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ORIGINAL RESEARCH
A Meta-analysis of Fluconazole versus
Amphotericin B for Treatment of Invasive
Candida Infections
Danielle M. Zerr, MD, MPH, Michelle M. Garrison, MPH, Kieren A. Marr, MD, and Dimitri A. Christakis, MD, MPH
• Objective: To compare the efficacy of amphotericin B and fluconazole in the eradication of invasive Candida Over the past 20 years, the number of invasive infec- tions caused by Candida species has increased in fre- quency due to advances in the care and prolonged survival of patients with malignancy and end-stage organ dis- • Data sources: Published and unpublished randomized recently, amphotericin B was the only effec- controlled trials comparing amphotericin B to flucona- tive therapy for invasive fungal infections. However, a high zole in the treatment of invasive Candida infections incidence of renal toxicity and other side effects associated were identified by searches of MEDLINE, the with this agent have limited its use and led to the develop- Cochrane Clinical Trials Registry, EMBASE, and the ment of the better-tolerated azole antifungal drugs, such as Medical Editors’ Trial Amnesty. The bibliographies of fluconazole. Since the late 1980s, there have been a number of all identified articles and relevant review articles also randomized controlled trials comparing amphotericin B with fluconazole for the treatment of invasive Candida infections.
• Study selection: For inclusion in the meta-analysis, Although these individual studies found no statistically sig- articles had to meet the following criteria: (1) random nificant differences in cure or survival frequencies between the allocation of patients, (2) objective inclusion criteria 2 treatment groups, the studies were relatively small and for documented Candida infections, and (3) subject- therefore may have lacked sufficient power to detect signifi- level data collection regarding mortality, microbiolog- cant differences. Furthermore, other factors such as under- ical failure, clinical success, and adverse events.
lying immunosuppression and catheter exchange practices • Outcome measures: Mortality, microbiological failure, might affect outcome without being apparent in studies with clinical success, and adverse event rates.
small sample size and heterogeneous patient populations. We • Results: 4 trials with 457 subjects were selected for conducted this meta-analysis to derive a more precise com- inclusion in the final analysis. There were no statistical- ly significant differences between the 2 therapies. Therelative risk (RR) of death was 0.99 (95% confidence interval [CI], 0.75 to 1.29) when fluconazole subjects Study Selection
were compared with amphotericin B subjects. In the Literature searches of the following computerized biblio- fluconazole-treated group, there was a trend toward graphic databases were conducted: MEDLINE database microbiological failure (RR = 1.34 [95% CI, 0.77 to (January 1966 to July 1999), the Cochrane Clinical Trials 2.34]) and clinical failure (RR = 1.18 [95% CI, 0.90 to Registry (CCTR, up to July 1999), and EMBASE (January 1.52]). In the fluconazole-treated groups, there were 1990 to July 1999). Searches for unpublished trials were lim- also trends toward clinical failure among immunocom- ited to the Medical Editors’ Trial Amnesty. The search terms petent patients (RR = 1.31 [95% CI, 0.96 to 1.67]) and “fluconazole” and “amphotericin” were used. The searches among those who did not receive flucytosine(RR = 1.19 [95% CI, 0.90 to 1.57]). • Conclusions: While there were no statistically significant differences in death, clinical failure, or microbiological From the Department of Pediatrics, University of Washington, Seattle, WA failure between the 2 agents, the RRs for clinical failure (Drs. Zerr and Christakis); the Child Health Institute, University of Washing-ton (Ms. Garrison and Dr. Christakis); the Department of Medicine, Univer- and microbiological failure favored amphotericin B for sity of Washington (Dr. Marr); and the Fred Hutchinson Cancer Research the treatment of invasive Candida infections. Vol. 9, No. 4 April 2002 JCOM 191
FLUCONAZOLE AND AMPHOTERICIN
Table 1. Characteristics of Trials Included in Meta-analysis
No. of Patients
Study Criteria
Fluconazole
Amphotericin B
Inclusion
Exclusion
Outcomes Measured
103 103 CAN NEU, LIVER, PRE, HIV MORT, MIC, CLIN, CR, LE, K036 036 CAN NEU, LIVER MORT, MIC, CLIN, CR, LE, K 037 037 CAN, PRES LIVER, PRE, RENAL, HIV MORT, CLIN, CR, LE, K 050 053 CAN NEU, LIVER, PRE, CATH MORT, MIC, CLIN, CR, K CAN = documented invasive candidal infection; CATH = removal of vascular catheter not expected to occur within 72 hours of enrollment; CLIN = clin-ical failure; CR = creatinine levels; HIV = AIDS or HIV+; K = hypokalemia; LE = liver enzymes; LIVER = decreased liver function; MIC = microbiologi-cal failure; MORT = mortality; NEU = neutropenic; PRE = previous unsuccessful therapy; PRES = presumed candidiasis; RENAL = renal failure.
*Patients with presumed Candida infections, wound infection, and lower urinary tract infections were excluded from the meta-analysis.
Table 2. Characteristics of Enrolled Patients by Study
Mean or Median Age, yr
Mean APACHE II Score
Malignancy, %*
C. albicans Infection, %†
58 60 16 16 32 31 68 61 58 60 20 20 14 11 72 64‡ 62 58 56 63 58 4665 58 15 13 20 22 80 62 AMB = amphotericin B; FLUC = fluconazole.
*The remainder had underlying disorders, including gastrointestinal disease, cardiovascular disease, respiratory disease, pancreatitis, trauma, dia-betes, pulmonary disease, and renal failure.
†The remainder had non-albicans Candida species or Candida species that were not determined.
‡Results for Age and Malignancy refer to the total study population, not the portion with confirmed infection.
of MEDLINE and EMBASE were also limited to articles sis. All studies included in this meta-analysis met these criteria identified as randomized controlled trials; however, no lan- for at least 2 of the outcomes measured. Data were then in- guage restrictions were imposed on the searches. In addi- dependently abstracted by 3 authors (DC, MG, and DZ) using tion, the bibliographies of all identified articles and relevant a standardized reporting form, and any disagreements were review articles were examined. Study titles and abstracts again resolved by consensus. Attempts to contact authors for were evaluated, and prospective trials comparing flucona- unpublished data as needed were unsuccessful. zole to amphotericin B in patients with invasive Candidainfections were selected for further review. Outcome Measures
These selected articles were independently reviewed by Mortality, microbiological failure, clinical success, and 2 authors (DC and DZ). At this stage, the investigators were adverse effect rates were chosen as a priori outcome mea- blinded to the journal and author names to avoid bias. To be sures. When trials measured mortality at multiple time- included in the meta-analysis, articles had to meet the fol- points, the measure closest to 4 weeks after initiation of ther- lowing criteria: (1) random allocation of patients to flucona- apy was selected for the analysis. Microbiological failure was zole and amphotericin B, (2) objective inclusion criteria for measured as the proportion of patients in each group who documented Candida infections, including pure Candida had positive objective tests (blood culture or biopsy) for sys- growth from a culture of a normally sterile site and/or temic fungal infection after treatment. Clinical failure data histopathology indicative of Candida infection, and (3) collec- were abstracted as reported in the individual articles. Ad- tion of data at the subject level regarding mortality, microbio- verse effect rates were abstracted from the studies for elevat- logical failure, clinical success, and/or adverse effects of ther- ed creatinine, elevated liver enzymes, and hypokalemia. apy. Disagreements were resolved through discussion, and The primary analysis included all trials with available out- consensus was achieved in the selection of articles for analy- come data that passed the quality review. Two subanalyses 192 JCOM April 2002 Vol. 9, No. 4
ORIGINAL RESEARCH
Table 3. Antifungal Dosing and Duration
Fluconazole
Amphotericin B
Duration
400 mg/day IV x 7 days then PO* 0.5–0.6 mg/kg/day† ≥ 14 days after resolution of symptoms or last positive culture, which ever waslonger 400 mg/day 1, then 200 mg/day 1–1.5 mg/kg every other day‡ 14 days 400 mg/day IV x 5 days then PO 25–50 mg/day§ FLUC: not specified 800 mg/day 1, then 400 mg/day 0.6 mg/kg/day FLUC: 4–8 weeks AMB = amphotericin B; FLUC = fluconazole; IV = intravenously; PO = orally.
*If patient’s weight is > 90 kg or < 50 kg, dosed at multiples of 50 closest to but not > 6 mg/kg.
†0.5–0.6 mg/kg/day x 7 days, then dosing could be adjusted to approximately 3 times per week as long as the average daily dose was0.5–0.6 mg/kg. ‡5-flucytosine was used in addition to amphotericin.
§Neutropenic patients: 0.67 mg/kg/day.  Neutropenic patients: total dose ≥ 750 mg.
Table 4. Criteria for Clinical Failure
Criteria
Unresponsive or progressive infection after 5 or more days of therapy; drug toxicity requiring change of therapy; Absence of complete clinical resolution of infection No change or worsening of laboratory and clinical signs of infection; relapse of infection; drug toxicity requiring Death within first week of treatment; evidence of progressive candidal infection; withdrawal from study due to drug toxicity, fungal superinfections, or inadequate clinical response were also performed; 1 involving studies that did not use 5-flucytosine in the amphotericin B group, and 1 involving Search Results
studies that restricted trial entry to, or provided stratified data The literature search returned 42 articles from the MEDLINE database, 53 articles from EMBASE, and 61 articles fromCCTR. No additional articles were detected from the search- Statistical Methods
es of the Medical Editors’ Trial Amnesty or from review of Because all of the study outcomes were dichotomous mea- the bibliographies of the included and relevant review arti- sures, we calculated Mantel-Haenszel adjusted relative risks cles. Of these articles, 6 were selected for blinded review on comparing patients who received fluconazole with those who the basis that they appeared to meet the initial selection cri- received amphotericin B. Two-tailed P values of less than 0.05 teria of being prospective randomized trials comparing flu- were used as the level of statistical significance, and 95% con- conazole and amphotericin B in the treatment of document- fidence intervals (CIs) were calculated. A chi-square test of ed invasive Candida infections. Two of these articles included homogeneity was also employed for each analysis to deter- other fungal isolates in addition to Candida species; therefore, mine if the data were similar enough to be appropriately pooled into an adjusted relative risk. Studies were reviewed for quality, but no scoring or weighting was applied.
dence of publication bias (P = 1.0) among the 4 trials.
Additionally, the potential for publication bias was investigat-ed with the test of Begg and Mazumdar, using a continuity Characteristics of Individual Trials
corr All statistical analyses were performed using Stata 6.0 (Stata Corporation, College Station, TX).
226 patients to fluconazole and 229 to amphotericin B Vol. 9, No. 4 April 2002 JCOM 193
FLUCONAZOLE AND AMPHOTERICIN
Table 5. Mortality, Microbiological Failure, and Clinical Failure Rates
Mortality, n (%)
Microbiological Failure, n (%)
Clinical Failure, n (%)
34 (33) 41 (40) 15 (15) 12 (12) 31 (30) 22 (21)13 (36) 14 (39) 16 (44) 14 (38) 06 (16) 3 (8) 14 (35) 15 (40)17 (34) 14 (26) 10 (20) 06 (13) 25 (50) 22 (42) AMB = amphotericin B; FLUC = fluconazole.
Table 6. Adjusted Relative Risks for Mortality, Clinical Failure,
5-flucytosine inaddition to amphotericin B. Analysis/Subanalyses
Studies*
All 4 trials measured mortality and clinical failure (Table 1), while 3 measured microbiological failur trial measured microbiological failure by Candida species analysis for this outcome. The criteria for clinical failure were sured adverse events were elevated creatinine levels, Analysis of Pooled Data
Case fatality ranged from 16% to 36% in the fluconazole groups and from 8% to 40% in the amphotericin B groups
(Table 5). The Mantel-Haenszel adjusted relative risk for
CI = confidence interval; RR = relative risk.
mortality was 0.99 (95% CI, 0.75 to 1.29) (Table 6 and
secondary subanalyses of mortality showed †P value = 0.09; all other P values were > 0.10.
similar results, neither of which reached statistical signifi- cance (Table 6). The frequency of microbiological failure was15% and 20% in the fluconazole groups and 12% and 13% inthe amphotericin groups. The adjusted relative risk was 1.34 (95% CI, 0.77 to 2.34), but this was not statistically significant.
itive blood culture; 3 of the studies additionally required Clinical failure ranged from 30% to 50% in the fluconazole signs of systemic illness, such as fever and low blood pres- groups and from 21% to 42% in the amphotericin groups.
The adjusted relative risk for clinical failure was 1.18 (95% with organ system infections, as defined by a pure Candida CI, 0.90 to 1.52) (Table 6 andAgain, the 2 sub- culture of a normally sterile site accompanied by systemic signs of infection and/or inflammation at the site of the There was wide variation in the adverse event rates report- with histologic evidence of blastomycetes in a tissue sam- between groups were detected in the prevalence of elevated Another study included patients with presumed liver enzymes or hypokalemia. While considerably more Candida results excluding these patients patients who received amphotericin had elevated creatinine for the outcomes mortality and clinical failure were report- levels, the data were too heterogenous to make a pooled ed and these results were included in the meta-analysis.
analysis appropriate (Table 7). Testing revealed no significant Neutropenic patients were excluded from 3 of the trials heterogeneity for the other comparisons performed. rovided stratified data by white All trials were conducted in primari- Discussion
ly adult populations with underlying medical problems, This meta-analysis attempted to summarize the current state and the majority of yeast isolates were Candida albicans of knowledge with respect to the comparative efficacies of 194 JCOM April 2002 Vol. 9, No. 4
ORIGINAL RESEARCH
Relative risks with 95% confidence intervals Relative risks with 95% confidence intervals Individual and pooled relative risks (with 95% confi- Individual and pooled relative risks (with 95% confi- Elevated Creatinine, n (%)
Elevated Liver Enzymes, n (%)
Hypokalemia, n (%)
2 (2) 38 (37) 14 (14) 10 (10) 2 (2) 10 (10) 0 (0) 11 (31) 09 (25) 07 (19) 2 (6) 05 (14)10 (20) 23 (43) 17 (34) 17 (32) AMB = amphotericin B; FLUC = fluconazole.
*Did not stratify adverse event data by presumed versus documented Candida infections.
fluconazole and amphotericin B in the treatment of invasive The estimated effect size for clinical failure shown in the fungal disease. We found no statistically significant differences present analysis would be clinically meaningful if it were with respect to mortality; however, we did find a statistical statistically significant. Unfortunately, neither the individual trend favoring amphotericin with respect to clinical failure. trials included in this analysis nor this meta-analysis itself Another meta-analysis published recently did not find a was powered to detect a difference of this magnitude. A ran- difference between amphotericin and fluconazole in the domized controlled trial would require 1738 patients, or treatment of Candida A trend in favor of 869 in each arm (α = 0.05, 1-β = 0.80), to detect this difference.
amphotericin B was noted only in non-albicans Candida Similarly, a study would require 1020 patients, or 510 in each infections. These investigators evaluated candidemia only arm (α = 0.05, 1-β = 0.80), to detect the effect size we esti- and used different inclusion criteria, analyzing observation- al trials in addition to randomized, controlled trials. This dif- A large-scale randomized controlled study to determine ferent methodology may explain the modest differences be- whether amphotericin B is more effective than fluconazole in tween their results and the results of our analysis.
the treatment of invasive Candida disease is warranted if Vol. 9, No. 4 April 2002 JCOM 195
FLUCONAZOLE AND AMPHOTERICIN
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ing a meta-analysis such as this; for instance, dosing of the Pittet D, Wenzel RP. Nosocomial bloodstream infections.
antifungal agents would be standardized as would inclusion Secular trends in rates, mortality, and contribution to total criteria and outcomes. The study would ideally include mor- hospital deaths. Arch Intern Med 1995;155:1177–84.
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low-toxicity antifungal agents, it seems unlikely that such a Steichen TJ. Tests for publication bias in meta-analysis. Stata large study comparing amphotericin and fluconazole will take place. However, future studies evaluating the newer Anaissie EJ, Darouiche RO, Abi-Said D, et al. Management of agents against the standard of care will face similar concerns.
invasive candidal infections: results of a prospective, random-ized, multicenter study of fluconazole versus amphotericin B The authors thank Peter Cummings, MD, MPH, for his statistical and review of the literature. Clin Infect Dis 1996;23:964–72.
Abele-Horn M, Kopp A, Sternberg U, et al. A randomized study comparing fluconazole with amphotericin B/5 Corresponding author: Danielle Zerr, MD, MPH, Children’s flucytosine for the treatment of systemic Candida infections Hospital, CH-32, 4800 Sand Point Way NE, Seattle, WA 98105, in intensive care patients. Infection 1996;24:426–32.
Phillips P, Shafran S, Garber G, et al. Multicenter random- ized trial of fluconazole versus amphotericin B for treatment Funding/support: Dr. Zerr is supported by an NIH K-23 Career of candidemia in non-neutropenic patients. Candidan Development Grant. Dr. Christakis is a Robert Wood Johnson Candidemia Study Group. Eur J Clin Microbiol Infect Dis Generalist Faculty Physician Scholar. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial com- Financial disclosures: Dr. Marr has served as a consultant and paring fluconazole with amphotericin B for the treatment of received honoraria from Pfizer, Bristol-Meyers Squibb, Ortho Biotech, candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 1994; Author contributions: conception and design, DMZ, MMG, DAC; analysis and interpretation of data, DMZ, MMG, KAM, DAC; draft- Kontoyiannis DP, Bodey GP, Mantzoros CS. Fluconazole ing of the article, DMZ, MMG, KAM, DAC; critical revision of the vs. amphotericin B for the management of candidemia in article for important intellectual content, DMZ, MMG, KAM, DAC; adults: a meta-analysis. Mycoses 2001;44:125–35.
final approval of the article, DMZ, MMG, KAM, DAC; provision of 11. Abi-Said D, Anaissie E, Uzun O, et al. The epidemiology of study materials or patients, MMG; statistical expertise, MMG, DAC; hematogenous candidiasis caused by different Candida species collection and assembly of data, MMG. [published erratum appears in Clin Infect Dis 1997;25:352].
Clin Infect Dis 1997;24:1122–8.
12. Nguyen MH, Peacock JE Jr, Morris AJ, et al. The chang- References
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