Antifungal prophylaxis in liver transplant patients: A systematic review and meta-analysis

ORIGINAL ARTICLE

Antifungal Prophylaxis in Liver TransplantPatients: A Systematic Review andMeta-analysisMario Cruciani,1 Carlo Mengoli,2 Marina Malena,1 Oliviero Bosco,1 Giovanni Serpelloni,1 andPaolo Grossi31Center of Preventive Medicine, HIV Outpatient Clinic, Verona, Italy, 2Department of Histology,Microbiology, and Medical Biotechnology, University of Padua, Padua, Italy, and 3Department ofInfectious Diseases and Tropical Medicine, University of Insubria, Ospedale di Circolo, Varese, Italy

Received September 12, 2005; accepted November 25, 2005.

We performed a meta-analysis to determine whether antifungal prophylaxis decreases infectious morbidity and mortality in livertransplant patients. We searched for randomized trials dealing with prophylaxis with systemic antifungal agents. We used afixed effect model, with risk ratio (RR) and 95% confidence interval (CI); we assessed study quality for heterogeneity andpublication bias. Six studies (5 double-blind), for a total of 698 patients, compared fluconazole, itraconazole, or liposomalamphotericin to placebo (5 studies) or oral nystatin. Prophylaxis reduced colonization (RR, 0.45; CI, 0.37-0.55), total provenfungal infections (RR, 0.31; CI, 0.21-0.46), which included both superficial (RR, 0.27; CI, 0.16-0.45) and invasive (RR, 0.33;CI, 0.18-0.59) infections, and mortality attributable to fungal infection (RR, 0.30; CI, 0.12-0.75). Prophylaxis did not affectoverall mortality (RR, 1.06; CI, 0.69-1.64) or empiric treatment for suspected fungal infection (RR, 0.80; CI, 0.39-1.67).The beneficial effect of antifungal prophylaxis was predominantly associated with the reduction of Candida albicansinfection and mortality attributable to C. albicans. Compared to controls, however, patients receiving prophylaxisexperienced a higher proportion of episodes of non–albicans Candida, and in particular of C. glabrata. No beneficial effecton invasive Aspergillus infection was observed. In conclusion, our analysis shows a clear, though limited, beneficial effectof antifungal prophylaxis in liver transplant patients. Concerns about the selection of triazole-resistant Candida strains,however, are realistic, and the potential disadvantages of prophylaxis should be weighed against the established benefits.Liver Transpl 12:850-858, 2006. © 2006 AASLD.

Systemic fungal infections are a significant cause ofmorbidity and mortality in solid-organ recipients.1-3

The incidence of fungal infections after liver transplan-tation has been reported in the range of 7-42%, withCandida spp. and Aspergillus spp. as the most commonpathogens responsible for infections.2-16 Actually, Can-dida spp. accounts for 35-91% of all invasive fungalinfections in liver transplant recipients, followed by As-pergillus spp., responsible for 9-34% of infec-tions.3,5,6,8,9,17,18

Invasive fungal infections after liver transplantationhave been associated with overwhelming outcome, withattributable mortality rates reported as high as 92-

100% for invasive aspergillosis and 70% for invasivecandidiasis.

9, 14, 16,18-22

Use of broad-spectrum antibiotic therapy, technicaldifficulties of surgical procedures, return to surgeryand retransplantation, cytomegalovirus disease, ab-sence of the protective effect of anaerobic bacteria to-ward the overgrowth of Candida in the gut, and overallseverity of illness in the patient (e.g., prolonged periodof dialysis, access to intensive care unit, use of centralvenous catheter, total parenteral nutrition, and me-chanical ventilation) are major risk factors for the de-velopment of invasive fungal infections.6,16,23-25 Amongthe other risk factors is immunosuppression, which

Abbreviations: CI, confidence interval; RR, risk ratio; ARR, absolute risk reduction; df, degree of freedom.Presented in part at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, October 30-November 2,2004.Address reprint requests to Mario Cruciani, MD, Center of Preventive Medicine/HIV Outpatient Clinic, V. Germania, 20-37135 Verona, Italy.Telephone: 39 045 8076266; FAX: 39 045 8622239; E-mail: [email protected]

DOI 10.1002/lt.20690Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 12:850-858, 2006

© 2006 American Association for the Study of Liver Diseases.

may be induced by major surgery, bacterial sepsis, di-abetes, steroids, chemotherapy, and immunosuppres-sive treatment after transplantation. As yet, however,there are few data showing a correlation between mea-sure of immune system function (e.g., ratios of T-helperto T-suppressor lymphocyte) and risk of fungal infec-tion in liver transplant patients.20

Due to the high incidence and mortality rate of inva-sive fungal infections, the use of a successful antifungalprophylaxis in liver transplant patients is very attrac-tive, and there have been several studies pertaining toprophylaxis in this field.26-41 These studies have beenrecently analyzed in a Cochrane review on antifungalagents for preventing fungal infections in solid-organ(heart, liver and kidney) transplant recipients.42 Wehave addressed some questions that were not consid-ered in this review (e.g., mortality attributable to fungalinfections, need for empiric antifungal treatment) andrestricted the analysis to liver transplant patients, withtheir distinctive predisposition to develop fungal infec-tions. Moreover, to evaluate the effect of systemic anti-fungal prophylaxis unaffected by the choice of controlregimen, we chose to include only trials controlled withplacebo, no prophylaxis, or minimal prophylaxis (oralnonabsorbable agents).

The aim of this study was to systemically identify andsummarize the quality of the randomized trials avail-able and the effects of antifungal prophylaxis in livertransplant patients.

MATERIALS AND METHODS

Search Strategies

The search was carried out on MEDLINE (1966-March2004), EMBASE (1980-March 2004), and the CochraneDatabase of Systematic Reviews (Issue 1, 2004). MeSHterms used were “antifungal agents/antifungal prophy-laxis & liver transplantation/organ transplant.” Thecomputer search was supplemented by consulting thebibliographies from the articles retrieved.

We included only randomized controlled trials evalu-ating the efficacy of antifungal prophylaxis in livertransplant patients. We required that studies comparedprophylactic regimens based on systemic antifungalagent to a control arm in which subjects were givenplacebo, no treatment, or minimal treatment with oralnonabsorbable antifungal agents (e.g., nystatin).

Outcome Measures

We extracted data on overall mortality, mortality attrib-utable to fungal infection, overall fungal infections (in-cluding defined and presumed fungal infections), su-perficial and invasive infections, fungal colonization,need for empiric antifungal treatment, adverse reac-tions to study drugs, and need for discontinuation oftreatment. An invasive infection was defined as the his-topathologic evidence of infection, or microbiologic evi-dence of fungi in tissue culture, or yeast from normallysterile body cavity or organ. A superficial infection wasdefined as isolation of a fungus from skin, oropharynx,

vagina, gastrointestinal tract, or urine in associationwith symptoms and signs of inflammation, ulceration,plaques, or exudates. Where possible, we also extractedtime-to-event data.

Quality Assessment

We assessed the methodology of each trial with a scaledeveloped by Jadad and colleagues that scores (from alow of 0 to a high of 5) the randomization, double-blinding, and reports of dropouts and withdrawals.43

Each trial was independently scored by 2 of us and anyareas of disagreement arbitrated by a third person.

Statistical Analysis

A conventional meta-analysis was performed with useof the Mantel-Haenszel fixed-effects model, applyingthe DerSimonian and Laird random effects model onlyin cases where the heterogeneity test give a P value�0.1.44,45 We calculated both the study-specific andthe common 95% confidence interval (CI) by the methodof Woolf.46 We used risk ratio (RR) as measure of theeffect size, and the procedure to combine the 2 � 2tables was the Mantel-Haenszel-like method by Green-land and Robins.47,48 Measures of efficacy that we haveused were the absolute risk reduction (ARR, defined asthe difference in the event rate in intervention groupand in control group), the relative risk reduction (de-fined as the ARR divided by the event rate in controlgroup), and the number of patients needed to be treatedto prevent 1 event (expressed as the reciprocal of theabsolute risk reduction) and related 95% CI.49,50 Sen-sitivity analysis was performed for determining if quan-titative results differed with the exclusion of individualstudies.

Assessment of Publication Bias andHeterogeneity

Graphical funnel plots were generated to visually in-spect for publication bias.51 The statistical methods fordetecting funnel plot asymmetry were the rank correla-tion tests of Begg and Mazumdar and the regressionasymmetry test of Egger et al.51,52 The heterogeneity ofstudy results was assessed by Cochran Q test and by atest of inconsistency (I2).53,54

RESULTS

As shown in the flow diagram (Fig. 1), 16 potentiallyrelevant controlled clinical trials were identified as be-ing appropriate for inclusion in our analysis.26-41 Ofthese, 6 studies were excluded because there was evi-dence of duplication of data.35-40 Data was not usablefrom a study published as an abstract.41 Three othertrials were excluded because they tested other interven-tions or because the type of outcome measure was dif-ferent from those specified in our protocol; these stud-ies included a randomized study by Ruskin et al.comparing oral nonabsorbable agents (nystatin and

ANTIFUNGAL PROPHYLAXIS IN LIVER TRANSPLANT 851

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

clotrimazole), a randomized study by Winston et al.comparing 2 systemic antifungal agents (itraconazoleand fluconazole), and a study by Tortorano et al. aimedat evaluating only the efficacy of fluconazole comparedto oral amphotericin B in preventing fungal coloniza-tion.32-34 Therefore, we included in the meta-analysisdata retrieved from 6 randomized clinical trials (5 dou-ble-blind) for a total of 698 patients.26-31

Description of Studies and QualityAssessment

Table 1 summarizes the main characteristics of in-cluded studies. Duration of antifungal prophylaxisvaried in the different studies, ranging from 5 days inthe study by Tollemar et al.26 to 4-10 weeks in theremaining trials. The diagnostic criteria for fungalinfection were fully consistent with our definition inall study but 1; in the definition of fungal infection thestudy by Biancofiore et al. included patients withpositive cultures from multiple (�3) peripheralsites.30

The most common underlying disease requiring livertransplantation was hepatic cirrhosis (mostly postviraland alcoholic liver disease), while a lower proportion ofpatients had liver transplantation following fulminanthepatic failure and hepatocellular carcinoma. All thepatients received immunosuppressive treatment (pred-nisone, azathioprine, cyclosporine or tacrolimus, andOKT3 or antithymocyte globulin for rejection). Fungal

colonization at entry varied in the different studies (Ta-ble 1).

Study drugs were fluconazole, itraconazole, liposo-mal Amphotericin B, and liposomal Amphotericin Bfollowed by itraconazole or fluconazole. These drugswere compared to placebo (5 studies) or to nystatin (1study).

The median Jadad score for quality was 3.5 (range,2-5); the mean score was 3.7 � 1.2. Two studies clearlyreported concealment of treatment allocation.26,31

Results of the Meta-analysis

Table 2 shows RR and related 95% CI, crude rates,absolute and relative risk reduction, and the number ofpatients needed to be treated to prevent 1 event. Fig-ures 2-4 {FIG 2-4}show RR and related 95% confidenceinterval (95%CI) for individual studies for the most rel-evant outcomes. Visual inspection of Figures shows astatistically significant reduction of total episodes offungal infection and superficial and invasive infection,as well as mortality attributable to fungal infections inpatients receiving prophylaxis with systemic antifungalagents. Prophylaxis, however, did not affect overallmortality (RR, 1.06; 95% CI, 0.69-1.64; P � 0.77) andneed for empirical antifungal treatment (RR, 0.80; 95%CI, 0.39-1.67; P � 0.55).

Side effects assessed as being related, or possiblyrelated, to drug were more common in antifungalprophylaxis recipients (RR, 1.38; 95% CI, 1.04-1.83;P � 0.02), but discontinuation of treatment due toside effects did not differ between study groups andcontrols (RR, 1.15; 95% CI, 0.65-2.04; P � 0.63). Inthe large majority of cases, adverse events consistedof mild gastrointestinal intolerance in fluconazoleand itraconazole recipients, and neurologic events(headache, seizures, tremors) in fluconazole recipi-ents; 3 patients receiving liposomal amphotericin Bhad back pain, 1 had a transient episode of throm-bocytopenia, and 1 suffered from suspected nephro-toxicity. Abnormalities in laboratory tests had similarrates of occurrence in treatment groups and controls.One study reported elevated cyclosporine levels influconazole recipients.29 Fungal colonization rateswere reported in 3 studies.27,29,30 Prophylaxis signif-icantly reduced colonization (RR, 0.45; CI, 0.37-0.55;P � 0.0001).

Rates of patients free from fungal infection at aspecific time were reported in 2 studies.29,31 Thestudy by Winston et al. showed that starting from day10 rates of proven fungal infection became signifi-cantly lower in treated patients compared to controls,both in all patients and in high-risk patients.29 Like-wise, in the study by Sharpe et al. the probability ofdeveloping a fungal infection requiring systemic an-tifungal therapy was significantly lower in treatedpatients beyond the first 2 weeks of prophylaxis.31

Figure 1. Meta-analysis profile summarizing trial flow.RCT, randomized clinical trial.

852 CRUCIANI ET AL.


TABLE 1. Main Characteristics of Randomized Clinical Studies Included in the Analysis

First Author, Year of Publication (reference).

Tollemar,199526 Lumbreras, 199627 Meyers, 199728 Winston, 199929

Biancofiore,200230 Sharpe, 200331

Intervention(number ofpatientsevaluated)

Liposomal AmB,1mg/kg (40)vs. placebo(37);duration: 5days. Double-blind

Fluconazole, 100 mgpo (76) vs.nystatin (67);duration: 4 weeks.Unblind

Fluconazole (23) vs.placebo (24) and,in both groups,oral clotrimazoleand nystatinvaginalsuppositories;duration: 10weeks. Double-blind.Fluconazole dosenot specified.

Fluconazole 400 mg,IV then po (108)vs. Placebo (104);duration: 10weeks.Double-blind

Liposomal AmB,1mg/kg/d for7 d, thenitraconazole,200 mg po(42 ) vs.fluconazole400 mg IV for7 d, thenitraconazole,200mg po(43) vs.placebo, IVand po (44);duration: 4weeks.Double-blind

Itraconazole 2.5-5mg/kg/d, po(25) vs. placebo(37); duration:8 weeks.Double-blind

Number ofrandomizedparticipants(age intreatedpatients iscompared toage incontrols)

85 livertransplantpatients,adults andchildren.Median age,(range): 40(1-63) yr vs.42 (1-67) yr.Males: 50%.Fungalcolonizationat entry: 64vs. 70%.

143 liver transplantpatients, adultsand children. Age:40 � 16 yr vs. 42� 16 yr Males:60%. Fungalcolonization atentry: 20.7 vs.17.9%. Child-Turcotte-Pugh Cscore: 17 vs. 15%.

55 liver transplantpatients. Meanage: 49.6 vs.48.2 yr. Males:63%.

236 liver transplantpatients, adults.Median age(range):49 (15-75)vs. 53 (19-74) yr.Males: 55%.Fungalcolonization atentry: 60 vs. 70%.

131 livertransplantpatients. Age(mean):46.2vs. 50.3 vs.51.5 yr.Males: 63%.Fungalcolonizationat entry:42.6%. Child-Turcotte-Pugh C score:7.2 vs. 154vs. 4.6%,respectively.

71 livertransplant pts,adults. Age(mean): 46yrMales: 59%.Fungalcolonization atentry: 44%.Child-Turcotte-Pugh C score:65%.

Setting Sweden andFinland, 2centers

Spain, 3 centers United States, 1center

United States, 1center

Italy, 1 center Canada, 1 center

Outcomes Mortality(overall andattributableto fungalinfection),invasive andsuperficialinfection,empiricantifungaltreatment,side effectsanddiscontinuationbecause ofside effects

Mortality (overalland attributableto fungalinfection), invasiveand superficialinfection,colonization,empiric antifungaltreatment, sideeffects anddiscontinuattionbecause of sideeffects

Mortality (overalland for fungalinfection),invasive andsuperficialinfection, empiricantifungaltreatment,discontinuationbecause of sideeffects

Mortality (overalland attributableto fungalinfection), invasiveand superficialinfection,colonization,empiric antifungaltreatment, sideeffects anddiscontinuationbecause of sideeffects

Mortality(overall andattributableto fungalinfection),invasive andsuperficialinfections,colonization,side effectsanddiscontinuationbecause ofside effects

Mortality (overallandattributable tofungalinfection),invasive andsuperficialinfection,empiricantifungaltreatment, sideeffects anddiscontinuationbecause of sideeffects

TABLE 2. Main Cumulative Meta-Analysis Data

OutcomeRisk Ratio*(95% CI) P Value

Crude Rates

ARR*-RRR† (%) NNT* (95% CI)Treated Controls

Total fungalinfections

0.31 (0.21-0.46) �0.0001 33/365 (9.0) 88/314 (28.0) 19.4-69.2 5.1 (3.9-7.2)

Invasiveinfections

0.33 (0.18-0.59) �0.0001 15/365 (4.1) 39/320 (12.1) 8.4-69.4 11.8 (8.0-23.0)

Superficialinfections

0.27 (0.16-0.45) �0.0001 19/365 (5.2) 60/314 (19.1) 13.9-72.7 7.1 (5.3-10.9)

Empiric treatmentfor suspectedfungalinfections

0.80 (0.39-1.67) 0.55 13/280 (4.6) 16/270 (5.9) 1.1-18.6 88.9 (21.1-40.2)

Side effects 1.38 (1.04-1.83) 0.02 83/342 (24.2) 57/290 (19.6) �7.3/�37.2 �13.6 (�87.1/�7.3)Mortality

attributable tofungalinfections

0.30 (0.12-0.75) 0.010 6/365 (1.6) 17/316 (5.3) 3.8-71.6 25.7 (14.7-100.7)

Abbreviations: RRR, relative risk reduction; NNT, number of patients needed to be treated to prevent 1 event; ARR, absoluterisk reduction.*Risk Ratio, ARR, and NNT are weighted estimates.†RRR-ARR/crude rate in controls.


In sensitivity analysis, the exclusion of any singlestudy yielded only minimal change on the effect size forall the outcomes analyzed except for side effects. Actu-ally, the difference in the occurrence of side effects wasno longer statistically significant after exclusion of 2studies with fluconazole.27,29

Data on fungal isolates according to treatment groupswere provided in 5 studies and are summarized in Table3.26,27,29-31 C. albicans was by far the most common iso-late in control groups, responsible for 64% of deaths at-tributable to fungal infections. Patients receiving prophy-laxis had a higher rate of infections sustained by otherspecies of Candida, including C. glabrata infections, and ahigher rate of death due to Aspergillus spp. Invasive as-pergillosis was responsible for 3 of the 6 deaths attribut-able to fungal infection in treated groups, in 2 cases inpatients receiving fluconazole and in 1 case in a patientreceiving intravenous fluconazole combined with oralitraconazole.27,29,30

Heterogeneity and Publication BiasAssessment

There was not evidence of intertrial heterogeneity forthe outcomes analyzed. The Cochrane Q statistic forheterogeneity provided the following results: totalfungal infections, Q � 8.97, (degree of freedom) � 5,P � 0.11; invasive infections, Q � 4.43, df � 4, P �0.35; superficial infections, Q � 5.47, df � 4, P �0.24; colonization, Q � 1.87, df � 2, P � 0.9; empir-ical treatment for suspected fungal infections, Q �2.39, df � 4, P � 0.66; side effects, Q � 1.3, df � 4,P � 0.86; discontinuation of treatment, Q � 1.73,df � 3, P � 0.63; overall mortality, Q � 4.98, df � 5,P � 0.41; attributable mortality, Q � 2.66, df � 3, P �0.4. There was also no evidence for publication biaswith funnel plots (symmetrical appearance) as well aswith the Begg and Mazudmar and Egger tests. TheBegg and Mazudmar test gave a P value � 1 for the

Figure 2. Pooled RR estimates and their 95% CI for the out-comes invasive and superficial fungal infections. Studies areidentified by first author. Size of squares is proportional tothe weighted RR. *Cannot be computed because the presenceof frequencies � 0.

Figure 3. Pooled RR estimates and their 95% CI for the over-all outcomes for mortality and mortality attributable to fungalinfections. Studies are identified by first author. Size ofsquares is proportional to the weighted RR. *Cannot be com-puted because the presence of frequencies � 0.

854 CRUCIANI ET AL.


outcomes total fungal infections, invasive infections,superficial infections, colonization, and attributablemortality, and a P value � 0.806 for side effects.

DISCUSSION

In this meta-analysis, we have included data from 6randomized clinical trials (5 double-blind, placebo-con-trolled) evaluating the effect of antifungal prophylaxisin 698 patients undergoing orthotopic liver transplan-tation. A Cochrane review on antifungal agents for pre-venting fungal infections in solid-organ transplant re-cipients was recently published by Playford et al.42 Wehave addressed some questions that were not consid-ered in this review (e.g., mortality attributable to fungalinfections, need for empiric antifungal treatment).Moreover, to evaluate the effect of systemic antifungalprophylaxis unconfounded by the choice of control reg-

imen, we chose to include only trials controlled withplacebo, no prophylaxis, or minimal prophylaxis (oralnonabsorbable agents). In this regard, the presentstudy provides more firm results than those availablefrom the Cochrane review, which included trials with avariety of control regimens. Moreover, contrary to theCochrane review, we have not included in our analysisstudies dealing with renal and cardiac transplant recip-ients, who are at lower risk of invasive fungal infectionscompared to liver transplant recipients.

The results of our meta-analysis show that antifungalprophylaxis had a significant effect on infectious mor-bidity and on mortality attributable to fungal infections,but not on overall mortality. Compared to controls, pa-tients who received prophylaxis experienced a reduc-tion of overall episodes of fungal infections (69.2% rel-ative risk reduction), as a result of a decrease ininvasive infections (69.4% relative risk reduction) andin superficial infections (72.7% relative risk reduction).There was also evidence for a decrease in mortalityattributable to fungal infections in patients receivingprophylaxis, with a 71.6% relative risk reduction. Bycontrast, empiric treatment for suspected fungal infec-tions and overall mortality were not affected by antifun-gal prophylaxis. Side effects were more commonly re-ported in recipients of study drugs compared tocontrols, but discontinuation of treatment did not differbetween groups.

The number of patients needed to be treated to pre-vent 1 event is another established method to expressthe magnitude of the effect of an intervention on theoutcomes considered. In the present meta-analysis, thenumbers of patients needed to be treated to prevent 1event were as follow: for total fungal infections, 5.1; forcolonization, 2.5; for invasive infections, 11.8; for su-perficial infections, 7.1; for empiric treatment of sus-pected fungal infections, 88.9; for overall mortality,-149; for mortality attributable to fungal infections,25.7; for side effects, -13.6.

Time to event data was available from 2 studies.29,31

Data from these trials shows that the probability ofdeveloping a fungal infection requiring systemic anti-fungal therapy was significantly lower in treated pa-tients beyond the first 10-14 days of prophylaxis. Tothis end, it is relevant to emphasize that in the study byTollemar et al., prophylaxis was given for only 5 days.26

Some limitations of this meta-analysis need to beacknowledged. First of all, the diagnosis of systemicfungal infections is difficult and open to bias that mayaffect the evaluation of end points. Moreover, as with allmeta-analyses, our conclusions can be only as accurateas the trials upon which they are based. Based onquality scores, the methodological quality of the studieswas, on average, more than satisfactory, though it var-ied considerably in individual studies. There was, how-ever, variability in the design and reporting of individ-ual studies. Study drugs were oral/intravenousfluconazole, 100-400 mg; oral itraconazole, 200 mg or2.5-5 mg/kg; and liposomal amphotericin B, 1 mg/kg.In 1 study, liposomal amphotericin B was followed byoral itraconazole and compared to intravenous flucon-

Figure 4. Pooled RR estimates and their 95% CI for the out-comes total fungal infections (superficial and invasive) andneed for empirical antifungal treatment. Studies are identi-fied by first author. Size of squares is proportional to theweighted RR. *Cannot be computed because the presence offrequencies � 0.



azole followed by oral itraconazole, or to placebo. Du-ration of prophylaxis varied from 5 days to 10 weeks. Allthe included studies reported overall mortality, mortal-ity attributable to fungal infections, proven fungal in-fections, and need for discontinuation of treatment;other outcomes, however, were not uniformly reportedin the trials analyzed.

Publication bias and heterogeneity represent signifi-cant threats to the validity of a meta-analysis. In thepresent meta-analysis, evidence of publication biaswith graphical and statistical methods was not detect-able for any of the outcomes analyzed. Moreover, therewas consistency in treatment effects, and no evidence ofheterogeneity was detected. This was also partially con-firmed in sensitivity analysis. For all the outcomes ex-cept for side effects, the exclusion of any single studyyielded only minimal change on the effect size.

Overall, the cumulative data from the available ran-domized studies suggest that among patients undergo-ing orthotopic liver transplantation, prophylaxis has abeneficial effect on morbidity and mortality attributableto fungal infections, but not on overall mortality. Thebeneficial effect of antifungal prophylaxis was predom-inantly associated with the reduction of C. albicansinfection and mortality attributable to C. albicans. Areduction of C. albicans infections can be adequatelyattained with azole prophylaxis; to this end, fluconazoleseems to be a suitable agent. Since the majority ofCandida infections seem to be acquired in the first 2-6weeks after transplantation, duration of prophylaxisshould be limited, as already suggested by Winston etal., to 6 weeks.29,31 On the other hand, there is growingevidence showing an important role of fluconazole in ashift toward non–C. albicans species, and several inves-tigators have noted increases in the frequency of C.glabrata isolation in conjunction with the selectivepressure exerted by azole use.55-59 This trend was alsoevident in the trials included in the analysis: Comparedto controls, patients receiving prophylaxis experienceda higher proportion of episodes of non-albicans Can-dida (56% vs. 33% of total proven infections), namely ofC. glabrata infections (26% vs. 14%).

In contrast to Candida infections, invasive aspergil-losis has a relatively low incidence and is more commonin the late posttransplantation period.1,9,19,22 Actually,

55% of these infections now occur after the first 3months following transplantation, making the imple-mentation of an effective, safe, and cost-effective pro-phylaxis problematic.9 Therefore, a pre-emptive ap-proach in high-risk patients (e.g., those with acute liverfailure) or an empirical treatment for suspected infec-tions with agents that have anti-Aspergillus activityseems more rational.1

The absence of evidence of either heterogeneityamong the studies or of any publication bias suggeststhat the conclusions we have drawn are reasonablygeneralizable and robust.

In conclusion, our analysis suggests that prophylaxisof fungal infections among liver transplant recipientshas beneficial effect on morbidity and mortality attrib-utable to C. albicans. However, the selection of triazole-resistant Candida strains is of concern and needs to becarefully addressed in future trials. These studiesshould include epidemiological data on the develop-ment of resistance over time.

REFERENCES

1. Paya CV. Prevention of fungal and hepatitis virus infec-tions in liver transplantation. Clin Infect Dis 2001;33(Suppl 1):S47-52.

2. Singh N. Antifungal prophylaxis for solid organ transplantrecipients: seeking clarity amidst controversy. Clin InfectDis 2000;31:545-553.

3. Singh N. Antifungal prophylaxis in solid-organ transplantrecipients: considerations for clinical trial design. Clin In-fect Dis 2004;39(Suppl 4):S200-206.

4. Kusne S, Torre-Cisneros J, Manez R, Irish W, Martin M,Fung J, et al. Factors associated with invasive lung as-pergillosis and the significance of positive Aspergillus cul-ture after liver transplantation. J Infect Dis 1992;166:1379-1383.

5. Paterson DL, Singh N. Invasive aspergillosis in transplantrecipients. Medicine (Baltimore) 1999;78:123-138.

6. Paya CV. Fungal infections in solid-organ transplantation.Clin Infect Dis 1993;16:677-688.

7. Alexander BD. Prophylaxis of invasive mycoses in solidorgan transplantation. Curr Opin Infect Dis 2002;15:583-589.

8. Fortun J, Martin-Davila P, Moreno S, De Vicente E, NunoJ, Candelas A, et al. Risk factors for invasive aspergillosisin liver transplant recipients. Liver Transpl 2002;8:1065-1070.

TABLE 3. Isolates From 687 Liver Transplant Patients (370 treated, 317 controls) With Defined Fungal Infections

Species (% of total isolates)

From Patients With Proven Infections

(invasive & superficial)

From Patients Who Died From Fungal

Infections

Overall Treatment Control Overall Treatment Control

C. albicans 64 (55) 11 (36) 53 (61) 12 (52) 1 (16) 11 (64)C. glabrata 20 (17) 8 (26) 12 (14) 3 (13) 1 (16) 2 (11)Other Candida species* 25 (21) 9 (30) 16 (18) 1 (4) 1 (16) -Aspergillus spp. 6 (5) 2 (6) 4 (4) 6 (26) 3 (50) 3 (17)Other 1 (0.8) - 1 (1) 1 (4) - 1 (5)Total (100%) 116 30 86 23 6 17

*Including C. krusei, C. pelliculosa, C. tropicalis, C. parapsilosis, and C. pseudotropicalis.

856 CRUCIANI ET AL.


9. Singh N, Avery RK, Munoz P, Pruett TL, Alexander B,Jacobs R, et al. Trends in risk profiles for and mortalityassociated with invasive aspergillosis among liver trans-plant recipients. Clin Infect Dis 2003;36:46-52.

10. Singh N, Wagener MM, Marino IR, Gayowski T. Trends ininvasive fungal infections in liver transplant recipients:correlation with evolution in transplantation practices.Transplantation 2002;73:63-67.

11. Fisher NC, Singhal S, Miller SJ, Hastings JG, Mutimer DJ.Fungal infection and liposomal amphotericin B (AmBi-some) therapy in liver transplantation: a 2 year review. JAntimicrob Chemother 1999;43:597-600.

12. Singh N, Arnow PM, Bonham A, Dominguez E, PatersonDL, Pankey GA, et al. Invasive aspergillosis in liver trans-plant recipients in the 1990s. Transplantation 1997;64:716-720.

13. Selby R, Ramirez CB, Singh R, Kleopoulos I, Kusne S,Starzl TE, et al. Brain abscess in solid organ transplantrecipients receiving cyclosporine-based immunosuppres-sion. Arch Surg 1997;132:304-310.

14. Briegel J, Forst H, Spill B, Haas A, Grabein B, Haller M, etal. Risk factors for systemic fungal infections in livertransplant recipients. Eur J Clin Microbiol Infect Dis1995;14:375-382.

15. Bonham CA, Dominguez EA, Fukui MB, Paterson DL,Pankey GA, Wagener MM, et al. Central nervous systemlesions in liver transplant recipients: prospective assess-ment of indications for biopsy and implications for man-agement. Transplantation 1998;66:1596-1604.

16. Husain S, Tollemar J, Dominguez EA, Baumgarten K,Humar A, Paterson DL, et al. Changes in the spectrumand risk factors for invasive candidiasis in liver transplantrecipients: prospective, multicenter, case-controlledstudy. Transplantation 2003;75:2023-2029.

17. Tollemar J, Ericzon BG, Barkholt L, Andersson J, RingdenO, Groth CG. Risk factors for deep candida infections inliver transplant recipients. Transplant Proc 1990;22:1826-1827.

18. Nieto-Rodriguez JA, Kusne S, Manez R, Irish W, Linden P,Magnone M, et al. Factors associated with the develop-ment of candidemia and candidemia-related death amongliver transplant recipients. Ann Surg 1996;223:70-76.

19. Linden PK, Coley K, Fontes P, Fung JJ, Kusne S. Invasiveaspergillosis in liver transplant recipients: outcome com-parison of therapy with amphotericin B lipid complex anda historical cohort treated with conventional amphotericinB. Clin Infect Dis 2003;37:17-25.

20. Kusne S, Dummer JS, Singh N, Iwatsuki S, Makowka L,Esquivel C, et al. Infections after liver transplantation. Ananalysis of 101 consecutive cases. Medicine (Baltimore)1988;67:132-143.

21. Singh N, Arnow PM, Bonham A, Dominguez E, PatersonDL, Pankey GA, et al. Invasive aspergillosis in liver trans-plant recipients in the 1990s. Transplantation 1997;64:716-720.

22. Patel R, Portela D, Badley AD, Harmsen WS, Larson-KellerJJ, Ilstrup DM, et al. Risk factors of invasive Candida andnon-Candida fungal infections after liver transplantation.Transplantation 1996;62:926-934.

23. Collins LA, Samore MH, Roberts MS, Luzzati R, JenkinsRL, Lewis WD, et al. Risk factors for invasive fungal infec-tions complicating orthotopic liver transplantation. J In-fect Dis 1994;170:644-652.

24. Singh N, Gayowski T, Wagener MM, Doyle H, Marino IR.Invasive fungal infections in liver transplant recipientsreceiving tacrolimus as the primary immunosuppressiveagent. Clin Infect Dis 1997;24:179-184.

25. Wald A, Leisenring W, van Burik JA, Bowden RA. Epide-miology of Aspergillus infections in a large cohort of pa-

tients undergoing bone marrow transplantation. J InfectDis 1997;175:1459-1466.

26. Tollemar J, Hockerstedt K, Ericzon BG, Jalanko H, RingdenO. Liposomal amphotericin B prevents invasive fungal infec-tions in liver transplant recipients. A randomized, placebo-controlled study. Transplantation 1995;59:45-50.

27. Lumbreras C, Cuervas-Mons V, Jara P, del Palacio A,Turrion VS, Barrios C, et al. Randomized trial of flucon-azole versus nystatin for the prophylaxis of Candida infec-tion following liver transplantation. J Infect Dis 1996;174:583-588.

28. Meyers B, Papanicolau G, Chodoff L, Sheiner P, Miller C,Mendelson M, et al. A double blind prospective controlledstudy of fluconazole vs placebo in the prevention of fungalinfections in patients undergoing orthotopic liver trans-plantation. Abstract presented at: 37th Interscience Con-ference on Antimicrobial Agents and Chemotherapy, To-ronto, Canada, September 28 - October 1, 1997. AbstractJ-97.

29. Winston DJ, Pakrasi A, Busuttil RW. Prophylactic flucon-azole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1999;131:729-737.

30. Biancofiore G, Bindi ML, Baldassarri R, Romanelli AM,Catalano G, Filipponi F, et al. Antifungal prophylaxis inliver transplant recipients: a randomized placebo-con-trolled study. Transpl Int 2002;15:341-347.

31. Sharpe MD, Ghent C, Grant D, Horbay GL, McDougal J,David Colby W. Efficacy and safety of itraconazole prophy-laxis for fungal infections after orthotopic liver transplan-tation: a prospective, randomized, double-blind study.Transplantation 2003;76:977-983.

32. Ruskin JD, Wood RP, Bailey MR, Whitmore CK, Shaw BW.Comparative trial of oral clotrimazole and nystatin fororopharyngeal candidiasis prophylaxis in orthotopic livertransplant patients. Oral Surg Oral Med Oral Pathol 1992;74:567-571.

33. Winston DJ, Busuttil RW. Randomized controlled trial oforal itraconazole solution versus intravenous/oral flucon-azole for prevention of fungal infections in liver transplantrecipients. Transplantation 2002;74:688-695.

34. Tortorano AM, Viviani MA, Pagano A, Paone G, Gridelli B,Breda G, et al. Candida colonization in orthotopic livertransplantation: fluconazole versus oral Amphotericin B.Journal de Mycologie Medicale 1995;5:21-24.

35. Biancofiore G, Baldassarri R, Bindi ML, Mosca C, Filip-poni F, Mosca F, et al. Prevention of mycotic infections inliver transplant recipients: comparison of two chemopro-phylactic protocols. Minerva Anestesiol 2001;67:475-482.

36. Sharpe MD, Colby WD, Ghent CN, Grant DR, Hunte I,McDougal J, et al. Safety of itraconazole prophylaxis forsystemic fungal infections in liver transplant recipients.presented at: 39th Interscience Conference on Antimicro-bial Agents and Chemotherapy, San Francisco, CA Sep-tember 26-29, 1999.

37. Colby WD, Sharpe MD, Ghent C, Grant DR, Hunte L,McDougal J, et al. Efficacy of itraconazole prophylaxisagainst systemic fungal infections in liver transplant re-cipients. presented at: 39th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco,CA, September 26-29, 1999. Abstract 650.

38. Tollemar J, Hockerstedt K, Ericzon BG, Jalanko H, Ring-den O. Prophylaxis with liposomal amphotericin B (AmBi-some) prevents fungal infections in liver transplant recip-ients: long-term results of a randomized, placebo-controlled trial. Transplant Proc 1995;27:1195-1198.

39. Tollemar J, Hockerstedt K, Ericzon BG, Sundberg B, Ring-den O. Fungal prophylaxis with AmBisome in liver andbone marrow transplant recipients: results of two ran-domized double-blind studies. Transplant Proc 1994;26:1833.



40. Viviani MA, Tortorano AM, Malaspina C, Colledan M, Pa-one G, Rossi G, et al. Surveillance and treatment of livertransplant recipients for candidiasis and aspergillosis.Eur J Epidemiol 1992;8:433-436.

41. Rossi SJ, Ferguson M, Gortesky S, Gelhoi A, Schroeder T,Hano D. A randomized prospective trial of fluconazoleversus nystatin/clotrimazole for fungal prophylaxis inliver transplant recipients. presented at: 14th AnnualMeeting of the American Society of Transplant Physicians,Chicago, IL, May 14-17, 1995.

42. Playford EG, Webster AC, Sorell TC, Craig JC. Antifungalagents for preventing fungal infections in solid organtransplant recipients. Cochrane Database Syst Rev 2004;(3):CD004291.

43. Jadad AR, Moore RA, Carroll D, Jenkinson C, ReynoldsDJ, Gavaghan DJ, et al. Assessing the quality of reports ofrandomized clinical trials: is blinding necessary? ControlClin Trials 1996;17:1-12.

44. Mantel N, Haenszel W. Statistical aspects of the analysis ofdata from retrospective studies of disease. J Natl CancerInst 1959;22:719-748.

45. DerSimonian R, Laird N. Meta-analysis in clinical trials.Control Clin Trials 1986;7:177-188.

46. Woolf B. On estimating the relation between blood groupand disease. Ann Human Genet 1955;19:251-253.

47. Greenland S and Robins JM. Estimation of a commoneffect parameter from sparse follow-up data. Biometrics1985;41:55-68.

48. Deeks JJ, Altman DG, Bradburn MJ. Statistical methodsfor examining heterogeneity and combining results fromseveral studies in meta-analysis. In: Egger M, DaveySmith G, Altman DG, eds. Systematic Reviews in HealthCare: Meta-analysis in Context. 2nd ed. Blackwell Pub-lishing/BMJ Books: London. 2001:285-312.

49. Laupacis A, Sackett DL, Roberts RS. An assessment ofclinically useful measures of the consequences of treat-ment. N Engl J Med 1988;318:1728-1733.

50. Cook RJ, Sackett DL. The number needed to treat: a clin-ically useful measure of treatment effect. BMJ 1995;310:452-454.

51. Egger M, Davey Smith G, Schneider M, Minder C. Bias inmeta-analysis detected by a simple, graphical test. BMJ1997;315:629-634.

52. Begg CB, Mazumdar M. Operating characteristics of arank correlation test for publication bias. Biometrics1994;50:1088-1011.

53. Cochran WG. The combination of estimates from differentexperiments. Biometrics 1954;10:101-129.

54. Higgins J, Thompson S, Deeks J, Altman D. Measuringinconsistency in meta-analyses. BMJ 2003;327:557-560.

55. Berrouane YF, Herwaldt LA, Pfaller MA. Trends in antifun-gal use and epidemiology of nosocomial yeast infections ina university hospital. J Clin Microbiol 1999;37:531-537.

56. Gleason TG, May AK, Caparelli D, Farr BM, Sawyer RG.Emerging evidence of selection of fluconazole-tolerantfungi in surgical intensive care units. Arch Surg 1997;132:1197-1201.

57. Rocco TR, Reinert SE, Simms HH. Effects of fluconazoleadministration in critically ill patients: analysis of bacte-rial and fungal resistance. Arch Surg 2000;135:160-165.

58. Nguyen MH, Peacock JE Jr, Morris AJ, Tanner DC,Nguyen ML, Snydman DR, et al. Changing face of candi-demia: emergence of non-Candida albicans species andantifungal resistance. Am J Med 1996;100:617-623.

59. Wingard JR. Importance of Candida species other than C.albicans as pathogens in oncology patients. Clin Infect Dis1995;20:115-125.

858 CRUCIANI ET AL.


Documents

Antifungal prophylaxis in liver transplant patients: A systematic review and meta-analysis