Poor compliance with antifungal drug useguidelines by transplant physicians: aframework for educational guidelines and aninternational consensus on patient safety

Munoz P, Rojas L, Cervera C, Garrido G, Farinas MCarmen, Valerio M,Giannella M, Bouza E. Poor compliance with antifungal drug use guidelinesby transplant physicians: a framework for educational guidelines and aninternational consensus on patient safety.Clin Transplant 2012: 26: 87–96. ª 2011 John Wiley & Sons A/S.

Abstract: The rate of compliance with antifungal drug use guidelines bytransplant physicians is mostly unknown. We performed a nationwideelectronic survey to assess antifungal use by different types of transplantphysicians.Sixty-one percent (53/87) of the transplant programs responded (accountingfor 85% of heart transplant procedures, 65% of kidney transplantations,and 71.5% of liver transplantations). Antifungal prophylaxis was used in41.5% programs (liver 93.3%, heart 30.8%, and kidney 16%). Prophylaxiswas universal in 32% of the programs and targeted only to selected patientsin 68%, mainly indicated after re-transplantation (73.3%), re-intervention(66.7%) and hemodialysis (60%). Main drugs for universal prophylaxiswere fluconazole and itraconazole (42.9% each), while fluconazole (60%),L-amphotericin B (AMB), and caspofungin (13.4% each) were preferred fortargeted prophylaxis. Overall, 84.9% of the programs used galactomannanfor the diagnosis of invasive aspergillosis (only 34% in BAL) and 66.6%used voriconazole as first-line monotherapy. Combination first-line therapyfor invasive aspergillosis was used by 31.3%, mainly with voriconazole withcaspofungin (40%) or anidulafungin (26.7%) or L-AMB-caspofungin(26.7%).Adherence of transplant physicians to current recommendations onantifungal treatment and prophylaxis is poor. An international consensusthat responds to differences in patients and centers and emphasizes patientsafety is clearly needed.

Patricia Munoza, Loreto Rojasa,Carlos Cerverab, GregorioGarridoc, Maria Carmen Farinasd,Maricela Valerioa, MaddalenaGiannellaa and Emilio Bouzaa, onbehalf of the COMIT Study Group*aMicrobiologıa Clınica-Enfermedades

Infecciosas, Hospital General Universitario

Gregorio Maranon, Madrid, Spain, GESITRA,

REIPI, CIBER de Enfermedades Respiratorias

(CIBERES), bEnfermedades Infecciosas, Hospital

Clınic, Barcelona, Spain, cOrganizacion Nacional

de Trasplantes (ONT) and dEnfermedades

Infecciosas, Hospital Universitario Marques de

Valdecilla, Santander, SpainKey words: antifungal prophylaxis –

aspergillosis – Aspergillus – Candida – invasive

fungal infections – solid organ transplant

Corresponding author: Patricia Munoz, Hospital

General Universitario Gregorio Maranon, Doctor

Esquerdo 46, 28007 Madrid, Spain.

Tel.: +3491 5868453; fax: +3491 5044906;

e-mail: pmunoz@micro.hggm.es

*Members of the Cooperation Mycology In Trans-

plant (COMIT) Study Group are given in Appendix.

Conflict of interest

This study was partially financed by the Infectious

Disease program of Fundacion BBVA – Fundacion

Carolina for the research fellowship of Loreto Rojas.

Dr. Munoz reported the following relationships:

served as a consultant for Pfizer, Astellas, Schering,

and Gilead; received payment for developing edu-

cational presentations or serving on speakers�bureaus from Pfizer, Astellas, Schering-Plough,

Gilead, and Novartis; and had travel or accommo-

dation expenses covered or reimbursed from Pfizer,

Astellas, Gilead, and Novartis. Dr. Bouza reported

the following relationships: served as a board mem-

ber or consultant for Pfizer, Novartis, Janssen, Bax-

ter, Astellas, Wyeth, Optimer, and Lederle; received

honoraria from Fundacion Ciencias de la Salud,

Pfizer, Novartis, Astra-Zeneca, Schering-Plough, and

Astellas; received payment for developing educa-

tional presentations or serving on speakers� bureaus

from Pfizer, Astellas, Schering-Plough, Gilead, and

Novartis. No other associations were reported.

Accepted for publication 07 December 2010

Clin Transplant 2012: 26: 87–96 DOI: 10.1111/j.1399-0012.2011.01405.xª 2011 John Wiley & Sons A/S.

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Invasive fungal infection (IFI) is a major cause ofmorbidity and mortality in solid organ transplant(SOT) recipients. Although incidence has decreasedin recent years, IFI rates in this population still rangefrom 1.4% to 42%, depending on the type oftransplantation and the fungi involved (1–3).Approximately 80% of IFI episodes in SOT

recipients are caused by Candida and Aspergillusspecies (4), and the associated mortality of theseinfections range from 29% to 88% (5–9). Recom-mendations on how to manage these infectionshave recently been published (10, 11), but littlereference to SOT recipients peculiarities is includedin these guidelines.Because of the high morbidity and mortality of

IFI in SOT recipients, the main objective ofantifungal management should be prevention.However, international consensus guidelines defin-ing high-risk transplant population or optimalantifungal agents are not available. Information onadministration of antifungal drugs by transplantphysicians is only available for liver transplantrecipients. In North America, 91% of liver trans-plant centers use antifungal prophylaxis (72% onlyfor high-risk patients) (12), while in Europe, asreflected in the European Liver and IntestineTransplant Association report, 88% of transplantcenters use antifungal prophylaxis (53% in high-risk patients only) (13).The availability and real use of non-culture-

related diagnostic methods for invasive aspergillosisby transplant physicians is unknown, becausemethods such as galactomannan determination areconsidered less effective in this population (14). Evenin the field of guided therapy for invasive aspergil-losis, the way in which general guidelines are appliedtoSOTpatients in day-to-daypractice is not defined.This study assesses general aspects of antifungal

management in different types of SOT transplantcenters by addressing indication criteria and exam-ining the antifungal agents used in the prophylaxis –against Candida spp. and Aspergillus spp. – andtherapy of established invasive aspergillosis. Impor-tant aspects of diagnosis and environmental surveil-lancearealsoanalyzed.Other fungiwill beaddressedin future studies.Ourobjective is to identify areas forimprovement that should be addressed in an inter-national consensus emphasizing center variabilityand patient safety.

Materials and methods

This study was carried out from March to June2009. All kidney, heart, and liver transplant centersin Spain were invited to collaborate by answeringan electronic survey sent by the Organizacion

Nacional de Trasplante (ONT). Clinicians incharge of transplant programs completed thequestionnaire, which was based in part on a similarstudy performed by Singh et al. in liver transplantcenters in the USA (12).

The questionnaire contained 27 items dividedinto four categories: demographics, prophylacticpractices, diagnostic methods, and therapeuticantifungal use for established invasive aspergillosis.

Demographics

Number of transplants performed annually, mostcommon indications for transplant in the program,use of T-cell-depleting antibodies for inductiontherapy, and number of IFI in the last year.Criteria for IFI diagnosis are standard (15).

Prophylactic practices

Use of antifungal prophylaxis, type of prophylaxis(universal or targeted), type of fungal infectiontargeted, risk factors for the initiation of prophyl-axis, type and dose of antifungal drug selected,duration of prophylaxis, use of high-efficiencyparticulate air (HEPA) filters in transplant rooms,and environmental sampling practices for quanti-fying fungal spore levels.

Diagnostic methods

Use of the galactomannan assay in serum andbronchoalveolar fluid and perceived usefulness ofthe test for the diagnoses and the management ofinvasive aspergillosis.

Antifungal therapy

Antifungals used as first-line therapy for invasiveaspergillosis, monotherapy or combination ther-apy, and salvage therapy.

Statistical analysis

The statistical analysis was performed using MSACCESS and SPSS, version 15.0 (SPSS, Chicago,IL, USA).

This study was approved by the local ethicscommittee.

Results

Demographics

A total of 53 SOT programs (61% of the transplantprograms in Spain) that performed 85% of heart

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transplantations, 65% of kidney transplantations,and 71.5% of liver transplantations during 2009responded to the survey. Demographic data,including mean number of procedures/year andindications for transplantation, are summarized inTable 1. T-cell-depleting antibodies were used forthe induction therapy by 31 (58.5%) centers,mostly in kidney programs (80%).

Transplant centers reported an incidence of IFIof 2.01% during 2009. Invasive candidiasis was themost common fungal infection in all centers (meannumber of cases/year per center 1.55 ± 1.6),followed by invasive aspergillosis (0.72 ± 0.7).Incidence of invasive candidiasis and invasiveaspergillosis according to transplant type was asfollows: liver recipients 1.6% and 1.3%, heartrecipients 1.3% and 3.2%, and kidney recipients0.4% and 0.7%.

We could not demonstrate a relationship be-tween the incidence or etiology of the infection andthe type of prophylaxis.

Prophylaxis

Use of both environmental protection and phar-macologic prophylaxis was assessed. HEPA filterswere installed in post-transplant rooms in only sixprograms (11.3%), and environmental Aspergillusspore levels were routinely measured in 37.7% ofthe centers.Antifungal prophylaxis was administered in 22

(41.5%) centers, mainly as targeted prophylaxis(68%). Table 2 presents the prophylactic strate-gies used in the different types of transplantprograms.

Liver transplant. Antifungal prophylaxis waswidely used in liver transplant centers (93.3%)during the study. Interestingly, universal prophyl-axis was still chosen by 26.7% of the centers andfluconazole (100 mg/d administered during admis-sion) was the preferred agent. Targeted prophy-laxis was selected by most centers (66.7%),

Table 1. General characteristics of the transplantation programs who responded to the questionnaire

Globaln = 53 (%)

Livern = 15 (%)

Heartn = 13 (%)

Renaln = 25 (%)

Number of transplants per year<50 36 (67.9) 9 (60) 12 (92.3) 15 (60)50–100 10 (18.9) 4 (26.7) 1 (7.7) 5 (20)100–150 6 (11.3) 2 (13.3) – 4 (16)>150 1 (1.9) – – 1 (4)

Indications for liver transplantCirrhosis caused by HCV – 9 (60) – –Alcoholic cirrhosis – 3 (20) – –Hepatocellular carcinoma – 2 (13.3) – –Othera – 1 (6.7) – –

Indications for heart transplantIschemic heart disease – – 9 (69.2) –Myocardiopathy – – 4 (30.8) –

Indications for renal transplantDiabetic nephropathy – – – 5 (20)Nephrosclerosis – – – 5 (20)Glomerulonephritis – – – 8 (32)Polycystic renal disease – – – 1 (4)Chronic pyelonephritis – – – 1 (4)Obstructive uropathy – – – 1 (4)Otherb – – – 4 (16)

Use of T-cell-depleting antibodiesYes 31 (58.5) 3 (20) 8 (61.5) 20 (80)No 22 (41.5) 12 (80) 5 (38.5) 5 (20)

Number of IFI/year (mean ± SD)Candidiasis 1.55 ± 1.6 2.33 ± 1.5 1.31 ± 1.7 1.2 ± 1.5Aspergillosis 0.72 ± 0.7 0.87 ± 0.74 0.69 ± 0.75 0.64 ± 0.81Zygomycosis 0.13 ± 0.22 0.2 ± 0.41 0.15 ± 0.37 0.08 ± 0.27Cryptococcosis 0.08 ± 0.26 0.13 ± 0.35 – 0.08 ± 0.27Scedosporiasis 0.09 ± 0.29 0.13 ± 0.35 – 0.12 ± 0.33

HCV, hepatitis C virus; SD, standard deviation; IFI, invasive fungal infection.aCryptogenic cirrhosis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, fulminant liver failure, biliary atresia, familial cholestasis, metabolic disease.bTubulo-interstitial disease, structural abnormalities, hereditary hypoplasia, cryptogenic renal failure.

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Table 2. Antifungal strategies used in solid organ transplant programs in Spain

GlobalN = 53 (%)

LiverN = 15 (%)

HeartN = 13 (%)

RenalN = 25 (%)

Air sampling of fungal spores 20 (37.7) 9 (60) 4 (30.8) 7 (28)Use of HEPA filters

Post-operatively 5 (9.4) 2 (13.3) 1 (7.7) 2 (28)Always 1 (1.9) – – 1 (4)

Use of prophylactic therapy 22 (41.5) 14 (93.3) 4 (30.8) 4 (16)Universal prophylaxis 7 (13.2) 4 (26.7) 2 (15.4) 1 (4)Type of fungi addressed

Candida 4 (57.1) 3 (75) 1 (50) –Aspergillus 2 (28.6) 1 (25) 1 (50) –Both 1 (14.3) – – 1 (100)

Antifungal prophylaxisFluconazole 3 (42.9) 3a (75) – –Itraconazole tablets 3 (42.9) 1 (25) 1 (50) 1 (100)Itraconazole oral solution 1 (14.3) – 1 (50) –

Duration of prophylaxisDuring admission 3 (42.9) 3 (75) – –Two months 1 (14.3) – 1 (50) –Three months 3 (42.9) 1 (25) 1 (50) 1 (100)

Targeted prophylaxis 15 (28.3) 10 (66.7) 2 (15.4) 3 (12)Indications

Re-transplantation 11 (73.3) 10 (100) 1 (50) –Re-intervention 10 (66.7) 9 (90) 1 (50) –Hemodialysis 9 (60) 8 (80) 1 (50) –Candida colonization 9 (60) 6 (60) 2 (100) 1 (33.3)Fulminant hepatic failure 8 (53.3) 8 (80) – –Prolonged antimicrobials 7 (46.7) 5 (50) 1 (50) 1 (33.3)CVVH 6 (40) 5 (50) 1 (50) –CMV disease 6 (40) 4 (40) 1 (50) 1 (33.3)Multiple transfusion 3 (20) 3 (30) – –Parenteral nutrition 1 (6.7) – 1 (50) –Prolonged MV/ICU 1 (6.7) 1 (10) – –Transplant rejection 1 (6.7) – 1 (50) –ATG 1 (6.7) 1 (10) – –Others 3 (20) 2 (20)b – 1 (33.3)c

Type of fungi addressedCandida 7 (46.7) 3 (30) 1 (50) 3 (100)Aspergillus 1 (6.7) 1 (10) – –Both 7 (46.7) 6 (60) 1 (50) –

Antifungal prophylaxisFluconazole 9 (60) 5 (50) 1 (50) 3 (100)Lipid formulations of AMB 2 (13.4) 2 (20) – –Aerosolized lipid AMB 1 (6.7) 1 (10) – –Caspofungin 2 (13.4) 2 (20) – –Anidulafungin 1 (6.7) – 1 (50) –

Mean doses (mg) ± SDFluconazoled 170 ± 113 225 ± 125 150 ± 0 104 ± 93AMB lipid complex 5 ± 0 5 ± 0 – –Liposomal AMB 2.4 ± 1.5 2.4 ± 1.5 – –Caspofungin 35 ± 0/35 35 ± 0 – –

Duration of prophylaxisAs long as risk factors persist 8 (53.3) 5 (50) – 3 (100)During admission 3 (20) 3 (30) – –Two wk – – – –One month 3 (20) 2 (20) 1 (50) –

AMB, amphotericin B; ATG, antithymocyte globulin; CMV, cytomegalovirus; CVVH, continuous veno-venous hemofiltration; HEPA, high-efficiency particulate air; ICU,intensive care unit; mg, milligrams; MV, mechanical ventilation; SD, standard deviation.aFluconazole dose: 25 mg/d, 100 mg/d, and 200/d mg (one program each).bDeferred abdominal closure and neutropenia.cAuto-bladder catheterization.dFluconazole dose: 1:100 mg/wk, 2:100 mg/d, 1:150 mg/d, 3:200 mg/d, 1:400 mg/d.

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although the antifungal agent varied widely:fluconazole, 50% (200 mg/d); lipidic amphotericinB (AMB), 30% (aerosolized in one center); andcaspofungin, 20%. The most important riskfactors considered indicative of targeted prophy-laxis were re-transplantation, re-intervention, he-modialysis, and fulminant liver failure, althoughthe selection of candidates was not uniform.Prophylaxis was usually maintained when riskfactors were present.

Heart transplant. Only 30.8% of heart transplantprograms used antifungal prophylaxis (50% uni-versal and 50% targeted). Itraconazole was thepreferred agent for universal prophylaxis and wasmaintained during the first two or three monthsafter transplant. Targeted prophylaxis was indi-cated in heart transplant recipients with any of thefollowing risk factors: Candida colonization, re-transplantation, re-intervention, hemodialysis, orcontinuous veno-venous hemofiltration, cytomeg-alovirus (CMV) disease, prolonged use of antimi-crobial therapy, parenteral nutrition, and graftrejection. The drugs of choice were fluconazole(150 mg/d) or anidulafungin for one month.

Kidney transplant. Only 16% of the kidney trans-plant programs used antifungal prophylaxis. Oneprogram used universal prophylaxis with itraco-nazole during the first three months after trans-plant, and the others used targeted prophylaxis ifany of the following risk factors were present:CMV disease, Candida colonization, prolonged useof antimicrobial therapy and bladder catheteriza-tion. All the programs used fluconazole (mean doseof 100 mg/d) for prophylaxis.

Diagnostic methods

As the diagnostic options for invasive candidiasiswere considered more standardized, we limited ourstudy to invasive aspergillosis (Table 3). Serumgalactomannan was widely used (84.9%), mainlyas an early diagnostic tool (93.3%) but also in thefollow-up of patients on therapy (35.6%), andbefore starting antifungal treatment (33.3%).However, transplant clinicians think that galacto-mannan determination is useful in only half of thecases. Interestingly, only a third of the programs(34%) order galactomannan level in bronchoalve-olar lavage fluid as a diagnostic test.

Antifungal therapy

Most programs (68.7%) used a single agent againstinvasive aspergillosis, with voriconazole as the

preferred first-line agent, followed by liposomalAMB. However, combination therapy was the firstchoice in 28.3% of the transplant programs, andthe most common combination was voriconazoleplus caspofungin, followed by voriconazole plusanidulafungin or caspofungin plus liposomalAMB. For salvage therapy, the respondents choseone of the following approaches: adding a secondantifungal (46.3%), changing one antifungal foranother (29.3%), and reformulating combinedtherapy completely (24.4%).

Diagnostic and therapeutic approach by type oftransplant

Liver transplant. Determination of serum galacto-mannan was used by 73.3% of the liver transplantteams, but only 54.4% considered it useful inpractice. Most programs initiated therapy ofinvasive aspergillosis with a single agent (73.3%),while 26.7% used combination treatment from thebeginning. The preferred agents were voriconazole(72.7%) and liposomal AMB (18.2%) in mono-therapy and voriconazole plus caspofungin incombination therapy (50%). For salvage therapy,the most common strategy was to add anotherantifungal agent to the regimen (50% of theprograms).

Heart transplant. Most heart programs (84.6%)used the determination of serum galactomannan,and 72.7% considered it useful in their practice.Most started therapy of invasive aspergillosis witha single agent (61.5%), with voriconazole as thepreferred option in monotherapy (50%), andposaconazole, AMB, and caspofungin as lesscommon alternatives (12.5% each). The preferredantifungals for combination therapy were vorico-nazole plus caspofungin or voriconazole plusanidulafungin (40% each). For salvage therapy,the most common practice was to switch antifungalagent (44.4%).

Kidney transplant. Determination of serum galac-tomannan was used in 92% of the programs,although only 66.6% considered it useful. For thetreatment of invasive aspergillosis, 70% kidneytransplant programs used a single agent and 30%chose combination therapy. Programs that pre-ferred a single agent used voriconazole (71.4%)and liposomal AMB (21.4%), and those thatpreferred combination therapy chose liposomalAMB plus another agent in most cases (66.7%).For salvage therapy, the preferred approach wasto add a second antifungal (50% of the pro-grams).

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Discussion

Ours is the first survey on antifungal managementthat includes different types of SOT physicians. Aprevious study including American liver transplantdoctors was answered by 63% of the centers andconcluded that it was necessary to better define therole of diagnostic assays and combination thera-peutic strategies for invasive aspergillosis in thispopulation (12). We have demonstrated that thesefindings can be expanded to other types of SOTand to other areas of the world. Some areas thatdeserve an international consensus are the utility ofdiagnostic methods (only 34% consider galacto-mannan detection in bronchoalveolar lavage[BAL]), the indication of universal prophylaxis(still preferred in 26.7% and 15% of liver and hearttransplant centers, respectively), or the use ofcombined therapy for first-line therapy of invasive

aspergillosis (31%). Drugs, doses, and length ofadministration were also very divergent.

Incidence of IFI varies with the type of allograftand is higher among liver recipients (4.7–42%) thanin heart (3.4–21%) or kidney recipients (1.3–14%)(1, 9, 16). Invasive aspergillosis is more frequent inheart recipients (1–15%), with a mortality of 78%(5, 17), followed by liver transplant recipients(1–8%) who have a mortality rate of 87% and tendto develop disseminated infections (1, 5, 7, 18).Kidney recipients have the lowest incidence ofinvasive aspergillosis (0–4%), with a mean mortal-ity rate of 77% (5, 17). Two recent multicenter seriesincluding adult SOT recipients have shown animprovement in the mortality rate of invasiveaspergillosis (IA), which ranged from 29.6% to41% (8, 9). Liver transplant recipients still presentthe lowest 12-wk survival compared with othertransplant recipients (log rank p = 0.05) (8).

Table 3. Use of diagnostic tests and therapeutic strategies for invasive aspergillosis

GlobalN = 53 (%)

LiverN = 15 (%)

HeartN = 13 (%)

RenalN = 25 (%)

Diagnosis of apergillosisUse of galactomannan in serum 45 (84.9) 11 (73.3) 11 (84.6) 23 (92)

In all patients 1 (2.2) 1 (9) – –For early diagnosis 42 (93.3) 9 (81.8) 11 (100) 22 (95.7)Before starting antifungal treatment 15 (33.3) 3 (27.3) 2 (18.2) 10 (43.5)To follow up therapeutic response 16 (35.6) 3 (27.3) 4 (36.4) 9 (39.1)

Galactomannan perceived as usefulPrograms that answer 43 11 11 21Always 5 (11.6) 1 (9) 1 (9) 3 (14.3)Almost always 8 (18.6) 1 (9) 3 (27.3) 4 (19)Sometimes 15 (34.9) 4 (36.4) 4 (36.4) 7 (33.3)Rarely 13 (30.2) 5 (45.5) 2 (18.2) 6 (28.6)Never 2 (4.7) – 1 (9) 1 (4.8)

Use of galactomannan in bronchoalveolar fluid 18 (34) 4 (26.7) 3 (23.1) 11 (44)Therapy of invasive aspergillosisFirst-line therapy

Programs that answer 48 15 13 20Monotherapy 33 (68.7) 11 (73.3) 8 (61.5) 14 (70)

Voriconazole 22/33 (66.6) 8/11 (72.7) 4/8 (50) 10/14 (71.4)Posaconazole 1/33 (3) – 1/8 (12.5) –Liposomal AMB 6/33 (18.2) 2/11 (18.2) 1/8 (12.5) 3/14 (21.4)Deoxycholate AMB 2/33 (6) – 1/8 (12.5) 1/14 (7.1)Caspofungin 2/33 (6) 1/11 (9.1) 1/8 (12.5) –

Combination therapy 15 (31.3) 4 (26.7) 5 (38.5) 6 (30)Voriconazole + caspofungin 6/15 (40) 2/4 (50) 2/5 (40) 2/6 (33.3)Voriconazole + anidulafungin 4/15 (26.7) 1/4 (25) 2/5 (40) 1/6 (16.7)Voriconazole + liposomal AMB 1/15 (6.7) – 1/5 (20) –Caspofungin + liposomal AMB 4/15 (26.7) 1/4 (25) – 3/6 (50)Anidulafungin + liposomal AMB – – – 1/6 (16.7)

Second-line therapyPrograms that answer 41 14 9 18

Switch antifungal agent 12/41 (29.3) 3/14 (21.4) 4/9 (44.4) 5/18 (27.8)Add another antifungal 19/41 (46.3) 7/14 (50) 3/9 (33.3) 9/18 (50)Change both antifungals 10/41 (24.4) 4/14 (28.6) 2/9 (22.9) 4/18 (22.2)

AMB, amphotericin B.

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Although the mortality of IFI in SOT recip-ients remains high, incidence has clearly dimin-ished. In our survey, the reported annualincidence of IFIs is 2.01%, which is very similarto the data shown by Pappas et al. in a recentstudy including 16 459 SOT recipients (IFI 3.1%,invasive candidiasis 1.9%, and invasive aspergil-losis 0.7%) (9). Accordingly, the use of antifun-gal drugs needs to be tailored to these newcircumstances.

Prophylaxis

The need for environmental air protection in SOTis under discussion, and admission of organrecipients to air-protected units is not universallyrecommended. However, several authors suggest aclear relationship between isolation of Aspergillusin the air and risk of invasive aspergillosis (19–21).

The need for antifungal prophylaxis in SOTprograms is a matter of debate, and no uniformguidelines are followed. The American TransplantSociety has published its recommendations inwhich targeted prophylaxis with itraconazole orvoriconazole is recommended for high-risk heartrecipients and a lipid formulation of AMB or anechinocandin for liver recipients at a high risk ofIFI. No prophylaxis is recommended for kidneyrecipients, and no universal prophylaxis is consid-ered justified in heart, liver, or kidney programs(22). In the recent IDSA guidelines on candide-mia, fluconazole and L-AMB are recommended aspost-operative prophylaxis for liver recipients(evidence A-I) (10). According to our data, mosttransplant programs (58.5%) do not use anyantifungal prophylaxis; however, 32% of theprograms that do use it prefer universal prophy-laxis. The preferred antifungal agents for universalprophylaxis are fluconazole or itraconazoleadministered during the first three months aftertransplant. As mentioned, this practice is notrecommended by the American Transplant Society(22).

Targeted prophylaxis is becoming more acceptedworldwide, mainly by liver transplant teams(66.7% in our study and 88–91% in Americanand European surveys) (12, 13). However, thecriteria for considering a transplant recipient as ahigh-risk patient for IFI differ widely (3, 16, 23).We found that the most common accepted riskfactors for targeted antifungal prophylaxis arere-transplantation, re-intervention, hemodialysis,and Candida colonization. However, many othercriteria of doubtful validity are also used indaily practice to indicate antifungal prophylaxis(e.g., prolonged antimicrobials, rejection, multiple

transfusion). These criteria should be reviewed toavoid unnecessary toxicity and cost.Choice of drug is also under debate, because

very little evidence-based data are available in thispopulation. Different clinical trials have shown adecrease in the incidence of IFI in high-risk liverand heart recipients using AMB, itraconazole, orcaspofungin (3, 16, 24–26). The other two candins,anidulafungin and micafungin, are under evalua-tion for prophylaxis in SOT recipients. However, inour study, fluconazole was the preferred agent fortargeted prophylaxis, although liposomal AMB,caspofungin, or anidulafungin were commonlyprescribed as well. In our opinion, high-risk SOTpatients should receive a drug that confers protec-tion against Aspergillus.Timing (when to initiate prophylaxis and when

to stop it) is even more controversial. Targetedprophylaxis was generally maintained while riskfactors were present, but liver transplant physi-cians, in particular, tend to use higher doses offluconazole for longer periods.

Diagnosis

Diagnosis of invasive aspergillosis is challengingand usually requires a combination of radiologicaland microbiological data obtained with an invasiveprocedure. A positive culture may merely indicatecolonization; nevertheless, the positive predictivevalue of Aspergillus in a respiratory sample is veryhigh in some types of SOT (2). A score has beenproposed to help in the interpretation of theclinical significance of Aspergillus fumigatusisolated from clinical samples in microbiologylaboratories (27).Indirect methods, such as the determination of

galactomannan in serum or bronchoalveolar fluid,may prove helpful, although sensitivity is lower inSOT recipients than in hematological patients(25% and 56–81%, respectively) (14, 27, 28). Ourstudy reveals that in most Spanish transplantcenters (79.2%), transplant physicians order aserum galactomannan test for establishing thediagnosis of invasive aspergillosis, but only30.2% considered it useful as a diagnostic testand during follow-up. Unfortunately, our surveyreveals that the detection of galactomannan inbronchoalveolar fluid is not widely used in Spanishtransplant centers (34%) despite its proven useful-ness. New molecular methods, such as polymerasechain reaction, are not available in all SOT centers,and in some they are still used for experimentalpurposes only. International guidelines shouldinclude a summary of specific diagnostic criteriafor SOT recipients.

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Treatment

Recent guidelines consider voriconazole in mono-therapy to be the treatment of choice for invasiveaspergillosis (11). Combination therapy is onlyrecommended for refractory cases. However, theseguidelines are based on a very low number of SOTpatients (14 in Herbrecht�s study) (29). In oursurvey, voriconazole was the first-choice treatmentof invasive aspergillosis in 66.6% of cases. Thedrawbacks of voriconazole include interaction withimmunosuppressive drugs (calcineurin inhibitoragents) because of the potent inhibition ofCYP34A isoenzymes (30) and the need to monitordrug levels to prevent associated toxicity or treat-ment failure (31, 32).The IDSA guidelines recommend the use of a

lipid formulation of AMB for invasive aspergillosisrefractory to voriconazole or in intolerant patients(11). However, we found that it is used as first-linetreatment in 18.2% of transplant programs.Caspofungin is recommended as salvage therapy

for invasive aspergillosis (11). A study including 12heart and lung recipients with invasive aspergillosistreated with caspofungin as first-line therapyreported an 83% response rate (33). We foundthat 6% of SOT programs used caspofungin asfirst-line treatment. Other candins, such as anidu-lafungin and micafungin, are still under evaluationfor the treatment of invasive aspergillosis in SOTrecipients.In the guidelines, combination of antifungals is

reserved for salvage therapy (11). However, reportson SOT suggest that voriconazole plus caspofunginused as first-line therapy may be preferable in high-risk patients such as those infected with A. fumig-atus or with kidney failure (34, 35). Surprisingly,combination therapy was used as a first-lineapproach in 31.3% of transplantation programsand as a second-line approach in 70.7%. In aprevious study, combination of antifungals wasused in 47% of American liver transplant centersas first-line therapy and in 80% as salvage therapy(12).Our study has limitations. The response rate was

61%, but the centers that did not complete thesurvey are smaller centers with few transplantpatients. Almost all large centers responded, andwe obtained information on 85% of heart recipi-ents, 65% of kidney recipients, and 71.5% of liverrecipients managed during 2009 in Spain. Our rateof response was very similar to that of the survey ofAmerican liver transplant physicians (12). Anotherlimitation is that our data could not be represen-tative of what is happening in other parts of theworld. We believe that data should be obtained

from countries in which new antifungal drugs arenot widely available or from areas with endemicmycoses. However, our data on liver transplantrecipients are not very different from those ofSingh, so they can probably be considered repre-sentative of countries with a medium-high income.Finally, the reason why transplant physicians havethis poor adherence to international recommenda-tions needs to be elucidated.

Our study reveals wide variability in the use ofdiagnostic methods and antifungal management bySOT physicians. The reasons for this variability arepoorly understood and merit further research. Therelatively low frequency of these infections, thepersonal experience, the antimicrobial policies ineach center, the different commercial pressures andmainly the lack of widely known specific guidelinesfor transplant recipients with evidence-based rec-ommendations may all play a role. In our opinion,the high mortality of IFI, the high cost of newantifungal drugs and their potential toxicity inSOT recipients justify an international consensusthat unifies clinical practices and improves patientsafety. An international consensus has recentlybeen published on CMV; therefore, we believe thata consensus on antifungal management is viable.This survey represents a foundation on which tobuild studies and criteria that can eventually leadto a consensus for clinical practice. Optimal careand treatment is not possible without knowledge ofcurrent practice. We encourage national surveys inother countries for the same reasons.

Acknowledgements

We thank Dr. Nina Singh for providing the surveyinstrument used in a similar previous study and forreviewing this manuscript. We are grateful to ThomasO�Boyle for editorial assistance.

Authorship

PM has made substantial contributions to theconception and design of the study, performed thestatistical analysis, wrote the manuscript and hasbeen involved in drafting the manuscript andreviewing it. She has given final approval of theversion to be published. LR participated in thedesign of the study, data collection, analysis andinterpretation of data and has been directlyinvolved in drafting and reviewing the manuscript.MV participated in the design of the study,acquisition, analysis, and interpretation of dataand has been directly involved in drafting andreviewing the manuscript. MG participated in thecollection, analysis, and interpretation of data and

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has been involved in drafting the manuscript. CChas been directly involved in drafting and review-ing the manuscript. GG has been directly involvedin drafting and reviewing the manuscript. MF hasbeen directly involved in drafting and reviewing themanuscript. EB conceived the study and partici-pated in its design and coordination and helped inthe drafting and edition of the manuscript and hasgiven final approval of the version to be published.

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17. Brown RS Jr, Lake JR, Katzman BA et al. Incidenceand significance of Aspergillus cultures following liver andkidney transplantation. Transplantation 1996: 61: 666.

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23. Gavalda J, Len O, San Juan R et al. Risk factors forinvasive aspergillosis in solid-organ transplant recipients: acase-control study. Clin Infect Dis 2005: 41: 52.

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25. Fortun J, Martin-Davila P, Moreno S et al. Preven-tion of invasive fungal infections in liver transplant recip-ients: the role of prophylaxis with lipid formulations ofamphotericin B in high-risk patients. J Antimicrob Che-mother 2003: 52: 813.

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L, Munoz P. Workload due to Aspergillus fumigatus andsignificance of the organism in the microbiology labora-tory of a general hospital. J Clin Microbiol 2005: 43: 2075.

28. Clancy CJ, Jaber RA, Leather HL et al. Bronchoalve-olar lavage galactomannan in diagnosis of invasive pul-monary aspergillosis among solid-organ transplantrecipients. J Clin Microbiol 2007: 45: 1759.

29. Herbrecht R, Denning DW, Patterson TF et al.Voriconazole versus amphotericin B for primary therapyof invasive aspergillosis. N Engl J Med 2002: 347: 408.

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Appendix

Members of the Cooperation Mycology In Transplant(COMIT) Study Group

The members of the Cooperation Mycology InTransplant (COMIT) Study Group are EduardoGallego, C Hospitalario Univ, Albacete. MarisaMir, Marta Crespo, H del Mar, Barcelona.Ricardo Lauzurica, Germans Trias i Pujol, Barce-lona Laura Llado, Salvador Gil-Vernet, NuriaSabe, Jordi Carratala, H de Bellvitge, Barcelona.Sonia Mirabet, Hospital Sant Pau, Barcelona.Asuncion Moreno, Carlos Cervera, Felix Perez-Villa, H Clınic, Barcelona. Itxarone Bilbao, H VallD¢Hebron, Barcelona. Luis Guirado, FundacionPuigvert, Barcelona. Gema Ariceta, Miguel Mont-ejo, H Cruces, Bilbao. Julian Torre Cisneros,

IMIBIC, UCO, H U Reina Sofıa, Cordoba. AngelAlonso, H U de la Coruna. Angelas Vasquez,C Hospitalario, La Coruna. Paloma Jara, LuisGarcıa-Guereta, Carlos Jimenez, MercedesNavarro, H La Paz, Madrid. Juan Jose Plaza,Fundacion Jimenez Dıaz, Madrid. Pilar Martın,Jesus Fortun, H Ramon y Cajal, Madrid AntonioRamos, Vıctor Sanchez, H Puerta de HierroMajadahonda, Madrid. Francisco Lopez, RafaelSan Juan, Jose Marıa Aguado, H 12 de Octubre,Madrid. Natalia Ridao, H Clınico San Carlos,Madrid. Fernando Anaya, Emilio Bouza, PaulaFernandez, Juan Fernandez-Yanez, MaddalenaGiannella, Augusto Luque, Patricia Munoz, JesusPalomo, Magdalena Salcedo, Diego Rincon,Marıa Luisa Rodrıguez, Loreto Rojas, MaricelaValerio, H G U Gregorio Maranon, Madrid.Ernesto Gomez, Jose Luis Rodrıguez Lambert,H Central de Asturias, Oviedo. Jose IgnacioHerrero, CIBERehd, C Universidad de Navarra,Pamplona. M. Carmen Farinas, Fernando Casa-font, Emilio Fabrega, Rosa Palomar, H UMarques de Valdecilla, Santander. Elisa Cordero,H U Virgen del Rocıo, Sevilla. Alicia Mendiluce,Antonio Orduna, H Clınico Universitario, Valla-dolid. Marıa Lourdes Perez, H U de las Canarias,Tenerife. Marisa Sanz, H Miguel Servet, Zar-agoza. Marıa Antonia Sepulveda, Virgen de laSalud, Toledo. Luis Almenar, Marino Blanes,Isabel Zamora, H La Fe, Valencia. GregorioGarrido, Rafael Matesanz, Organizacion Nacionalde Trasplantes. Nina Singh, Pittsburgh University.

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