Leveraging Four Decades of Archived Clinical Isolates to Redefine Nontuberculous Mycobacterial Disease

The incidence of nontuberculous mycobacterial (NTM) disease in the United States is steadily increasing, with the average annual incidence rising from 15.8 to 23.7 per 100,000 among Medicare beneficiaries aged ≥65 years between 2010 and 2019. This change underscores a rapidly expanding public health challenge. An aging population, increased awareness, improved diagnostic recognition, and potentially increased environmental exposure are among the factors that could explain this upward trend. Pulmonary disease (PD) accounts for 90% of all NTM infections caused by Mycobacterium avium complex (MAC), making it the most common causative organism. Despite rising disease prevalence, current standard therapies remain suboptimal. Treatment typically requires prolonged courses of multiple antibiotics, poorly tolerated, with significant toxicity and drug-drug interactions, particularly among elderly patients with multiple comorbidities. High rates of treatment discontinuation, antibiotic resistance, and disease recurrence significantly limit therapeutic success. Collectively, these challenges highlight an urgent unmet need for novel, more tolerable, and less toxic therapeutic strategies. Our clinical Microbiology laboratory has maintained a comprehensive archive of all clinical NTM isolates since 1985, creating a repository of more than 14,000 isolates that remain largely unexplored. This unparalleled collection offers a unique opportunity to investigate the evolution of NTM disease over four decades within a population that mirrors major demographic shifts in the United States. Leveraging these isolates will allow us to: Examine temporal trends in NTM species distributionIdentify populations at greatest riskCorrelate clinical presentations with demographic and social factorsTrack the emergence and evolution of antibiotic resistance. The knowledge generated from this work will directly inform the development of improved prevention strategies, diagnostic tools, and therapeutic interventions, benefiting both patients and the broader medical community. This research initiative will serve as the foundation for a long-term, multidisciplinary program aligned with the mission of the Center of Excellence for NTM at the University of California, Irvine.