Development of macrolide resistance and reinfection in refractory Mycobacterium avium complex lung disease

Byung Woo Jhun, Su Young Kim, Seong Mi Moon, Kyeongman Jeon, O. Jung Kwon, Hee Jae Huh, Chang Seok Ki, Nam Yong Lee, SungJae Shin, Charles L. Daley, Won Jung Koh

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 preand 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.

Original languageEnglish
Pages (from-to)1322-1330
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume198
Issue number10
DOIs
Publication statusPublished - 2018 Nov 15

Fingerprint

Mycobacterium avium Complex
Macrolides
Lung Diseases
23S Ribosomal RNA
rRNA Genes
Therapeutics
Sputum
Coinfection
Point Mutation

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Jhun, Byung Woo ; Kim, Su Young ; Moon, Seong Mi ; Jeon, Kyeongman ; Kwon, O. Jung ; Huh, Hee Jae ; Ki, Chang Seok ; Lee, Nam Yong ; Shin, SungJae ; Daley, Charles L. ; Koh, Won Jung. / Development of macrolide resistance and reinfection in refractory Mycobacterium avium complex lung disease. In: American Journal of Respiratory and Critical Care Medicine. 2018 ; Vol. 198, No. 10. pp. 1322-1330.
@article{b3cf452dcd0d4001ae83fa0ea30d37dd,
title = "Development of macrolide resistance and reinfection in refractory Mycobacterium avium complex lung disease",
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 preand 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.",
author = "Jhun, {Byung Woo} and Kim, {Su Young} and Moon, {Seong Mi} and Kyeongman Jeon and Kwon, {O. Jung} and Huh, {Hee Jae} and Ki, {Chang Seok} and Lee, {Nam Yong} and SungJae Shin and Daley, {Charles L.} and Koh, {Won Jung}",
year = "2018",
month = "11",
day = "15",
doi = "10.1164/rccm.201802-0321OC",
language = "English",
volume = "198",
pages = "1322--1330",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "10",

}

Development of macrolide resistance and reinfection in refractory Mycobacterium avium complex lung disease. / Jhun, Byung Woo; Kim, Su Young; Moon, Seong Mi; Jeon, Kyeongman; Kwon, O. Jung; Huh, Hee Jae; Ki, Chang Seok; Lee, Nam Yong; Shin, SungJae; Daley, Charles L.; Koh, Won Jung.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 198, No. 10, 15.11.2018, p. 1322-1330.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Development of macrolide resistance and reinfection in refractory Mycobacterium avium complex lung disease

AU - Jhun, Byung Woo

AU - Kim, Su Young

AU - Moon, Seong Mi

AU - Jeon, Kyeongman

AU - Kwon, O. Jung

AU - Huh, Hee Jae

AU - Ki, Chang Seok

AU - Lee, Nam Yong

AU - Shin, SungJae

AU - Daley, Charles L.

AU - Koh, Won Jung

PY - 2018/11/15

Y1 - 2018/11/15

N2 - 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 preand 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.

AB - 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 preand 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.

UR - http://www.scopus.com/inward/record.url?scp=85056636524&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056636524&partnerID=8YFLogxK

U2 - 10.1164/rccm.201802-0321OC

DO - 10.1164/rccm.201802-0321OC

M3 - Article

VL - 198

SP - 1322

EP - 1330

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 10

ER -