Evaluation of four calcium channel blockers as fluconazole resistance inhibitors in Candida glabrata.

OBJECTIVES

The aim of this study was to evaluate the ability of four calcium channel blockers (CCBs), namely verapamil, diltiazem, nicardipine (NIC) and nifedipine (NIF), to enhance the susceptibility of Candida glabrata strains to fluconazole (FLC).

METHODS

Synergistic antifungal effects of the CCBs with FLC were examined by the chequerboard method, and fractional inhibitory concentration indices (FICIs) were determined. The time-kill curve method was used for the most promising combination to further evaluate the synergetic effects.

RESULTS

NIC showed an additive effect with FLC against FLC-resistant and FLC-susceptible-dose-dependent strains (DSY 565 and CBS 138) known to express efflux pumps, but not against FLC-susceptible strains. NIF exhibited an additive effect with FLC both by the chequerboard method (0.5<FICI<1) and time-kill curves (<2 log10 CFU/mL decrease in viable count). In addition, NIF had its own antifungal effect consistently against most of the strains used in this study, with minimum inhibitory concentrations (MICs) of 8μg/mL.

CONCLUSIONS

NIC showed an additive effect with FLC against FLC-resistant C. glabrata strains, most probably via efflux pump inhibition as demonstrated selectively in FLC-resistant strains with known efflux pumps. NIF displayed a promising antifungal effect alone as well as an additive effect with FLC against most of the strains.