In Vitro Assessment of Fluconazole and Cyclosporine A Antifungal Activities: A Promising Drug Combination Against Different Candida Species.

Abstract

Invasive candidiasis is a common fungal infection associated with multiple risk factors, such as cancer, neutropenia, corticosteroid therapy, catheterization, and the use of broad-spectrum antibiotic treatment. Candida albicans is the predominant causative agent, although other Candida species have been emerging in the last years, together with a rise in a number of strains resistant to the currently available antifungal drugs, which poses a challenge when treating these infections. Drug repurposing and drug combinations are promising strategies for the treatment of invasive mycoses. In this study, we evaluated the effect of the combination of fluconazole (FLZ) and cyclosporine A (CsA) against 39 clinical isolates and reference strains of Candida. Two methods, the Loewe additivity model and Bliss independence model, were used to assess the antifungal activity of the drug combination according to CLSI and EUCAST guidelines. The results demonstrated a synergistic effect between fluconazole (FLZ) and cyclosporine A (CsA) against 15-17 Candida isolates, depending on the evaluation model used, including FLZ-resistant strains of C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis. Notably, the combination significantly reduced the minimum inhibitory concentration (MIC) of FLZ in a substantial number of isolates, including those with resistance to FLZ. Additionally, time-kill curve studies confirmed the synergistic interaction, further validating the potential of this combination as an alternative therapeutic strategy for candidiasis treatment. These findings emphasize the importance of investigating innovative drug combinations to address the challenges posed by antifungal resistance and improve treatment options for invasive fungal infections.