In Vitro Studies with 5-Fluorocytosine

Abstract

5-Fluorocytosine, an antifungal agent with potential value as a chemotherapeutic agent, is being evaluated in the treatment of human cryptococcosis. In vitro studies with this agent have been hindered by the fact that it is inhibited significantly in the presence of partially degraded biological substances. This loss of activity is presumed to result from a competitive inhibition between the agent and its natural analogues. Procedures are described for in vitro studies with 5-fluorocytosine. These include methods for susceptibility testing and a bioassay for 5-fluorocytosine in biological fluids. Minimal inhibitory and minimal fungicidal concentrations of 5-fluorocytosine for Cryptococcus neoformans were usually in the range of 0.46 to 3.9 μg/ml and 3.9 to 15.6 μg/ml, respectively. Corresponding values for Candida albicans were 0.46 to 3.9 μg/ml and 15.6 μg/ml or greater, respectively. Strains of C. neoformans and C. albicans resistant to greater than 1,000 μg/ml were encountered both after exposure to the drug and in the absence of any known exposure. Bioassays of specimens from patients treated with 5-fluorocytosine indicated that serum and cerebrospinal fluid concentrations of 10 to 30 μg/ml and 8 to 20 μg/ml, respectively were readily achieved with a dosage of 100 mg per kg per day.