Ethanolic extract of Withania somnifera (EEWS) augments the activity of fluconazole against drug-resistant vulvovaginal candidiasis

Candida albicans –induced vulvovaginal candidiasis (VVC), particularly fluconazole (FLZ)-resistant strains, poses a growing therapeutic challenge. Withania somnifera , a traditional medicinal plant, contains bioactive compounds with antifungal potential. This study evaluated whether its ethanolic extract (EEWS) could enhance FLZ efficacy, overcome resistance, and reduce associated toxicity. Antifungal and synergistic effects of EEWS and FLZ were evaluated in vitro and in vivo . Minimum inhibitory concentrations (MICs), biofilm inhibition, renal toxicity (blood urea nitrogen and creatinine), inflammatory cytokines (IL-1β, IL-6, TNF-α), and histopathological changes in vaginal tissues were assessed. EEWS synergistically enhanced FLZ efficacy against resistant C. albicans , reducing the MIC eightfold, inhibiting biofilms by 89%, and decreasing fungal load by >99% in mice. Combination therapy also alleviated FLZ-induced nephrotoxicity (reducing blood urea nitrogen by ∼46%) and suppressed IL-1β, IL-6, and TNF-α levels, promoting epithelial recovery. EEWS markedly enhances FLZ’s antifungal efficacy, reduces toxicity and inflammation, and supports tissue healing, highlighting its potential as a potent antifungal adjuvant for drug-resistant VVC.