Aerosolized antifungal therapy in pulmonary fungal disease: pharmacology, drug delivery and emerging clinical applications.

Pulmonary fungal diseases remain associated with substantial morbidity and mortality, particularly in immunocompromised individuals, transplant recipients, and critically ill patients. Although systemic antifungal therapy remains the cornerstone of treatment, its effectiveness may be limited by suboptimal penetration into selected pulmonary compartments, while systemic toxicity, drug-drug interactions, and prolonged treatment requirements may restrict therapeutic options. Aerosolized antifungal therapy provides a pharmacologically attractive approach to increase local pulmonary drug exposure while limiting systemic exposure. Among currently available formulations, liposomal amphotericin B has the most extensive clinical experience for inhaled administration, supported by favorable pulmonary retention, respiratory tolerability, and compatibility with contemporary nebulization technologies. Advances in vibrating mesh nebulizers and aerosol delivery during invasive mechanical ventilation and high-flow respiratory support have further improved the technical feasibility of targeted pulmonary drug administration. Current clinical evidence is strongest for prophylaxis of invasive pulmonary aspergillosis in selected high-risk populations, particularly patients with prolonged neutropenia. Aerosolized amphotericin B formulations are also incorporated into prophylactic strategies after lung transplantation, although protocols remain heterogeneous and evidence is predominantly observational. By contrast, therapeutic applications beyond prophylaxis remain investigational. The potential role of aerosolized therapy differs substantially among pulmonary fungal diseases according to pathogen biology, anatomical distribution, host characteristics, and accessibility of the affected pulmonary compartment. Chronic pulmonary aspergillosis may provide a rationale for localized drug delivery, but cavitary disease and heterogeneous ventilation may limit aerosol deposition. For pulmonary mucormycosis, cryptococcosis, Pneumocystis jirovecii pneumonia, and endemic mycoses, current evidence is insufficient to support routine inhaled antifungal therapy. This Mini Review summarizes current evidence on aerosolized antifungal formulations, pulmonary pharmacology, nebulization technologies, and disease-specific clinical applications, while highlighting current limitations and priorities for future translational and clinical research.