Oral versus Intravenous Flucytosine in Patients with Human Immunodeficiency Virus-Associated Cryptococcal Meningitis

Centre of Infection, St George's University of London, London SW17 ORE, United Kingdom.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 04/2007; 51(3):1038-42. DOI: 10.1128/AAC.01188-06
Source: PubMed


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.

Download full-text


Available from: Thomas Harrison, Feb 01, 2014
  • Source
    • "Data from in vitro, animal model and some clinical studies suggests that flucytosine displays concentration-independent, time-dependent pharmacodynamics.17,27–29 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.
    Full-text · Article · Jun 2013 · Journal of Antimicrobial Chemotherapy
  • Source
    • "In Thailand, the bioavailability of oral 5-FC in patients with cryptococcal meningitis was only around 50%, and the levels of 5-FC were well below those usually associated with toxicity. 5-Fluorouracil was infrequently detected in serum[20]. However, given the probable importance of the gut flora in conversion of 5-FC to 5-fluorouracil, the pharmacokinetics of 5-FC and 5-fluorouaracil may be different across geographically and ethnically diverse populations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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). 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. 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). 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.
    Full-text · Article · Apr 2012 · AIDS (London, England)
  • Source
    • "This protocol is based upon the use of outbred mice weighing 20-30 g, presuming that the animal consumes, as was observed, 5-10 mls of drinking water daily, to receive an equivalent dose of 80-750 mg/kg/day of 5FC. In a recent human study, 100 mg/kg/day orally was found to be safe over a course of two weeks this was used as a basis for the lower dose [10]. The existing IP delivery method using 1 g/kg/day was considered as a guide for the higher dose in this experiment. "
    [Show abstract] [Hide abstract]
    ABSTRACT: An improved methodology is presented here for transgenic Plasmodium berghei lines that express the negative selectable marker yFCU (a bifunctional protein that combines yeast cytosine deaminase and uridyl phosphoribosyl transferase (UPRT)) and substitutes delivery of selection drug 5-fluorocytosine (5FC) by intraperitoneal injection for administration via the drinking water of the mice. The improved methodology is shown to be as effective, less labour-intensive, reduces animal handling and animal numbers required for successful selection thereby contributing to two of the "three Rs" of animal experimentation, namely refinement and reduction.
    Full-text · Article · Mar 2012 · Malaria Journal
Show more