A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis

Jackson, Arthur T.; Nussbaum, Jesse C.; Phulusa, Jacob; Namarika, Dan; Chikasema, Maria; Kanyemba, Creto; Jarvis, Joseph N.; Jaffar, Shabbar; Hosseinipour, Mina C.; van der Horst, Charles; Harrison, Thomas S.

doi:10.1097/qad.0b013e328354b419

Cited by 86Fungal Infections and StudiesAntifungal resistance and susceptibilityBacterial Infections and Vaccines

A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis

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Jackson, Arthur T., Nussbaum, Jesse C., Phulusa, Jacob, Namarika, Dan, Chikasema, Maria, Kanyemba, Creto, Jarvis, Joseph N., Jaffar, Shabbar +3 more·2012·AIDS

DOI 10.1097/qad.0b013e328354b419PMC PMC3776948

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Abstract

BACKGROUND: Cryptococcal meningitis in Africa is associated with up to 70% mortality at 3 months and 500 000 deaths annually. We examined strategies to improve on fluconazole (FLU) monotherapy: addition of flucytosine (5-FC) and/or addition of short-course amphotericin B (AmB). METHODS: In step 1, previously reported, patients were randomized to receive FLU 1200 mg per day with or without 5-FC 100 mg/kg per day for 14 days. In step 2, 43 patients were similarly randomized, with addition of AmB 1 mg/kg per day for 7 days to both arms. After 2 weeks, patients received FLU monotherapy and were followed to 10 weeks. The primary endpoint was rate of clearance of infection (early fungicidal activity, EFA). Secondary endpoints related to safety and mortality. RESULTS: Forty patients (25% with Glasgow Coma Scale <15) were analyzed. EFA for the triple combination arm was greater than that for AmB-FLU: -0.50 ± 0.15 log CFU/day vs. -0.38 ± 0.19 log colony forming units per day (P=0.03); and greater than that for step 1 with FLU-5-FC (-0.28 ± 0.17) or FLU alone (-0.11 ± 0.09). Combined analysis across steps revealed that addition of 5-FC and AmB had significant, independent additive effects on EFA, with trends toward fewer early deaths with addition of 5-FC (4/41 vs. 11/39, P = 0.05) and fewer deaths overall with addition of AmB (13/39 vs. 20/40, P = 0.1). CONCLUSION: Addition of 5-FC and short-course AmB to high-dose FLU significantly enhanced EFA and may be associated with favorable trends in survival. Both these strategies should be tested in a larger phase III study.

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Expanding scope to all failed antifungal treatments, such as adding 5-FC or amphotericin B to fluconazole monotherapy, alleviates mortality rate and achieves up to 90% efficacy.
“Expanding the scope to all failed antifungal treatments, such as adding 5-FC or amphotericin B to fluconazole monotherapy, alleviates mortality rate and achieves up to 90% efficacy [177,178,179].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [178]
The Early fungicidal activity section reports that adding 5-FC or short-course amphotericin B to high-dose fluconazole significantly increased fungal clearance in cryptococcal meningitis. The Mortality section reports fewer deaths in some combination groups but says the study was not powered to establish a survival difference and found no statistically significant survival differences at 2 or 10 weeks. The paper does not report 90% treatment efficacy; its reference to greater than 90% concerns statistical power. (LLM, conf=0.88)
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[21]Jarvis J Meintjes G Rebe K Williams N Bicanic T Williams A Adjunctive IFN-gamma Immunotherapy for the Treatment of HIV-Associated Cryptococcal Meningitis: A Randomized Controlled Trial Conference on Retroviruses and Opportunistic Infections Boston, USA February, 2011 2011

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Combination Flucytosine and High‐Dose Fluconazole Compared with Fluconazole Monotherapy for the Treatment of Cryptococcal Meningitis: A Randomized Trial in Malawi
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Authors: Jackson, A. T., Nussbaum, J. C., Phulusa, J., Namarika, D., Chikasema, M., Kanyemba, C., Jarvis, J. N., Jaffar, S., Hosseinipour, M. C., van der Horst, C., & Harrison, T. S.
Affiliations: University of California, San Francisco (US)
Kamuzu Central Hospital (MW)
University of Cape Town (ZA)
London School of Hygiene & Tropical Medicine (GB)
University of North Carolina at Chapel Hill (US)
St George's, University of London (GB)
Corresponding author: Jackson, Arthur T.
ORCID: Jackson, Arthur T.
Nussbaum, Jesse C.
Phulusa, Jacob
Jarvis, Joseph N.
Jaffar, Shabbar
Hosseinipour, Mina C.
Harrison, Thomas S.
Venue: AIDS
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2012-07-17
Volume: 26
Issue: 11
Pages: 1363-1370
ISSN: 0269-9370 (ISSN-L)
DOI: 10.1097/qad.0b013e328354b419
PMC: PMC3776948
OpenAlex: W2015004946
Cited by: 86
References: 20
Citations by year: 2026: 7 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 7 · 2017: 6 · 2016: 12 · 2015: 6 · 2014: 8 · 2013: 7 · 2012: 3
FWCI: 5.73
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: AIDS (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Wellcome Trust (081794)
National Institute of Allergy and Infectious Diseases (P30 AI50410, P30AI050410)
Fogarty International Center (D43TW001039, FIC 2-D43 TW01039-06)
Topics: Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords: cryptococcal meningitis, 5-fluorocytosine, fluconazole, amphotericin B, combination antifungal therapy, mortality, HIV-associated cryptococcosis
MeSH terms: Acquired Immunodeficiency Syndrome, Administration, Oral, Adult, Aged, Amphotericin B, Antifungal Agents, Drug Therapy, Combination, Female, Flucytosine, Humans, Malawi, Male, Middle Aged, Fluconazole, Treatment Outcome, Meningitis, Cryptococcal, AIDS-Related Opportunistic Infections, Young Adult

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A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis

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