In a randomized controlled trial of
amphotericin B-based
therapy for human immunodeficiency virus (HIV)-associated
cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous
flucytosine at 100 mg/kg of
body weight/day for the initial 2 weeks. Half of 32 patients assigned to the two arms containing
flucytosine were randomized to oral and half to intravenous
flucytosine. Early fungicidal activity was determined from serial quantitative cultures of cerebrospinal fluid (CSF), and toxicity was assessed by clinical and laboratory monitoring.
Flucytosine and
fluorouracil concentrations in plasma and CSF were measured by high-performance liquid chromatography. No significant bone marrow or hepatotoxicity was seen, there was no detectable difference in bone marrow toxicity between patients on intravenous and those on oral formulation, and no patients discontinued treatment. In patients receiving intravenous
flucytosine, the median 24-h area under the concentration-time curve was significantly higher than in the oral group. Despite this difference, there was no difference in early fungicidal activity between patients on intravenous compared with patients on oral
flucytosine. The results suggest that either formulation can be used safely at this dosage in a developing country setting, without
drug concentration monitoring. The bioavailability of the oral formulation may be reduced in late-stage HIV-infected patients in Thailand. Concentrations of
flucytosine with intravenous formulation at 100 mg/kg/day may be in excess of those required for maximal fungicidal activity.