Synergistic combinations of azoles and antihistamines against Candida species in vitro

Fungal infections are a major cause of skin and mucosal membrane disease. Immunocompromised individuals, such as those undergoing chemotherapy, are most susceptible to fungal infections. With a growing population of immunocompromised patients, there are many reports of increasing numbers of infections and of fungal strains resistant to current antifungals. One way to treat drug-resistant infections is to administer combinations of drugs to patients. Azoles are the most prescribed antifungals, as they are broad-spectrum and orally bioavailable. Terfenadine (TERF) and ebastine (EBA) are second-generation antihistamines, with EBA being used in many countries. In this study, we explored combinations of seven azole antifungals and two antihistamines (TERF and EBA) against a panel of 13 Candida fungal strains. We found 55 out of 91 combinations tested of TERF and EBA against the various fungal strains to be synergistic with the azoles. To evaluate the efficiency of these combinations to inhibit fungal growth, we performed time-kill assays. We also investigated the ability of these combinations to disrupt biofilm formation. Finally, we tested the specificity of the combinations towards fungal cells by mammalian cytotoxicity assays. These findings suggest a potential new strategy for targeting drug-resistant Candida infections.