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.