Non-antifungal medications administered during fungal infections drive drug tolerance and resistance in Candida albicans.

Introduction. Fungal infections are increasingly concerning, particularly in immunocompromised patients. These patients often suffer from comorbidities and receive multiple, non-antifungal medications.Gap Statement. The effects of these co-administered medications on fungal cells - and their potential to influence antifungal drug efficacy - are poorly understood.Aim. This study investigates non-antifungal medications commonly administered in parallel to antifungals and evaluates their impact on fungal susceptibility.Methodology. We systematically reviewed clinical guidelines to identify non-antifungal medications frequently co-prescribed with antifungals. Focusing on Candida albicans, the most prevalent fungal pathogen, we examined whether the presence of these drugs influences antifungal responses of C. albicans. First, we tested the selected compounds together with antifungals in combination assays. Interactions were then characterized using checkerboard assays, and the impact on antifungal resistance and tolerance was evaluated through disc diffusion assays. To further explore these effects in vivo, the influence of selected antagonistic interactions on treatment efficacy was assessed using a Galleria mellonella model of disseminated candidiasis.Results. From 119 medications used to manage 40 conditions linked to a high risk of fungal infections, we identified 34 compounds that altered the effectiveness of the antifungals fluconazole (FLC) and/or anidulafungin. Most of these compounds reduced or antagonized antifungal efficacy, often due to increased resistance or tolerance. Validation in a G. mellonella infection model confirmed that compounds antagonistic to FLC, including loperamide, estradiol and levothyroxine, interfere with antifungal treatment efficacy in this in vivo model.Conclusion. Our findings highlight that medications frequently used by patients at risk for fungal infections can inadvertently increase fungal pathogen drug tolerance or resistance. We suggest that drugs targeting non-fungal conditions yet affecting fungal pathogens might represent an underestimated factor contributing to rising antifungal resistance and tolerance.