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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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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