title: Efficacy of amphotericin B in combination with flucytosine against flucytosine-susceptible or flucytosine-resistant isolates of Cryptococcus neoformans during disseminated murine cryptococcosis.
abstract: Whether or not flucytosine should be administered to patients infected with Cryptococcus neoformans isolates found to be resistant to flucytosine in vitro remains a controversial issue. Thus, the efficacy of amphotericin B and flucytosine in combination was investigated by mortality and fungal burden studies in a murine model of disseminated cryptococcosis using two clinical isolates of Cryptococcus neoformans, one susceptible and one resistant (i.e., 64 microg/ml) to flucytosine. Amphotericin B was given intraperitoneally at 0.25 or 0.5 mg/kg/day, while flucytosine was given at 100 or 250 mg/kg/day orally. Treatment was started 24 h or day 6 after inoculation and continued for 5 days in fungal burden and mortality studies, respectively. The combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day was significantly more effective than monotherapies for reducing fungal burden in brain, spleen, and lungs after infection by the flucytosine-susceptible isolate and in brain and spleen for the flucytosine-resistant isolate. For the flucytosine-resistant isolate, the combination of amphotericin B at 0.5 mg/kg/day with flucytosine at 100 mg/kg/day was significantly better than monotherapies for reducing the fungal burden in the brain. Survival obtained after the combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day increased compared to that obtained with monotherapies for both isolates, but the difference was statistically significant only for the flucytosine-susceptible isolate. Antagonism was never observed. This study demonstrates the beneficial effect of the addition of flucytosine to amphotericin B against experimental disseminated cryptococcal infection even when the C. neoformans isolate is resistant to flucytosine.
authors.affiliation: Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, Institut Pasteur, CNRS FRE2849, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schwarz
authors.forename: Françoise
authors.initials: F
authors.lastname: Dromer
authors.forename: Olivier
authors.initials: O
authors.lastname: Lortholary
authors.forename: Eric
authors.initials: E
authors.lastname: Dannaoui
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000382:microbiology; D003453:Cryptococcosis / Q000188:drug therapy / Q000382:microbiology* / Q000401:mortality; D003455:Cryptococcus neoformans / Q000187:drug effects*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005437:Flucytosine / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D000666:Amphotericin B; D005437:Flucytosine