Combination antifungal therapy for cryptococcal meningitis

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.).

Figure 1. Study Enrollment, Treatment Assignments, and Analysis Populations

Of 375 patients who underwent assessment, 299 were enrolled in the study. One patient, who underwent randomization but did not have cryptococcal meningitis, did not receive the assigned treatment and was excluded from the intention-to-treat analysis.

Figure 2. Kaplan–Meier Survival Estimates and Cerebrospinal Fluid (CSF) Fungal Counts, According to Treatment Group

Panel A shows the Kaplan–Meier survival estimates according to treatment group. For mortality at 70 days, P = 0.04 for the comparison of amphotericin B plus flucytosine with amphotericin B monotherapy, and P = 0.13 for the comparison of amphotericin B plus fluconazole with amphotericin B monotherapy. Panel B shows the CSF quantitative fungal counts over time, according to treatment group. Study day 1 corresponds to the day of randomization. All recorded CSF quantitative counts are shown, including those in patients who subsequently died. CSF fungal decline in the first 14 days and time to clearance were significantly faster among patients receiving amphotericin B plus flucytosine than among patients in the other treatment groups (P<0.001 for all comparisons). In each graph, gray lines indicate data for individual patients; the red line indicates a loess scatterplot smoother calculated with the use of local regression. CFU denotes colony-forming units.