing bone infection can be difficult butis essential to ensure appropriate treatment. A definitediagnosis of osteomyelitis requires both the presence ofhistological findings consistent with bone infection (inflam-matory cells, necrosis) and the isolation of bacteria from anaseptically obtained bone sample [2]. Because these proce-dures are not routinely available in many settings, cliniciansmust often use surrogate diagnostic markers, includingclinical, laboratory and imaging findings.

The clinical presentation of osteomyelitis in the diabeticfoot can vary with the site involved, the extent of infectedand dead bone, the presence of associated abscess and softtissue involvement, the causative organism(s) and the ade-quacy of limb perfusion. The main problems in diagnosingosteomyelitis are the delay in detecting bony changes inearly infection on plain radiographs and the difficulty in dis-tinguishing bony changes caused by infection from thoserelated to Charcot neuro-osteoarthropathy (CN) on mostimaging studies. As will be discussed, analyses fromrecent expert publications [2,23] and systematic reviews[2,24,25] provide guidance on the best diagnostic studies.

Clinical evaluationClinicians should suspect osteomyelitis when an ulceroverlying a bony prominence fails to heal despite ade-quate off-loading or when a toe is erythematous and indu-rated. The likelihood ratio (LR) of a clinician’s suspicion ofosteomyelitis is surprisingly good: positive LR 5.5 and

negative LR 0.54 [24,25]. The presence of exposed bonehas a positive LR for osteomyelitis of 9.2; large ulcers(area> 2 cm2) are much more likely to have underlyingbone infection than smaller ones [24–27]. Osteomyelitiscan, however, occur in the absence of overlying local signsof inflammation [26].

Probe-to-bone testThis is a useful clinical diagnostic tool. Striking bone(detected by the hard, gritty feel) with a blunt sterile metalprobe gently inserted through a wound increases the likeli-hood that the patient has osteomyelitis if the prevalence ofbone infection is high (i.e. >60%) in the population underscrutiny [28,29]. Conversely, a negative probe-to-bone testin a patient at low risk (i.e. ≤20%) essentially rules outosteomyelitis [30–32].

Blood testsThe erythrocyte sedimentation rate is diagnostically useful;when elevated (usually defined as>70mm/h), it increasesthe likelihood of osteomyelitis underlying a diabetic footwound (positive LR 11), while lower levels reduce the like-lihood (negative LR of 0.34) [24,26,33,34]. Based on fewerdata, an elevated C-reactive protein, procalcitonin or bloodleukocyte count may also be predictive of the presence ofosteomyelitis [34,35].

Imaging studiesPlain radiography. Characteristic features of osteomyelitison plain X-rays of the foot (usually two or three views) aresummarized in Table 2 [26,36–38]. Among the manystudies that have assessed the accuracy of plain radiographyin diagnosing osteomyelitis [26,36,38–53], nine were pro-spective in design [26,36,38–41,44,45,52]. Overall, the

Table 2. Common imaging features of diabetic footosteomyelitis

Plain radiographs

•Periosteal reaction or elevation•Loss of cortex with bony erosion•Focal loss of trabecular pattern or marrow radiolucency•New bone formation•Bone sclerosis with or without erosion•Sequestrum: devitalized bone with radiodense appearance thathas become separated from normal bone•Involucrum: a layer of new bone growth outside existing boneresulting from the stripping off of the periosteum and new bonegrowing from the periosteum•Cloacae: opening in involucrum or cortex through whichsequestra or granulation tissue may be discharged

Magnetic resonance imaging

•Low focal signal intensity on T1-weighted images•High focal signal on T2-weighted images•High bone marrow signal in short tau inversion recovery (STIR)sequences•Less specific or secondary changes:oCortical disruptionoAdjacent cutaneous ulceroSoft tissue massoSinus tract formationoAdjacent soft tissue inflammation or oedema

For both modalities, bony changes are often accompanied bycontiguous soft tissue swelling.

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sensitivity varied from 28% to 75%. The timing of the imag-ing greatly influences its usefulness, as longer-standingcases are more likely to show bony abnormalities on plainradiographs than those present for less than a couple ofweeks. In the systematic review by Dinh et al. [25], thepooled sensitivity of the four eligible studies was 0.54 andthe pooled specificity was 0.68, with a diagnostic odds ratioof 2.84 and a Q statistic of 0.60 [26,36,38,52]. In the sys-tematic review by Butalia et al. [24], analysing seven studiesof plain radiographs, the summary positive likelihood ratiowas 2.3 [95% confidence intervals (CI) 1.6–3.3], whilethe negative likelihood ratio was 0.63 (95% CI 0.5–0.8)[26,36,38,43,47,48,50]. These results suggest that radio-graphic findings are only marginally predictive of osteomy-elitis if positive and even less predictive of the absence ofosteomyelitis if negative. Of note is that neither reviewidentified a study that obtained sequential plain radio-graphs of the foot over time. Changes in radiological appear-ance over an interval of at least 2weeks are more likely topredict the presence of osteomyelitis than a single study,although correctly targeted antibiotic therapy may preventthese changes.

Magnetic resonance imaging. Magnetic resonance imaging(MRI) is a valuable tool for diagnosing osteomyelitis, aswellas defining the presence and anatomy of deep soft tissueinfections [16]. The key features suggestive of osteomyelitison MRI are listed in Table 2. In their meta-analysis, Dinhet al. [25] identified four trials using MRI, all of which wereprospective [27,36,38,54] and two of which used a consec-utive recruitment method [36,38], but only one was con-ducted within the past 10 years [27]. The prevalence ofosteomyelitis in the four studies ranged from 44% to 86%.The pooled sensitivity of MRI for diabetic foot osteomyelitis(DFO) was 0.90 (CI 0.82–0.95), and the diagnostic odds ra-tio was 24.4. In 16 trials identified in the meta-analysis byKapoor et al. [55], 9 were prospective studies and 11 in-cluded only subjects with diabetes, although enrolment cri-teria were quite varied. The prevalence of standard definedosteomyelitis was 50% (range 32% to 89%), the pooled sen-sitivity was 77–100% and the specificity was 40–100%. Insubjects with diabetes, the diagnostic odds ratio was 42 (CI15–120), the summary positive likelihood ratio was 3.8 (CI0.2.5–5.8) and the summary negative likelihood ratio was0.14 (CI 0.08–0.26) [27,36,38,41,45,49,51,56–64]. More re-cently performed studies reported lower diagnostic odds ra-tios (25, CI 6–117) compared with older ones, perhaps be-cause their study designs were better. The subgroups ofpatients with other diagnoses (e.g. CN) were too small to an-alyse any differences among the studies.

Nuclear medicine. Three recent meta-analyses reviewednuclear medicine techniques for evaluating the diabeticfoot [25,55,65]. Capriotti et al. reviewed 57 papers, in-cluding seven reviews on the clinical value of severalnuclear medicine methods [65]. Among the severaltypes of nuclear imaging scans, a bone scan, usuallyperformed with 99mTc-methylene diphosphate anddone in time-sequence phases, is considered suggestiveof osteomyelitis when it discloses increased blood-pool

activity and radionuclide intensity localized to the bone[25]. Three-phase bone scans are sensitive (90%), butnot specific (46%) [65], with a calculated summarynegative predictive value of 71% and positive predic-tive value of 65%. Among six studies with 185 subjectsthat qualified for the meta-analysis by Dinh et al. [25],the pooled sensitivity was 80%, but the specificity wasonly 28% [26,36,38,52,66,67]. The pooled diagnosticodds ratio was 2.1, indicating poor discriminating ability,while the Q statistic was 0.6, indicating moderate accuracyfor the diagnosis of osteomyelitis [25]. On the basis of sevenstudies, Kapoor et al. [55] found the performance character-istics of a triple-phase bone scan were markedly inferior toMRI [38,41,45,49,58,63,64], with a diagnostic odds ratioof 3.5 (CI 1.0–13) versus 150 (CI 55–411), respectively[55]. Healthy bone may also have an increased uptake ofthe radiopharmaceutical, especially in the forefoot [65].While a positive bone scan is certainly not specific forosteomyelitis (or CN), a negative one largely rules it out.

Radiolabelled white blood cells (usually using either99mTechnetium or 111Indium) are generally not taken upby healthy bone, making positive leukocyte scans morespecific than bone scans for diagnosing osteomyelitis(and excluding CN) [65]. In a review of these scans byCapriotti et al., the summary positive predictive valuesfor osteomyelitis were 90% and 72%, respectively, andthe negative predictive values were 81% and 83%, respec-tively [65]. 99mTc labelling appears to provide superiorphysical characteristics, leading to better spatial resolu-tion than 111In [65]. In another recent review, Palestroand Love concluded that among radionuclide procedures,labelled leukocyte imaging is the best choice for evaluatingdiabetic pedal osteomyelitis, with a sensitivity of 72% to100% and specificity of 67% to 98% [68]. Dinh et al. [25]identified six studies using 111Indium-radiolabelled leuko-cytes, with a pooled sensitivity of 74% and a specificity of68% [26,36,38,52,66,67]. The pooled diagnostic odds ratiowas 10, indicating moderately good discriminating charac-teristics, while the Q statistic of 0.59 suggests a low to mod-erate accuracy for the diagnosis of osteomyelitis [25].Kapoor et al. [55] found that in three studies, MRI outper-formed leukocyte scanning (with 99mTc [64] or 111In[45,49]) with diagnostic odds ratios of 120 (CI 62–234)and 3.4 (CI 0.2–62), respectively. The combination of la-belled leukocytes with a bone scan (dual tracer technique)does not substantially improve diagnostic accuracy [46].

Other available nuclear medicine techniques includein vivo methods of labelling leukocytes, radiolabeled poly-clonal IgG and radiolabelled antibiotics. Results of studiesusing these techniques have varied, and most of the meth-ods are unavailable inmany countries. 99mTc-/111In labelledhuman immunoglobin G uptake is related to vascular per-meability, not inflamed tissue, and thus not as specific asradiolabelled leukocytes [50,69]. The pooled positive andnegative predictive values for this technique, calculatedfrom 97 lesions, were 72% and 88%, respectively [65].

Other imaging techniques. Two published studies of com-puter tomography (CT) and CT combined with positron

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emission tomography (PET) scans for the diagnosis of osteo-myelitis [25] did not include histopathological examinationof bone [70,71]. A recent prospective study that enrolled110 patients reported that PET/CT scan had a sensitivity of81%, specificity of 93%, positive predictive value of 78%,negative predictive value 94% and accuracy of 90%, whichwas somewhat better than a simultaneous MRI [72]. Whilethe data on this new procedure are limited, there seems tobe a place for CT (especially if combined with PET) scanswhen MRI is unavailable or contraindicated.

Bone biopsyThe weight of current evidence supports evaluating abone specimen as the best available diagnostic techniquefor both diagnosing bone infection and providing reliabledata on the responsible organisms and their antibiotic sus-ceptibility profile [3]. Soft tissue or sinus tract cultures arenot sufficiently accurate in predicting bone pathogens[73,74]. Ideally, it would be best to process a bone speci-men for both culture and histopathology. While infectedbone usually has inflammatory cells (granulocytes earlyand mononuclear cells later), the histomorphology of un-infected bone is normal in diabetic patients, including inthose with neuropathy or vasculopathy [75]. Unfortu-nately, both histology and culture may be misleadingresults. Culture of a bone specimen may be falsely nega-tive because of sampling errors, prior antibiotic therapyor a failure to isolate fastidious organisms. It may alsobe falsely positive because of contamination by wound-colonizing flora not involved in bone infection. Similarly,bone histopathology may be falsely negative due to sam-pling error or potentially falsely positive due to somenon-infectious inflammatory disorder. In a recent analysisof 44 patients, a comparison of microbiological and histo-pathological testing demonstrated that they performedsimilarly in identifying the presence of pedal osteomyelitisin the diabetic foot [76].

In one retrospective multicentre study, using bone cul-ture-guided antibiotic treatment was associated with asignificantly better clinical outcome than using soft tissueculture results [77]; this finding requires confirmation bya prospective study. While success rates of 75% or higherhave been reported with empiric treatment of diabeticfoot osteomyelitis (DFO) it is difficult to compare theresults of available published studies because of their dif-ferences in the populations enrolled, in the criteria forboth diagnosis and remission of infection and in durationsof follow-up [78]. Bone culture is not always neededwhen DFO is suspected, but clinicians should consider thisprocedure when the diagnosis of osteomyelitis remainsuncertain despite clinical and imaging evaluations, incases of non-informative data from soft tissue cultures,when the infection has failed to respond to initial empiricantibiotic therapy or when considering an antibiotic regi-men with a higher potential for selecting resistant organ-isms (e.g. rifampin, fluoroquinolones, fusidic acid or clin-damycin) [2].

To reduce the likelihood of false-negative cultureresults, it is presumably best to perform bone biopsy after

an antibiotic-free period in clinically stable patients. Ascertain antibiotic agents have a prolonged release frombone tissue, holding antibiotics for 2weeks is ideal, buteven a couple of days may be helpful [79]. Because DFO(in the absence of substantial soft tissue infection) is typ-ically a slowly progressive disease, such a delay is usuallysafe. Percutaneous biopsy of bone through clinically unin-volved skin reduces the likelihood of false positive culture,although one study found good results (based on favour-able clinical outcome) using a simpler per-wound bonebiopsy after careful debridement [79]. Similarly, whilethere are potential risks of bone biopsy, that is, trackingcontaminating organisms into the bone or causing a bonefracture, several large series have shown that complica-tions from percutaneous (and surgical) procedures arevery rare [26,80]. Any properly trained physician (e.g. afoot surgeon, interventional radiologist) can perform thebiopsy. Percutaneous biopsy should preferably be per-formed under fluoroscopic or CT guidance, traversingintact and uninfected skin. Patients with sensory neurop-athy often do not need anaesthesia. If possible, the opera-tor should attempt to obtain at least two specimens – onefor culture and the other for histological analysis. Withsmall toe bones, it may only be possible to aspirate a fewbony spicules.

The presence of clinically significant foot ischemiamakes both diagnosis and treatment of infection consider-ably more difficult.

Assessing severity

Accurately assessing a diabetic foot wound usuallyrequires debridement of callus and necrotic tissue. Keysto classifying a foot infection are defining the extent ofthe tissues involved, determining the adequacy of arterialperfusion and assessing for systemic toxicity [16,82,83].While mild infections are relatively easily treated, moder-ate infections may be limb threatening and severe infec-tions may be life threatening (Table 3A). Infection severitylargely guides the choice of antibiotic and its route of ad-ministration and helps to determine the need for hospita-lisation (Table 3B), the potential necessity and timing offoot surgery and the likelihood of amputation [15,83–85].

Deep space infections may have deceptively few super-ficial signs, but clinicians should consider this possibilityin a patient with systemic toxicity (e.g. fever, chills, leuko-cytosis), inflammation distant from the skin wound, per-sistent infection or elevated inflammatory markers despiteappropriate therapy, or pain in a previously insensate foot[13,22,86].

Microbiological considerations

When to send specimens for culture

Knowing the likely etiologic agent(s) helps the clinicianselect appropriate antimicrobial therapy. Acute infectionsin previously untreated patients are usually caused by

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aerobic gram-positive cocci (often as a monomicrobial in-fection) [87], but deep or chronic wounds may harbourpolymicrobial flora, including gram-negative and anaero-bic bacteria [82]. Skin disorders, environmental expo-sures or recent antibiotic therapy can predispose tounusual or antibiotic-resistant pathogens. Wound culturesare helpful for most infections but are difficult to obtain incases with just cellulitis (where skin aspiration has limitedsensitivity) and generally unnecessary for clinically unin-fected lesions. Blood cultures are only needed for severeinfections, and bone cultures help diagnose and directtherapy of osteomyelitis. In the past decade, molecularmicrobiological techniques have demonstrated a far morecomplex mix of organisms in DFIs [88,89], but the clinicalsignificance of these isolates is not yet clear.

Obtaining specimens for wound cultures

A wound culture is useful only if the specimen is appropri-ately collected and processed. Antibiotic susceptibilityresults generally help in focusing (and often constraining)antibiotic regimens. Deep tissue specimens, obtained asepti-cally at surgery, usually contain only the true pathogens,while cultures of superficial lesions often yield contami-nants [87,90]. Curettage (tissue scraping) with a curetteor scalpel from the base of a debrided ulcer or needle aspi-rate of purulent secretions generally providesmore accurateresults than wound swabbing [87,91]. If swabs are the onlyavailable method, they should be taken only after debridingand cleaning the wound. Specimens should be sent to thelaboratory promptly, in suitable sterile transport containers.

Interpreting wound culture results

Sole or predominant bacteria identified on culture (and,where available, Gram-stained smear) and isolated from

reliable specimens are likely true pathogens. If multipleorganisms are isolated, especially from superficial ulcers,it can be difficult to determine which are pathogens.Targeting treatment against less virulent isolates (e.g.coagulase-negative staphylococci, corynebacteria) maybe unnecessary. These species can, however, representtrue pathogens, especially if they grow repeatedly or fromreliable specimens. Staphylococcus aureus is the most fre-quently isolated and among the more virulent pathogensin DFIs; even when it is not the sole isolate, it is usually acomponent of a mixed infection. Streptococci (variousgroups of b-haemolytic and others) are also importantpathogens. Enterococci are relatively frequent isolates butusually of secondary clinical importance.

Infections requiring hospitalisation are often polymicro-bial, including aerobes and anaerobes [16,92]. Gram-negative bacilli (mainly Enterobacteriaceae, sometimesPseudomonas aeruginosa or other non-fermentativespecies) are usually isolated in conjunction with gram-positive cocci from patients with chronic or previouslytreated infections; they are often, but not always, truepathogens. Many recent studies have reported that gram-negative organisms are the most frequent isolates in DFIsoccurring in patients in warm climates, especially in devel-oping countries [93–96]. It is unclear if this is related toenvironmental factors, footwear preferences, personalhygiene practices, antimicrobial pretreatment or otherfactors. Obligate anaerobic species are most frequent inwounds with ischaemic necrosis or those that involve deeptissues; they are rarely the sole pathogen and most oftenare part of a mixed infection with aerobes [97].

Multidrug-resistant organisms, especially methicillin-resistant S. aureus (MRSA), are more frequently isolatedfrom patients who have recently received antibiotic ther-apy, have been previously hospitalized or reside in achronic care facility [98]. After the rates of MRSA dramat-ically increased in many countries starting in the late

Table 3. Characteristics suggesting a more serious diabetic foot infection and potential indications for hospitalization

(A) Findings suggesting a more serious diabetic foot infectionWound specific

Wound Penetrates into subcutaneous tissues, i.e., fascia, tendon, muscle, joint, boneCellulitis Extensive (>2 cm), distant from ulceration or rapidly progressiveLocal signs Severe inflammation, crepitus, bullae, marked induration, discoloration,

necrosis/gangrene, ecchymoses or petechiaeGeneral

Presentation Acute onset or rapidly progressiveSystemic signs Fever, chills, hypotension, confusion, volume depletionLaboratory tests Leukocytosis, severe or worsening hyperglycaemia, acidosis, azotaemia,

electrolyte abnormalitiesComplicating features Presence of a foreign body (accidental or surgically implanted),

puncture wound, abscess, arterial or venous insufficiency, lymphoedemaCurrent treatment Progression while on apparently appropriate antibiotic therapy

(B) Factors suggesting hospitalization may be necessary•Severe infection (Table 3A)•Metabolic instability•Intravenous therapy needed (and not available/appropriate as outpatient)•Diagnostic tests needed that are not available as outpatient•Critical foot ischemia present•Surgical procedures (more than minor) required•Failure of outpatient management•Patient’s inability or unwillingness to comply with outpatient-based treatment•Need for more complex dressing changes than patient/caregivers can provide

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1990s, they have begun to decline in most recent reports,concomitant with improved hospital (and outpatient) in-fection control measures [99–101]. The previously usefuldistinction of community-acquired (less likely to be resis-tant to other antibiotics) versus healthcare-associatedstrains has become blurred in recent years. In some, butnot all, reports on DFIs, those caused by MRSA have beenassociated with worse outcomes, that is, higher clinical fail-ure and amputation rates [102–104]. In the past decade,other multidrug-resistant organisms, especially gram-negatives with extended-spectrum beta-lactamases (ESBL)and occasionally vancomycin-resistant enterococci, havebeen more commonly isolated from DFIs [96,105,106].ESBL-producing organisms usually require treatment withvery broad-spectrum antibiotics, that is, carbapenems.Fungi may be isolated from both infected and uninfectedfoot wounds, but this rarely necessitates systemic antifungaltherapy [107]. They are, however, a frequent cause ofonychomycosis.

Bone infection

DFO can present the clinician with formidable diagnosticand therapeutic challenges [78]. It complicates about50% to 60% of serious, and 10% to 20% of apparently lesssevere, foot infections in patients presenting to diabeticfoot clinics. Bone infection typically occurs by contiguousspread from overlying soft tissue, which may penetratethrough the cortex into the marrow. Bone destructioncaused by neuroarthropathy (CN) may be difficult todistinguish from that caused by infection, although theformer is less common, tends to occur in patients withprofound peripheral neuropathy but adequate arterialperfusion, more frequently involves the midfoot and oftenoccurs in the absence of a skin break [108,109]. Manycases of osteomyelitis are monomicrobial, but most arepolymicrobial; S. aureus is the most commonly isolatedagent (~50% of cases), while S. epidermidis (~25%),streptococci (~30%) and Enterobacteriaceae (~40%)are also frequent isolates [108].

Treatment

Patients with a severe infection (Table 3A) should usuallybe hospitalised, as they often require surgical inter-ventions, fluid resuscitation and control of metabolicderangements. Also, consider admitting patients withmoderate infections if they are unable or unwilling to beadequately involved in wound care, can or will not be ableto off-load the affected area, are unlikely to comply withantibiotic therapy, require parenteral antibiotic therapy(that is not available as an outpatient) or need close mon-itoring of treatment response (Table 3B). Most otherpatients with a moderate infection, and almost all with amild infection, can cautiously be treated as outpatients,with instructions to return if the infection worsens or in-office re-evaluation every few days initially [91].

Surgery is the cornerstone of treating many deep softtissue infections [86], and early intervention might be as-sociated with better outcomes [22,110–112]. Interveningemergently, however, is only needed in specific circum-stances, such as severe infection in an ischaemic limb;an abscess accompanied by compartment syndrome ornecrosis; systemic sepsis syndrome; or local infection withbullae, ecchymoses, extreme pain or unexpected anaes-thesia. The treating clinician should consider the needfor surgery in every infection, which may range fromminor debridement or drainage to extensive resections ormajor amputation. When the wound has a dry eschar, espe-cially in an ischemic foot, it is often best to avoid debridingthe necrotic tissue. Major amputation should, and usuallycan, be avoided except when the limb is non-viable, isaffected by life-threatening infection (e.g. gas gangrene ornecrotizing fasciitis) or is functionally useless. Revasculari-sation may be needed for an infected ischemic limb.Surgeons operating on a patient with a DFI should haveadequate knowledge of the complex anatomy of the foot[22,113]. Figure 1 shows an algorithmic overview of theapproach to treating a diabetic patient with a foot lesion.

Antimicrobial therapy

Indications for therapyInfected diabetic foot wounds require antibiotic therapy,as failure to properly treat infected wounds is usually as-sociated with progressive tissue destruction and poorwound healing. Because antibiotic therapy is associatedwith frequent adverse effects, financial costs and increas-ing risk of antibiotic resistance [98], it should be reservedfor treating wounds that are infected. Using antimicrobialtherapy has not been proven beneficial for managing clin-ically uninfected skin wounds, irrespective of theoreticalconsiderations of the bacterial ‘bioburden’ of chronicwounds [114–118]. There is no published evidence thatthey either accelerate wound healing or reduce the likeli-hood of clinical infection developing. Where the clinicalassessment for the presence of infection is equivocal, theclinician must make a decision to treat the wound eitheras uninfected or as infected (using an infection gradingsystem) and then carefully monitor progress.

Route of therapyFor an antibiotic to reach a therapeutic concentration atthe site of infection, it must first achieve an adequate se-rum level [119]. Because parenteral antibiotics achievefaster and higher serum levels, they are recommendedfor patients who are systemically ill or have a severe infec-tion. They may also be required for those unable totolerate oral agents or who are infected with pathogensinsensitive to oral agents. After the patient’s clinical con-dition has stabilized and the infection is responding, mostcan switch to oral therapy. Where available, outpatient in-travenous therapy can be used for those requiring pro-longed parenteral treatment, for example for some casesof osteomyelitis or infections resistant to oral agents.

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Compared with parenteral therapy, oral antibioticsare more convenient, generally associated with fewercomplications and are less expensive. Gastrointestinalabsorption of oral antibiotics, while variable, is excellentfor several agents. Fluoroquinolones in particularachieve high tissue concentrations in DFIs [119–121],even in patients with gastroparesis [122], but mostother currently used oral antibiotics also achieve ade-quate serum and tissue levels. Newly marketed agentsgenerally have an expanded spectrum of activity, greateractivity against antibiotic-resistant gram-positive cocci, alonger half-life (allowing for less frequent dosing) andgood oral bioavailability. They are, however, generallyconsiderably more expensive and have a shorter trackrecord for safety evaluations.

Peripheral vascular disease, but not diabetes alone, maylimit the delivery, and therefore penetration, of antibioticsto infected foot tissues [122,123]. Even in an ischemiclimb, however, antibiotics play an important role in pre-venting further spread of infection. Problems with limbarterial insufficiency have led some to experiment withnovel methods of antibiotic delivery to the lower limb,for example retrograde intravenous perfusion under pres-sure [124,125], intra-arterial (e.g. femoral) administra-tion [126] or primary closure of debrided wounds withcatheter instillation of antibiotics [127]. These techniqueshave not yet proven their usefulness.

Using topical antibiotic therapy for a foot wound isappealing, as it allows high concentrations at the site ofinfection without potentially toxic systemic levels [128].It also allows treatment with agents not available forsystemic therapy. While not appropriate when there isextensive (>2 cm) cellulitis, a large randomized trialfound an investigational topical antibiotic peptide (pexi-ganan) as effective as oral therapy with a fluoroquinolonefor mildly infected diabetic foot ulcers [129]. A limitednumber of marketed topical antimicrobial agents, as wellas antimicrobial impregnated wound dressings (e.g. thosecontaining various forms of silver and iodine), might beuseful for preventing, or possibly treating, mild infections[115]. Available data are too limited to recommend localantimicrobial treatment, but further research is warranted[130–132]. For deep wounds, antibiotic-loaded beads, ce-ment or biodegradable bovine collagen sponges can sup-ply high local antibiotic concentrations for a long durationand, in some instances, fill dead space [133,134]. A recentsystematic review concluded that the data supporting theuse of gentamicin-loaded beads is too limited to allowmaking recommendations [135].

Choice of antibioticsInitial antibiotic regimens are usually empirical. Theseshould cover the most common pathogens but be modi-fied according to infection severity and available clinical

Diabetic patient with a suspected foot infection

• Cleanse, debride and probe the wound • Assess neurological and vascular status of foot • Assess for purulence or signs of inflammation • Consider obtaining plain radiographs (or MRI) • Obtain appropriate specimen(s) for culture • Obtain other appropriate laboratory tests • Assess any medical co-morbidities • Determine if surgical consultation is needed • Assess patient’s psycho-social situation

Classify the wound (if infected)

Mild/Moderate Severe | |

• Assess the need for inpatient treatment • Hospitalize the patient • Review any available microbiological data • Attend to fluid, electrolyte, metabolic needs • Select initial antibiotic regimen (consider oral, • Obtain blood cultures

relatively narrow-spectrum) • Select empiric, broad-spectrum parenteral • Select appropriate wound care (dressings, off-loading) antibiotic regimen (consider MDROs) • If treated as outpatient, set up return visit, consultations • Arrange for urgent surgery, if needed

If not hospitalized, reassess in 2-4 days, Reassess clinically at least once daily; or before earlier if substantially worsens check inflammatory markers as needed

Assess clinical signs/symptoms of infection / \

Improving Not improving/worsening Improving Not improving/worsening / \

• Consider de-escalating • Review culture & • Switch to appropriate • Define extent of tissue involved antibiotic regimen sensitivity results oral antibiotic regimen (MRI, surgical exploration) (narrower spectrum, • Assess patient’s • Follow-up as outpatient • Review culture & sensitivity less toxic, expensive) adherence to results; cover all isolates • Reassess ~ weekly until treatment regimen • Consider broadening antibiotic Infection resolves • Reassess wound care, spectrum • If fails to resolve or relapses need to hospitalize • Reassess need for surgery, consider deep abscess, • Consider further imaging including revascularization, osteomyelitis or resistant • Re-culture wound or amputation pathogen ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- MDRO= multi-drug resistant organism

Figure 1. Approach to the infected diabetic foot

170 B. A. Lipsky et al.

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or microbiological clues. Relatively narrow-spectrumagents are preferred for minor infections, with adjust-ments if clinical response is inadequate. Initial regimensfor severe infections should be a broader spectrum, andtreatment must be delivered promptly. An empirical regi-men must also take into consideration factors related tothe current infection, the likely pathogen(s), the specificpatient and potential drug-related issues (Table 4). AGram-stained smear of a wound specimen may help directempiric antibiotic therapy by informing the clinician ofthe number and gram types of pathogens present [136].

An empiric regimen should virtually always include anantibiotic active against non-resistant isolates of staphylo-cocci and streptococci. Consider adding an agent activeagainst MRSA if the patient has risk factors for this organ-ism (e.g. recent stay in healthcare setting, recent antibi-otic therapy or known MRSA colonization). Patients whohave been previously treated with an antibiotic (for what-ever reason), or who have a more severe infection, mayneed extended coverage for common gram-negative bacilliand perhaps for Enterococcus species. Empiric anti-anaerobictherapy is appropriate for necrotic, gangrenous or foul-smelling wounds. Combination therapy may be appropriatefor infections presumed (or proven) to be caused by morethan one organism, when the pathogen has a high potentialfor developing resistance (e.g. Pseudomonas) or when select-ing an agent (e.g. rifamp(ic)in) to which resistance mayquickly develop when used alone.

When culture and sensitivity results are available, con-sider changing to a more specific regimen targeted at theisolated pathogens. To reduce the likelihood of antibioticresistance, narrower spectrum agents are preferable, butit is important to assess how the infection has responded

to the empirical regimen. If the infection is improvingand the patient is tolerating therapy, there may be noreason to change, even if some or all of the isolated organ-isms are resistant to the agents prescribed [137]. If theinfection is not responding, however, modify treatmentto cover all isolated organisms. If the infection is worsen-ing despite the isolated bacteria being susceptible to theselected regimen, reconsider whether surgical interven-tion is needed, the possibility that fastidious infectingorganisms were not recovered on culture or that patientadherence to the treatment regimen has been suboptimal.

Several antibiotic agents have been used successfully totreat DFIs for decades, despite not having been evaluatedin prospective comparative studies; these include penicil-linase-resistant penicillins (e.g. dicloxacillin, nafcillin),cephalosporins (e.g. cefazolin, ceftriaxone), glycopeptides(teicoplanin), rifampi(ci)n, fusidic acid, pristinamycin,trimethoprim–sulfamethoxazole and doxycycline. Agentsthat have demonstrated clinical effectiveness, alone or incombination, in published prospective studies of DFIsinclude the following (Table 5) [3]:

• Cephalosporins (cephalexin orally; cefoxitin and cefti-zoxime, parenterally)

• Penicillin/b-lactamase inhibitor congeners (amoxicillin/clavulanate, orally; ampicillin/sulbactam, piperacillin/tazobactam and ticarcillin/clavulanate, parenterally)

• Carbapenems (imipenem/cilastatin and ertapenem,parenterally)

• Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxa-cin and moxifloxacin, all both orally and parenterally)

• Other agents: clindamycin (orally and parenterally);amdinocillin (parenterally); linezolid (orally and par-enterally); daptomycin (parenterally); and vancomycin(parenterally)

Other agents in the same antibiotic classes as thoselisted (or in Table 5) are also likely to be effective. Overall,the clinical and microbiological response rates have beensimilar in published trials with various antibiotics,and there is no one preferred agent or combination[2,3,103,138,139]. Understanding the principles of antibi-otic therapy is more important than knowing the specificagents currently in favour, especially as new antibioticsare introduced and some older ones are made obsoleteby emergence of resistance or newly appreciated toxicities[136,138]. In the absence of a compelling reason tochoose a specific antibiotic, the one with the lowest acqui-sition cost is preferred, even though antibiotics accountfor only a small portion of the treatment costs for a footinfection [140]. There is a compelling need for compara-tive trials and economic analyses of various anti-infectiveregimens for DFIs [141,142]. Suggested empirical antibi-otic regimens, by type of infection, are given in Table 5.

Duration of therapyThe optimal duration of antibiotic therapy for varioustypes of DFIs is unknown. On the basis of data from avail-able studies, for mild to moderate infections, 1 to 2weeks

Table 4. Factors that may influence choices of antibiotictherapy for diabetic foot infections (specific agents, route ofadministration and duration of therapy)

Infection related– Clinical severity of the infection (Table 1)– History of antibiotic therapy within previous 3months– Presence of bone infection (presumed or proven)Pathogen related– Likelihood of non-GPC etiologic agent(s)– History of colonisation or infection with MDROs– Local rates of antibiotic resistancePatient related– Allergies to antibiotics– Impaired immunological status– Patient treatment preferences– Renal or hepatic insufficiency– Impaired gastrointestinal absorption– Arterial insufficiency in affected limb– Exposure to environment with high risk of MDROs or unusualpathogensDrug related– Safety profile (frequency and severity of adverse effects)– Drug interactions potential– Frequency of dosing– Formulary availability/restrictions– Cost considerations (acquisition and administration)– Approval for indication– Likelihood of inducing C. difficile disease or antibiotic resistance– Published efficacy data

GPC, gram-positive cocci (aerobic); MDRO, multidrug-resistantorganism.

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is usually effective [3,91], while for more serious infec-tions, 2 to 4weeks is usually sufficient [3,137,143–145].Antibiotic therapy can generally be discontinued whensigns and symptoms of infection have resolved, even ifthe wound has not healed – antibiotics are employed tocure infection, not heal wounds. More extended treat-ment may be needed for immunocompromised patients,for wounds that are poorly perfused, deep, large or ne-crotic or for osteomyelitis (vide infra), but this decisionshould be accompanied by clinical re-evaluations to justifyand document the treatment strategy. The necessaryduration of therapy may be shortened by adequatedebridement, resection or amputation of infected tissue.Some patients who cannot (or refuse to) undergo surgicalresection, or who have an implanted foreign body at theinfection site, may require prolonged or intermittent sup-pressive antibiotic therapy.

Wound care

For DFIs, antibiotics are necessary but not sufficient toovercome inadequate vascular supply, poor glycaemiccontrol or improper wound care [146,147]. Most woundsneed to be carefully cleaned and debrided of necrotic tis-sue and surrounding callus. Those with heavy exudate

need a dressing that absorbs the moisture, while drywounds heal best in a moist environment. Dressingsshould optimally be changed at least daily, to allow care-ful examination of the wound. Published studies do notadequately support using any available topical antimicro-bials on most wounds. For patients with a DFI, it is bestnot to use a device (e.g. a total contact cast, topical nega-tive pressure) that does not allow easy daily visualizationof the wound. Remove or redistribute any pressure fromthe wound by encouraging the patient to be non-ambula-tory or by providing an appropriate off-loading device.

Treating osteomyelitis

The IWGDF has produced a full systematic review of, andguidelines for, the treatment of DFO [2]. Among the im-portant factors to consider when treating osteomyelitisare the following: the anatomic site of infection, the localvascular supply, the extent of soft tissue and bone destruc-tion, the presence of systemic signs of infection and thepatient’s preferences. While many cases of DFO require,or benefit from, surgical debridement or resection ofbone, some can be treated successfully by medical therapyalone. Several published retrospective series have shown

Table 5. Selecting an empiric antibiotic regimen for diabetic foot infections

Infection severity Additional factors Usual pathogen(s) Potential empirical regimens1

MildNo complicating features GPC (staphylococci or

streptococci)S-S pen; first gen Ceph2

Recent antibiotic exposure GPC+GNR b-L-ase-1; T/S; FQBeta-lactam allergy orintolerance

Clindamycin; FQ; T/S; macrolide

High risk for MRSA MRSA Linezolid; T/S; doxycyclineModerate andsevere3

No complicating features GPC�GNR b-L-ase 1; second/third gen CephRecent antibiotics b-L-ase 2; second/third gen Ceph, group 1

carbapenem (depends on prior therapy;seek advice)

Macerated ulcer, warm climate GNR, includingPseudomonas

FQ; b-L-ase 2; group 2 carbapenem

Ischemic limb/necrosis/gasforming

GPC�GNR� anaerobes b-L-ase 1 or 2; group 1 or 2 carbapenem; orsecond/third gen Ceph+clindamycin ormetronidazole

MRSA risk factors MRSA Consider addition of, or substituting with,glycopeptides, linezolid, daptomycin; fusidicacid, T/S, doxycycline

Risk factors for resistant GNR Pseudomonas*/ESBL Pip/tazo*, carbapenems, FQ, aminoglycoside,colistin

b-L-ase= b-lactam, b-lactamase inhibitor.b-L-ase 1=amoxicillin/clavulanate, ampicillin/sulbactam.b-L-ase 2= ticarcillin/clavulanate, piperacillin/tazobactam.Group 1 carbapenem=ertapenem.Group 2 carbapenem= imipenem, meropenem, doripenem.Ceph=cephalosporin; gen=generation.Pip/tazo=piperacillin/tazobactam.FQ=fluoroquinolone with good activity against aerobic gram-positive cocci (e.g. levofloxacin or moxifloxacin).T/S= trimethoprim/sulfamethoxazole.ESBL, extended-spectrum beta-lactamase; GPC, gram-positive cocci (aerobic); GNR, gram-negative rods; MRSA, methicillin-resistantStaphylococcus aureus.1Given at usual recommended doses for serious infections. Modify doses or agents selected for azotaemia, liver dysfunction etc.Recommendations based upon theoretical considerations and available clinical trials.2A high local prevalence ofmethicillin resistance among staphylococci may require using vancomycin or other appropriate anti-staphylococcalagents active against these organisms.3Oral antibiotic agents should generally not be used for severe infections, except as follow-on (switch) after initial parenteral therapy.

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that DFO can be arrested (or even apparently cured) withantibiotic therapy and no surgical intervention in abouttwo-thirds of cases [77,148–150]. In these reports, clini-cians have generally employed antibiotic doses at thehigher recommended ranges and given for at least two(and usually 3–6) months. Unfortunately, available stud-ies do not provide information to inform which casesmay require surgery [77,148–150]. In some cases, limitedsurgery combined with antibiotic therapy may be most ap-propriate [112].

The choice of an antimicrobial agent for osteomyelitisshould optimally be based on the results of a bone culture,especially because of the need for long-duration therapy[77,108]. If empiric therapy is necessary, always select aregimen that covers S. aureus, as it is the most commonpathogen; the patient’s history or culture results may sug-gest a need for broader coverage. Some antibiotics maynot penetrate well to infected bone, but the unreliabilityof measuring bone levels limits the value of publisheddata on this issue. Furthermore, the association betweenhigh bone levels of antibiotics and improved outcomehas not yet been studied. Traditionally, treatment of oste-omyelitis has usually been parenteral (at least initially)and prolonged (at least 4weeks), but these recommenda-tions are not based on strong data. Many patients canprobably be switched to oral therapy after about a weekof parenteral treatment. Any oral antibiotics selectedshould have good bioavailability [e.g. fluoroquinolones,rifampi(ci)n (always combined with another agent), clin-damycin or trimethoprim–sulfamethoxazole]. If all of theinfected bone is surgically removed, a shorter course ofantibiotic therapy (i.e. 2–14 days) may be sufficient,depending on the status of the soft tissues [3]. Extendingpost-debridement antibiotic therapy beyond six weeks, orgiving IV treatment longer than one week, does not ap-pear to increase the remission rate [151]. For somepatients with apparently incurable infection, long-termsuppressive therapy, or intermittent short courses of treat-ment for recrudescent symptoms, may be the most appro-priate approach. Antibiotic impregnated beads [133] ororthopaedic implants have been used successfully to treatDFO in a few small series [134].

Adjunctive therapies

Several studies have reported the results of additionalmeasures used in an effort to improve infection resolu-tion, wound healing or host response. These include neg-ative pressure wound therapy, recombinant granulocytecolony stimulating factor (G-CSF), systemic hyperbaricoxygen (HBO) and larval (maggot) therapy. The availableevidence does not support that any of these should be rou-tinely used specifically for treatment of infection. Theremay, however, be a role for some or all in the overall careof the patient with a diabetic foot wound, though the ev-idence for cost effectiveness remains weak. On the basis ofthe results of a meta-analysis of generally low-qualitystudies, G-CSF therapy is associated with significantly

fewer surgical procedures, including amputations and dura-tion of hospital stay, but not with the likelihood of resolu-tion of infection, wound healing or the duration of systemicantibiotic therapy [3,152]. For HBO therapy, systematicreviews of largely poor quality randomised controlled trials(RCTs) [153], and a more recent well-done RCT [154], sug-gest a potential role in wound healing but have provided noevidence for a role in treating soft tissue or bone infection.For treating onychomycosis, there are many suggested rem-edies, including topical and oral medications and device-re-lated methods. While oral antifungal therapy (e.g. itracona-zole, terbinafine) is perhaps the best current treatment,newermethods (e.g. improved nail penetrating topical com-pounds, light based devices) appear to be promising [155].

Outcome of treatment

With appropriate treatment, the signs and symptoms ofmild infections almost always resolve without need foramputation. When infection involves deep soft tissuestructures or bone, the outcome is often less favourable;many require surgical debridement, bone resection or par-tial amputations. With extensive infection, or in medicalcentres with limited expertise or resources, lower extrem-ity amputation rates may reach 50–60% [3,156]. In thehands of an experienced surgeon, most amputations canbe foot sparing (i.e. below the malleoli), and long-termcontrol of infection is achieved in over 80% of cases[157]. The presence of limb or foot ischemia has an im-portant adverse effect on the outcome, synergising withinfection to worsen the prognosis [158].

Unfortunately, having had one foot infection is associatedwith an increased likelihood of another; foot infection recursin 20% to 30% of diabetic patients, especially those with un-derlying osteomyelitis [159]. While it is difficult to knowwhen osteomyelitis is cured, evidence suggesting remissionincludes a drop in the erythrocyte sedimentation rate orC-reactive protein level, reconstitution of destroyed boneon plain radiograph and healing of any overlying soft tissuewound. Factors that predict healing include the absence ofany exposed bone, palpable pedal pulses, blood pressurein the toe of >45mmHg or in the ankle of >80mmHg,a peripheral white blood cell count of <12000/mm3 anda lower extremity transcutaneous oxygen tension of>40mmHg [9,160]. Because of the risk of reinfection,educating patients who have a DFI on prevention techniquesand encouraging prompt consultation for foot problems arecritical. While much has been learned about diagnosingand treating infections in the past few decades, many funda-mental questions remain, and more research is required.

Issues of particular importance indeveloping countries

These guidelines must, of course, be adapted to the localcircumstances in which a healthcare provider sees

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patients. Many aspects of the management of DFIs maydiffer in developing, compared with more developed,countries. To begin with, in developing countries, infec-tions are often a consequence of wounds caused by thediabetic person either wearing footwear that is not suffi-ciently protective (e.g. sandals) or poorly fitting, or wear-ing none at all. Moreover, the person may delay seeing ahealthcare provider for a longer period of time becauseof a lack of financial resources, nearby clinics or propereducation. During this period, the patient may attemptto treat the infection with various home remedies, includ-ing plants or other locally accepted treatments. Patientscan often buy antibiotics without a prescription in devel-oping countries; thus, they will often have treated them-selves, sometimes with the advice of a pharmacist or othertrusted but non-licensed persons, before presenting to aphysician. This unsupervised treatment, sometimes withexpired medications at inadequate doses, is likely toresult in infections caused by more antibiotic-resistantorganisms.

Healthcare providers in developing countries may alsoface added difficulties. They may not have access to amicrobiology laboratory, so they cannot ascertain theidentity and antibiotic susceptibility of foot pathogensinfecting an individual patient or of current isolates inthe community. Similarly, many will not have access toeven basic (not to mention more sophisticated) imagingequipment. Even when a patient sees a physician andreceives an antibiotic prescription, indigent patients maybe unable to purchase the full course of therapy or maybe prescribed inexpensive but potentially more toxic orless effective agents. Home or work circumstances maymake it very difficult for them to stay off their foot, or toafford or be able to use an off-loading device. Further-more, they may have travelled a long distance to see aphysician and cannot easily return for follow-up visits. Im-proving management of DFIs in developing countries willlikely require a combination of education (for patients,

pharmacists and healthcare providers) and funding (fordiagnostic, therapeutic and preventative services).

Acknowledgements

We thank the following, who served as corresponding membersof the Expert Panel:

Dr Z. G. Abbass, TanzaniaDr F. J. Aragón Sánchez, SpainDr M. Eneroth, SwedenDr B. M. Ertugrul, TurkeyDr H. Gawish, EgyptDr I. Gurieva, RussiaDr A. Jirkovska, Czech RepublicDr F. de Lalla, ItalyDr S. Kono, JapanDr A. Nather, SingaporeDr J.-L. Richard, FranceDr N. Rojas, ChileDr L. Tudhope, South AfricaDr S. Twigg, AustraliaDr V. Viswanathan, IndiaDr O. Udovichenko, RussiaDr D. Yue, AustraliaDr Z. Xu, ChinaWe thank Dr Karel Bakker for his support, guidance, insights

and leadership.

Conflict of interest

BAL has served as a consultant to Merck, Pfizer, Cubist,DiPexium, Johnson & Johnson. ARB was a Pfizer VisitingProfessor in 2011 to the University of Washington Depart-ment of Allergy and Infectious Diseases, an educationallyunrestricted programme for which funding was awardedto DAID on a peer reviewed and competitive basis. ARBreceived no personal financial benefit from this programme.ES has served as an investigator in the EU-CORE databasestudy (NOVARTIS).

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