This chapter focuses on nontuberculous mycobacteria (NTM), organisms that are ubiquitous in the environment and are thus referred as “environmental mycobacteria” by some experts. <italic>Mycobacterium avium</italic> complex (MAC), which includes <italic>M. kansasii, M. fortuitum</italic>, and <italic>M. abscessus</italic>, is the most common NTM associated with human disease in the United States. It also Although NTM species rarely cause clinically relevant human disease, they are frequently isolated as specimen contaminants. The chapter describes infection that is thought to occur from environmental exposure to the NTM through three potential portals of entry: the respiratory tract, the gastrointestinal tract, and direct inoculation of the skin and soft tissues, although chronic pulmonary disease is the most common clinical manifestation of NTM infection in the immunocompetent host. The chapter discusses the testing, evaluation, and treatment of patients infected by NTM and MAC.

RATIONALE.MAC is the leading cause of NTM lung disease, which may be progressive and associated with significant symptom burden.Patients who initiate treatment for MAC lung disease often do not achieve microbiological benefit (culture conversion), and there is currently no validated PRO instrument that can evaluate clinical benefit of treatment.METHODS.ARISE (NCT04677543) and ENCORE (NCT04677569) are ongoing concurrent randomized, double-blind, placebo-controlled studies in which adults with a new diagnosis of MAC lung disease are randomized 1:1 to receive either amikacin liposome inhalation suspension 590 mg QD (ALIS) + azithromycin 250 mg QD (AZI) + ethambutol 15 mg/kg QD (ETH) or empty liposome control (ELC)+AZI+ETH.The primary objective of ARISE is to generate evidence demonstrating the domain specification, reliability, validity, and responsiveness of PRO endpoints at Month 7 [1 month off treatment].The psychometric validation of the Quality of Life -Bronchiectasis (QOL-B) respiratory domain and/or Patient-Reported Outcome Measurement Information System -Fatigue-Short Form 7a (PROMIS F-SF 7a) within the MAC lung disease population will be used to generate data for the computation of a score for the primary endpoint in the ENCORE study (clinical benefit of treatment in respiratory symptoms at month 13 [1 month off treatment]).Microbiological secondary endpoints in ENCORE include the proportion of patients with durable culture conversion at 3 months off all MAC treatment.RESULTS.These studies are taking place at approximately 220 sites globally.A sample size of 50 patients per group in ARISE will provide ≥80% power for detecting a clinically meaningful difference at 1-month post treatment between patients achieving culture conversion during the study and those who did not.A sample size of 125 patients per group in ENCORE will provide sufficient power to assess superiority of ALIS+AZI+ETH over the active comparator (ELC+AZI+ETH) in the primary endpoint (clinical benefit of treatment in respiratory symptoms at month 13) and the durability of culture conversion at month 15.CONCLUSIONS.MAC lung disease has a significant unmet medical need as many patients may not attain microbiological benefit with treatment.Limited data are available to assess clinical benefit of treatment, and there are no PRO instruments that have been validated in this patient population.ARISE and ENCORE represent a unique parallel trial approach, while generating data sequentially, to potentially validate instruments in MAC lung disease and subsequently assess the clinical benefit of treatment.

Introduction: Treatment options for refractory MAC-LD are limited. By month 6 in CONVERT, culture conversion rates in adults with refractory MAC-LD were 29.0% (65/224) with ALIS, a nebulized, liposome-encapsulated amikacin formulation, + guideline-based therapy (GBT) vs 8.9% (10/112; P<.0001) with GBT alone. Aims: We report safety, culture conversion durability, and functional response (6-minute walk test; 6MWT) with extended (up to 16 mo) ALIS therapy. Methods: In CONVERT, patients were randomly assigned to receive ALIS 590mg QD + GBT or GBT alone. Patients with culture conversion (3 consecutive monthly MAC-negative sputum cultures) by month 6 continued treatment for 12 months after the time of culture conversion. Results: In patients who converted by month 6 and continued treatment, 63% (41/65) of those on ALIS+GBT and 30% (3/10) on GBT alone remained culture negative after 12 months of subsequent treatment; 63% (41/65) vs 0% (0/10) remained culture-negative 3 months off all antibiotics. There was no difference between treatment arms in the change in 6MWT distance from baseline to month 8 (P=0.84). Extended ALIS exposure did not alter overall safety findings (Griffith, AJRCCM 2018) with ALIS+GBT and GBT alone; respectively, 84.7% (195/223) and 50.9% (57/112) had respiratory treatment-emergent adverse events (TEAEs); 20.2% (45/223) and 20.5% (23/112) had serious TEAEs. Conclusion: Addition of ALIS to GBT in patients with refractory MAC-LD improved culture conversion, which was maintained during therapy and for 3 months posttreatment. No new safety signals emerged with extended treatment.