Byung Woo Jhun1, Su-Young Kim1, Seong Mi Moon1, Kyeongman Jeon1, O Jung Kwon1, Hee Jae Huh2, Chang-Seok Ki2, Nam Yong Lee2, Sung Jae Shin3, Charles L Daley4, Won-Jung Koh1. 1. 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and. 2. 2 Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 3. 3 Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and. 4. 4 Division of Mycobacterial and Respiratory Infections, Department of Medicine, National Jewish Health, Denver, Colorado.
Abstract
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).
RATIONALE: Patients with refractory Mycobacterium avium complexlung 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).
Authors: Hee Jae Huh; Su-Young Kim; Hyang Jin Shim; Dae Hun Kim; In Young Yoo; On-Kyun Kang; Chang-Seok Ki; So Youn Shin; Byung Woo Jhun; Sung Jae Shin; Charles L Daley; Won-Jung Koh; Nam Yong Lee Journal: J Clin Microbiol Date: 2019-07-26 Impact factor: 5.948
Authors: Nils Wetzstein; Thomas A Kohl; Tilman G Schultze; Sönke Andres; Carla Bellinghausen; Christian Hügel; Volkhard A J Kempf; Annette Lehn; Michael Hogardt; Hubert Serve; Maria J G T Vehreschild; Timo Wolf; Stefan Niemann; Florian P Maurer; Thomas A Wichelhaus Journal: J Clin Microbiol Date: 2020-11-18 Impact factor: 5.948