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Oral versus intravenous flucytosine in patients with HIV-associated cryptococcal meningitis.

Author(s): Brouwer AE, van Kan HJ, Johnson E, Rajanuwong A, Teparrukkul P, Wuthiekanun V, Chierakul W, Day N, Harrison TS

Affiliation(s): Centre for Infection, St. George's University of London, UK; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Internal Medicine and Nijmegen University Centre for Infectious Diseases, University Medical Centre Nijmegen, the Netherlands; Department of Clinical Pharmacy, Academic Medical Centre, Amsterdam, the Netherlands; Mycology Reference Laboratory, Health Protection Agency South-West Regional Laboratory, Bristol, UK; Department of Medicine, Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, U.K.

Publication date & source: 2006-12-28, Antimicrob Agents Chemother., [Epub ahead of print]

In a randomized controlled trial of amphotericin B based therapy for HIV-associated cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous flucytosine at 100 mg/kg/d for the initial 2 weeks. Half of 32 patients assigned to the 2 arms containing flucytosine were randomized to oral and half to intravenous flucytosine. Early fungicidal activity was determined from serial quantitative cultures of 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-hour 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 5FC. The results suggest either formulation can be used safely at this dosage in a developing country setting, without drug concentration monitoring. Bioavailability of oral formulation may be reduced in late stage HIV-infected patients in Thailand. Concentrations of flucytosine with intravenous formulation at 100 mg/kg/d may be in excess of those required for maximal fungicidal activity.

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