INTRODUCTION Invasive fungal infections require prolonged antifungal therapy and can pose significant therapeutic challenges, particularly when they involve deep-seated sites or when treatment is complicated by antifungal resistance, toxicity, drug-drug interactions, or limited source control. Rezafungin is a novel once-weekly echinocandin with an extended half-life and favorable pharmacokinetic properties; however, clinical experience beyond candidemia and invasive candidiasis remains limited. AREAS COVERED We reviewed the available real-world clinical evidence on rezafungin, focusing on patient characteristics, infection types, therapeutic intent, antifungal resistance, treatment strategies, safety, and clinical outcomes across approved and off-label indications. EXPERT OPINION Rezafungin represents a promising therapeutic option for deep-seated and other difficult-to-treat fungal infections requiring prolonged antifungal therapy. Its once-weekly administration, prolonged half-life, and limited potential for drug-drug interactions may offer substantial advantages in long-term treatment and outpatient therapy. However, current evidence largely comes from case reports and small observational studies. Prospective studies and larger real-world cohorts are needed to define better the efficacy, optimal treatment duration, and positioning of rezafungin in deep-seated fungal infections.
