Merck

Combination antifungal therapy for cryptococcal meningitis.

The New England journal of medicine (2013-04-05)
Jeremy N Day, Tran T H Chau, Marcel Wolbers, Pham P Mai, Nguyen T Dung, Nguyen H Mai, Nguyen H Phu, Ho D Nghia, Nguyen D Phong, Cao Q Thai, Le H Thai, Ly V Chuong, Dinh X Sinh, Van A Duong, Thu N Hoang, Pham T Diep, James I Campbell, Tran P M Sieu, Stephen G Baker, Nguyen V V Chau, Tran T Hien, David G Lalloo, Jeremy J Farrar
ABSTRACT

Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
5-Fluorocytosine, nucleoside analog
Sigma-Aldrich
Amphotericin B from Streptomyces sp., ~80% (HPLC), powder
Sigma-Aldrich
Amphotericin B from Streptomyces sp., BioReagent, suitable for cell culture, ~80% (HPLC)
Supelco
Amphotericin B trihydrate, VETRANAL®, analytical standard
Amphotericin B for peak identification, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Amphotericin B solution, 250 μg/mL in deionized water, 0.1 μm filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
Amphotericin B solubilized, powder, γ-irradiated, BioXtra, suitable for cell culture