In-vitro interactions of itraconazole with flucytosine against clinical isolates of Cryptococcus neoformans

Treatment failures can occur in AIDS patients infected with Cryptococcus neoformans, despite aggressive antifungal therapy. Combination regimens with additive or synergic drugs could provide additional options for treating cryptococcosis. We studied the effects of itraconazole combined with flucytosine against 16 strains of C. neoformans var. neoformans, Combination therapy revealed different results for the various strains, including synergy (fractional inhibitory concentration (FIC) index 0.5, 63% of the interactions), addition (FIC >0.5 to 1.0, 31% of the interactions) and indifference (FIC >1.0 to <2.0, 6% of the interactions). Antagonism (FIC >2.0) was not observed. The efficacy of combination therapy was confirmed by quantitative cfu and killing curve assays. In particular, killing curves conducted in replicating cells showed that the addition of itraconazole prevented the development of flucytosine-resistant mutants of C. neoformans, These data show that the combination of itraconazole and flucytosine is significantly more active than either drug alone against C, neoformans in vitro.