A promising approach of overcoming the intrinsic resistance of Candida krusei to fluconazole (FLC)--combining tacrolimus with FLC.

Abstract

Candida krusei is intrinsically resistant to fluconazole (FLC). This study aimed to investigate whether tacrolimus (FK506) could enhance the susceptibility of FLC against C. krusei. The tested strains included the following: five isolates with minimal inhibitory concentration (MIC) of 32 μg mL(-1), two with MIC of 256 μg mL(-1), and one with MIC of 512 μg mL(-1). MICs of FK506 and FLC alone and in combination were determined by checkerboard assay, with data analyzed by fractional inhibitory concentration index model. The time-kill curves were plotted to investigate the antifungal activity at 0, 6, 12, 24, and 48 h after drug exposure. The results revealed that FK506 reduced the resistance of all isolates obviously and degree of reduction in MICs varied with susceptibilities of strains. Addition of FK506 resulted in a fourfold and 16-fold downward shift in MICs of the isolates with MICs of 32 μg mL(-1) and of ≥ 256 μg mL(-1), respectively. The synergy was further confirmed by the time-kill assay. When they were in combination against CK4/CK9 with MIC of 32/256 μg mL(-1), there was a 2.25/2.03 log10 CFU mL(-1) decrease at 24 h compared with FLC alone, respectively. In conclusion, combination of FK506 and FLC may represent a promising approach of overcoming the intrinsic resistance of C. krusei to FLC.