Managing Azole Resistance in Aspergillus.

Azole antifungals are the cornerstone of therapy for aspergillosis, yet the global rise in azole-resistant Aspergillus fumigatus has become a major clinical concern. Resistance rates vary widely across regions, with particularly serious implications for chronic pulmonary aspergillosis (CPA), which requires long-term azole therapy. Resistance mechanisms largely involve cyp51A mutations, although additional genetic alterations and environmental factors, such as agricultural azole use, also play important roles. Cross-resistance among azoles is frequent, leaving clinicians with limited alternatives, such as liposomal amphotericin B or echinocandins, which are constrained by toxicity, fungistatic activity, and intravenous administration. Currently, antifungal susceptibility testing for filamentous fungi remains technically demanding and is not routinely available in many countries, including Japan, further complicating its management. Emerging approaches include the development of novel antifungal compounds and optimization of existing drugs through inhaled or nanoformulated delivery systems. Furthermore, fungal vaccines are attracting increasing attention as promising long-term solutions to stagnant antifungal pipelines and the growing challenge of drug resistance.