5-fluorocytosine resistance in Cryptococcus neoformans.
Isolates of Cryptococcus neoformans from six patients were obtained before and after unsuccessful therapy with 5-fluorocytosine (5-FC). Post-therapy isolates exhibited massive and stable 5-FC resistance. The frequency of drug-resistant mutants in susceptible isolates of C. neoformans was <0.001% (70.4 +/- 17.9 per 10(7) cryptococci), whereas mutant frequencies in resistant isolates approached 100%. Non-drug-induced, spontaneously appearing 5-FC resistant mutants were documented in four susceptible isolates of C. neoformans by use of the statistical method of fluctuation analysis. Mutation rates on these same four isolates ranged from 1.2 x 10(-7) to 4.8 x 10(-7). Total intracellular uptake and incorporation of cytosine-5-(3)H (CyH(3)) and 5-fluorocytosine-2-(14)C (5-FC(14)) into a trichloroacetic acid-insoluble fraction were markedly reduced in six isolates with in vivo-acquired resistance when compared with susceptible pretreatment strains from the same patients. Five of these six isolates also had acquired massive resistance to 5-fluorouracil (5-FU), suggesting that a mutation in the uridine-5'-monophosphate pyrophosphorylase was responsible for drug resistance. The sixth isolate, which remained susceptible to 5-FU, appeared to have a defect in a cytosine-specific permease accounting for 5-FC resistance. A single isolate with in vitro-acquired 5-FC and 5-FU resistance had no reduction in uptake or incorporation of CyH(3) or 5-FC(14). The mechanism of resistance in this isolate is discussed.
D000935:Antifungal Agents / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D003454:Cryptococcus / Q000187:drug effects*; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000472:pathogenicity; D003596:Cytosine / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D005437:Flucytosine / Q000494:pharmacology; D009154:Mutation; D014316:Tritium
D000935:Antifungal Agents; D002250:Carbon Radioisotopes; D014316:Tritium; D003596:Cytosine; D005437:Flucytosine