Antifungal Activity and Potential Mechanism of Caspofungin in Combination with Ribavirin Against Candida albicans

The number of invasive Fungal infections has increased dramatically, resulting in high morbidity and mortality among immunocompromised patients. With the increasing use of caspofungin (CAS), resistant strains emerged frequently and led to limitations in the treatment of patients with severe invasive Candida albicans infections. Combination therapy is an important method to deal with this dilemma. Thus, we investigated the activity of CAS with ribavirin (RBV) against C. albicans. The results of in vitro study showed that the MICs of CAS and RBV when they were used alone were 0.5-1μg/mL and 2-8μg/mL, respectively, while the MICs of CAS decreased from 0.5-1μg/mL to 0.0625-0.25μg/mL when in combination group, with fractional inhibitory concentration index (FICI)≤0.5. Besides, the combination group also displayed synergistic effects against C. albicans biofilm performed over 4h; the sessile MIC (sMIC) of CAS decreased from 0.5-1µg/mL to 0.0625-0.25µg/mL, RBV's sMIC decreased from 4-16µg/mL to 1-2µg/mL, with FICI<0.5. The survival rate of C. albicans-infected Galleria mellonella was prolonged, the Fungal burden was decreased and the area of tissue damage was reduced after combination therapy.. Further studies showed that the mechanisms of the synergistic effect were related to the inhibition of biofilm formation, the inhibition of hyphal growth, and the activation of metacaspase, but it may not be related to the accumulation of Reactive Oxygen Species (ROS). We hope these findings will contribute to the understanding of drug resistance in C. albicans and provide new insights for the application of RBV.

Antifungal activity; Antifungal mechanisms; Candida albicans; Caspofungin; Drug combination; Ribavirin.