Combined activity of amphotericin B and 5-fluorocytosine against Cryptococcus neoformans in vitro and in vivo in mice.
The in vitro and in vivo activities of amphotericin B and 5-fluorocytosine (5-FC) alone and in combination were studied to determine possible drug interactions against two strains of Cryptococcus neoformans, one sensitive to 5-FC and one resistant to 5-FC. In vitro tube dilution studies demonstrated only additive effects with the 5-FC-sensitive organism but antagonism with eth 5-FC-resistant organism. A mouse model of cryptococcal meningitis allowed comparative drug trails in a new model for the detection of drug interactions. Drug combinations were no more effective against meningitis caused by the 5-FC-sensitive organism than the additive effects of the individual drugs. However, meningitis caused by the 5-FC-resistant Cryptococcus responded less to drug combinations than to either drug alone. Serum levels of amphotericin B and 5-FC were comparable in all groups. No evidence of toxicity from the drug combinations was found. No inhibition of development of resistance to 5-FC by the combination with amphotericin B was detected.
D000666:Amphotericin B / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D003453:Cryptococcosis / Q000188:drug therapy*; D003454:Cryptococcus / Q000187:drug effects*; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D005437:Flucytosine / Q000008:administration & dosage* / Q000494:pharmacology; D008581:Meningitis / Q000209:etiology; D051379:Mice
D000666:Amphotericin B; D003596:Cytosine; D005437:Flucytosine