Therapeutic Advances in Mycobacterium avium Complex Pulmonary Disease: Current Treatments and Emerging Host-Directed Approaches

Mycobacterium avium complex (MAC) is the leading cause of non-tuberculous mycobacterial (NTM) pulmonary disease, with increasing incidence among aging and immunocompromised populations. Despite guideline-recommended multidrug therapy consisting of a macrolide, ethambutol, and a rifamycin, treatment remains prolonged and complicated by incomplete culture conversion, adverse effects, recurrence, and antimicrobial resistance. Intracellular persistence, biofilm formation, and intrinsic resistance mechanisms further challenge disease management. This review summarizes MAC pathogenesis, host immune responses, current treatments, and emerging therapeutic strategies. Promising approaches include novel antimicrobial agents, optimized multidrug regimens, drug repurposing, inhaled delivery systems, and host-directed therapies. Particular emphasis is placed on glutathione (GSH), an intracellular antioxidant with immunomodulatory properties, as a potential adjunctive therapy. Experimental studies suggest that GSH and its precursor N-acetylcysteine may influence oxidative stress, inflammatory responses, and antimycobacterial activity. However, MAC-specific evidence remains primarily in vitro, and clinical efficacy in MAC pulmonary disease has not been established. Findings from related mycobacterial infections provide mechanistic insights but cannot be directly extrapolated to MAC pulmonary disease. Further preclinical and clinical studies are needed to determine whether GSH-based interventions can safely complement conventional antimicrobial therapy and improve treatment outcomes.