Interactions among amphotericin B, 5-fluorocytosine, ketoconazole, and miconazole against pathogenic fungi in vitro.

Interactions among amphotericin B, 5-fluorocytosine, ketoconazole, and micoconazole were tested for all possible paired and triple drug combinations and all four drugs combined against three isolates of Candida albicans, three Candida spp., two isolates of Cryptococcus neoformans, and three isolates Aspergillus fumigatus. An assay for inhibitory activity was developed in which growth in the presence of an antifungal agent was expressed as a percentage of the growth in drug-free cultures. For nearly all of the antifungal combinations, the interaction was additive against most fungal isolates. Drug combinations that included amphotericin B and ketoconazole were most often synergistic, i.e., amphotericin plus ketoconazole, amphotericin plus 5-fluorocytosine plus ketoconazole, and amphotericin plus 5-fluorocytosine plus ketoconazole plus miconazole, whereas the combination of ketoconazole plus miconazole showed the strongest tendency towards antagonism. The data in this screening survey provide a basis for further studies of drug interactions in vivo and in vitro.