LAUSR

Rationale: Patients with refractory Mycobacterium avium complex lung disease (MAC‐LD) undergo long‐term macrolide therapy, but macrolide resistance develops infrequently. Objectives: The aim of this study was to determine whether reinfection was a factor in the low incidence of macrolide resistance in patients with refractory MAC‐LD. Methods: Among 481 patients with treatment‐naive MAC‐LD who started antibiotic treatment between January 2002 and December 2013, we identified 72 patients with refractory disease, characterized by persistently positive sputum cultures despite ≥12 months of treatment. Molecular analyses of the 23S ribosomal RNA gene responsible for macrolide resistance and serial mycobacterial genotyping were performed using stored MAC isolates. Measurements and Main Results: The median duration of treatment was 32 months (interquartile range, 24‐41 mo) in 72 patients. After treatment for a median of 33 months (interquartile range, 21‐44 mo), macrolide resistance developed in 16 (22%) patients. Molecular analysis of isolates from 15 patients revealed that 80% (12 of 15) had a point mutation at position 2,058 or 2,059 of the 23S ribosomal RNA gene. Of the 49 patients who had stored pre‐ and post‐treatment isolates, mycobacterial genotyping revealed that reinfection by new MAC strains occurred in 36 (73%) patients. New MAC strains were found in 24 (49%) patients, and mixed infections with original and new strains occurred in 12 (24%) patients. Only 13 (27%) patients had persistent infections with their original MAC strains. Conclusions: Refractory MAC‐LD is commonly caused by reinfection with new strains rather than persistence of the original strain, which may explain the infrequent development of macrolide resistance in refractory MAC‐LD. Clinical trial registered with www.clinicaltrials.gov (NCT00970801).