Interactions of posaconazole and flucytosine against Cryptococcus neoformans

A checkerboard methodology, based on standardized methods proposed by the N ational Committee for Clinical Laboratory Standards for broth microdilution antifungal susceptibility testing, was applied to study the in vitro inter actions of flucytosine (FC) and posaconazole (SCH 56592) (FC-SCH) against 1 5 isolates of Cryptococcus neoformans, Synergy, defined as a fractional inh ibitory concentration (FIC) index of <0.50, was observed for 33% of the iso lates tested. When synergy was not achieved, there was still a decrease in the MIC of one or both drugs when they were used in combination. Antagonism , defined as a FIC of >4.0, was not observed. The in vitro efficacy of comb ined therapy was confirmed by quantitative determination of the CFU of C, n eoformans 486, an isolate against which the FC-SCH association yielded a sy nergistic interaction. To investigate the potential beneficial effects of t his combination therapy in vivo, we established two experimental murine mod els of cryptococcosis by intracranial or intravenous injection of cells of C. neoformans 486. At 1 day postinfection, the mice were randomized into di fferent treatment groups. One group each received each drug alone, and one group received the drugs in combination, While combination therapy was not found to be significantly more effective than each single drug in terms of survival, tissue burden experiments confirmed the potentiation of antifunga l activity with the combination. Our study demonstrates that SCH and FC com bined are significantly more active than either drug alone against C. neofo rmans in vitro as well in vivo. These findings suggest that this therapeuti c approach could be useful in the treatment of cryptococcal infections.