Novel antifungal agents for treating endemic mycoses: hope on the horizon?

PURPOSE OF REVIEW: Current treatments for endemic mycoses are limited by toxicity, drug-drug interactions, the need for therapeutic drug monitoring, and suboptimal penetration to sequestered sites. At the same time, several new antifungal strategies and agents are nearing clinical availability and may change practice. RECENT FINDINGS: Current literature highlights limitations of standard therapy for histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, talaromycosis, sporotrichosis, and emergomycosis, which often rely on amphotericin B-based induction regimens followed by triazole antifungals. Emerging studies are evaluating single high-dose liposomal amphotericin B, shorter treatment durations for histoplasmosis, and flucytosine combined with amphotericin B-based induction for talaromycosis. Novel antifungals such as olorofim, fosmanogepix, and turletricin are especially promising, and treatment strategies guided by patient phenotypes and immune endotypes are also beginning to emerge. SUMMARY: Growing evidence suggests therapy for endemic mycoses may change substantially in the near future. New drugs and alternative treatment approaches have the potential to improve safety, tolerability, oral availability, drug-drug interaction profiles, and treatment duration, with important implications for both clinical care and future research.