A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects
Abstract
A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.
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In a single randomized clinical trial comparing high-dose fluconazole versus standard fluconazole dosing and amphotericin B in patients with candidemia, there was a trend in favor of the combination for several outcomes, but the 2 groups had significant differences in baseline APACHE II score favoring the combination arm.
“For several outcomes there was a trend in favor of the combination; however, the 2 groups had significant differences in baseline APACHE II score favoring the combination arm.”
From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [105]
C. albicans infections are typically treated with azole inhibitors of ergosterol biosynthesis, often leading to drug resistance.
“Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance.”
From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Rex et al., 2003
Fluconazole combined with amphotericin B had a higher overall treatment success rate and a lower rate of failure to clear the bloodstream than fluconazole monotherapy.
“A study comparing fluconazole monotherapy with fluconazole combined with amphotericin B found a higher overall treatment success rate and a lower rate of failure to clear the bloodstream with the combination regimen [28].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [28]
Patients with the lowest and highest APACHE II scores benefited the least from combination therapy with fluconazole and amphotericin B.
“Patients with the lowest and highest APACHE II scores benefited the least from combination therapy, suggesting that fluconazole monotherapy is adequate for candidemic patients with mild disease, whereas for the sickest patients, failure rates are high regardless of treatment choice [28].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [28]
Fungemia due to C. glabrata has been treated successfully with fluconazole (6 mg/kg per day).
“Although fungemia due to C. glabrata has been treated successfully with fluconazole (6 mg/kg per day) [105, 132]”
From Guidelines for Treatment of Candidiasis (2004) · cites this paper as [132]
Onset of retinal lesions is rare following an otherwise apparently successful course of systemic therapy for candidemia.
“The results of large prospective therapy studies that included careful ophthalmological examinations suggest that onset of retinal lesions is rare following an otherwise apparently successful course of systemic therapy (there were no such cases in 441 successfully treated subjects [17,105,132].”
From Guidelines for Treatment of Candidiasis (2004) · cites this paper as [132]
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- Authors
- Rex, J. H., Pappas, P. G., Karchmer, A. W., Sobel, J., Edwards, J. E., Hadley, S., Brass, C., Vazquez, J. A., Chapman, S. W., Horowitz, H. W., Zervos, M., McKinsey, D., Lee, J., Babinchak, T., Bradsher, R. W., Cleary, J. D., Cohen, D. M., Danziger, L., Goldman, M., Goodman, J., Hilton, E., Hyslop, N. E., Kett, D. H., Lutz, J., Rubin, R. H., Scheld, W. M., Schuster, M., Simmons, B., Stein, D. K., Washburn, R. G., Mautner, L., Chu, T., Panzer, H., Rosenstein, R. B., Booth, J., & the National Institute of Allergy and Infectious Diseases Mycoses Study Group
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- University of Alabama at Birmingham (US)
- Beth Israel Deaconess Medical Center (US)
- Wayne State University (US)
- Harbor–UCLA Medical Center (US)
- Buffalo Medical Group (US)
- University of Mississippi Medical Center (US)
- Westchester Medical Center (US)
- Beaumont Health (US)
- Thomas Jefferson University (US)
- University of Arkansas for Medical Sciences (US)
- University of Illinois Chicago (US)
- Indiana University School of Medicine (US)
- University of Minnesota (US)
- Tulane University (US)
- University of Miami (US)
- Community Medical Centers (US)
- Brigham and Women's Hospital (US)
- University of Virginia (US)
- Hospital of the University of Pennsylvania (US)
- Methodist University Hospital (US)
- Albert Einstein College of Medicine (US)
- Overton Brooks VA Medical Center (US)
- Corresponding author
- Rex, John H.
- ORCID
- Venue
- Clinical Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-05-15
- Volume
- 36
- Issue
- 10
- Pages
- 1221-1228
- ISSN
- 1058-4838 (ISSN-L)
- 1537-6591
- OpenAlex
- W1974953831
- Cited by
- 495
- References
- 18
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 10 · 2023: 2 · 2022: 7 · 2021: 18 · 2020: 11 · 2019: 9 · 2018: 12 · 2017: 10 · 2016: 5 · 2015: 19 · 2014: 19 · 2013: 19 · 2012: 23
- FWCI
- 26.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- Pfizer
- AstraZeneca
- Brigham and Women's Hospital
- Wayne State University
- University of Pennsylvania
- University of Minnesota
- Louisiana State University
- Thomas Jefferson University
- U.S. Public Health Service (N01-AL-65296)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Ophthalmology › Ocular Infections and Treatments
- Keywords
- candidemia, fluconazole, amphotericin B deoxycholate, combination antifungal therapy, non-neutropenic patients, treatment failure, drug antagonism
- MeSH terms
- Adult, Amphotericin B, Antifungal Agents, Candida, Candidiasis, Catheterization, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Neutropenia, Fluconazole, Fungemia, Treatment Outcome
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