Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial

• Published in: The Lancet (British edition) Vol. 363; no. 9423; pp. 1764 - 1767
• Main Authors: Brouwer, Annemarie E, Rajanuwong, Adul, Chierakul, Wirongrong, Griffin, George E, Larsen, Robert A, White, Nicholas J, Harrison, Thomas S
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 29.05.2004; Lancet; Elsevier Limited
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; AIDS-Related Opportunistic Infections - cerebrospinal fluid; AIDS-Related Opportunistic Infections - diagnosis; AIDS-Related Opportunistic Infections - drug therapy; AIDS-Related Opportunistic Infections - microbiology; Amphotericin B; Amphotericin B - administration & dosage; Antifungal Agents - administration & dosage; Antigens, Fungal - cerebrospinal fluid; Biological and medical sciences; Cerebrospinal fluid; Cerebrospinal Fluid - cytology; Cerebrospinal Fluid - microbiology; Cerebrospinal Fluid Pressure; Clinical outcomes; Colony Count, Microbial; Cryptococcosis; Cryptococcus neoformans - isolation & purification; Drug therapy; Drug Therapy, Combination; Evidence-based medicine; Female; Fluconazole; Fluconazole - administration & dosage; Flucytosine; Flucytosine - administration & dosage; Fungi; Fungicidal activity; Fungicides; General aspects; HIV; Human immunodeficiency virus; Human mycoses; Human viral diseases; Humans; Infectious diseases; Laboratories; Male; Medical sciences; Medical treatment; Meningitis; Meningitis, Cryptococcal - cerebrospinal fluid; Meningitis, Cryptococcal - diagnosis; Meningitis, Cryptococcal - drug therapy; Meningitis, Cryptococcal - microbiology; Miscellaneous mycoses; Mortality; Multivariate analysis; Mycoses; Patients; Public health; Randomization; Research ethics; Therapy; Tuberculosis; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; New York; United Kingdom > UK; Thailand; United States > US; Human; Immunopathology; Nervous system diseases; Drug combination; Mycosis; Indication; Cryptococcosis; Retroviridae; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Medicine; Antifungal agent; Viral disease; Central nervous system disease; Clinical trial; Meningitis; Combined treatment; Human immunodeficiency virus
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(04)16301-0

It frequently takes more than 2 weeks for drug treatments for cryptococcal meningitis to sterilise cerebrospinal fluid (CSF). In-vitro and animal studies lend support to the use of combinations of amphotericin B, flucytosine, and fluconazole for treatment of cryptococcosis. We compared the fungicidal activity of combinations of these drugs for initial treatment of patients with cryptococcal meningitis. 64 patients with a first episode of HIV-associated cryptococcal meningitis were randomised to initial treatment with: amphotericin B (0·7 mg/kg daily); amphotericin B plus flucytosine (100 mg/kg daily); amphotericin B plus fluconazole (400 mg daily); or triple therapy with amphotericin B, flucytosine, and fluconazole. Our primary endpoint was fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment. Baseline CSF CFU counts were an important prognostic factor. Clearance of cryptococci from the CSF was exponential and was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone (p=0·0006), amphotericin B plus fluconazole (pp=0·02), or triple therapy (p=0·02). At these doses, amphotericin B plus flucytosine is the most rapidly fungicidal regimen. Quantification of CSF cultures provides a powerful new means to accurately assess the fungicidal activity of new treatment regimens for cryptococcal meningitis.