Synergic effects of tacrolimus and azole antifungal agents against azole-resistant Candida albicans strains

We investigated the effects of combining tacrolimus and azole antifungal ag ents in azole-resistant strains of Candida albicans by comparing the accumu lation of [H-3]itraconazole. The CDR1-expressing resistant strain C26 accum ulated less itraconazole than the CaMDR-expressing resistant strain C40 or the azole-sensitive strain B2630. A CDR1-expressing Saccharomyces cerevisia e mutant, DSY415, showed si marked reduction in the accumulation of both fl uconazole and itraconazole. A CaMDR-expressing S. cerevisiae mutant, DSY416 , also showed lower accumulation of fluconazole, but not of itracconazole. The addition of sodium azide, an electron-transport chain inhibitor, increa sed the intracellular accumulation of itraconazole only in the C26 strain, and not in the C40 or B2630 strains. Addition of tacrolimus, an inhibitor o f multidrug resistance proteins, resulted ire the highest increase in itrac onazole accumulation in the C26 strain. The combination of itraconazole and tacrolimus was synergic in azole-resistant C. albicans strains. In the C26 strain, the MIC of itraconazole decreased from >8 to 0.5 mg/L when combine d with tacrolimus. Our results showed that two multidrug resistance phenoty pes (encoded by the CDR1 and CaMDR genes) in C. albicans have different sub strate specificity for azole antifungal agents and that a combination of ta crolimus and azole antifungal agents is effective against azole-resistant s trains of C. albicans.