Serotonin reuptake inhibitors effect on fluconazole activity against resistant Candida glabrata strains

The study aimed to evaluate four selective serotonin reuptake inhibitors (SSRIs) as modifiers of fluconazole activity against resistant strains of Candida glabrata.

The effect of SSRIs on fluconazole activity was studied using the checkerboard method against C. glabrata strains (CBS 138, CBS 850821, DSY 562, DSY 565, ATCC 22553 and ATCC 90030); fractional inhibitory concentration index (FIC) was calculated and time-kill curve was used for the most prominent combination for further evaluation.

All used SSRIs have antifungal activity against the C. glabrata strains tested. A combination of fluconazole with fluoxetine or fluvoxamine showed indifferent effects (fractional inhibitory concentration index [FICI] in all strains >1 but <4), whereas a paroxetine-fluconazole combination showed an additive effect against DSY565 and CBS138, known to express efflux pumps as well as on ATCC strain (0.5 < FIC < 1) with indifferent effect on other strains used. The most promising combination was that of fluconazole with sertraline (FICI ≤0.5), where a synergistic effect was observed against all resistant and susceptible dose-dependent strains, including those known to express efflux pumps. This synergistic effect was confirmed by time-kill curve assay against all resistant C. glabrata and ATCC strains with a >2-log10 CFU/mL reduction caused by combination compared with a single active agent of fluconazole after 24 hours of incubation. A sertraline-fluconazole combination produced an additive effect on the reference ATCC strain.

Our data suggest that blocking active efflux pumps by sertraline may be considered the probable mechanism of synergism with fluconazole. The combination of sertraline with fluconazole could be a promising remedy for treatment of infections caused by resistant C. glabrata.