title: Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease.
abstract: BACKGROUND
  The clinical features and outcome of macrolide-resistant Mycobacterium avium complex (MAC) lung disease are not known.
  
  
  OBJECTIVE
  Characterize patients, treatment, and isolates in macrolide-resistant MAC lung disease.
  
  
  METHODS
  Retrospective chart review, susceptibility testing, molecular fingerprinting, and DNA sequence analyses of resistant MAC isolates.
  
  
  RESULTS
  We identified 51 patients over a 15-yr period with clarithromycin-resistant MAC (minimum inhibitory concentration (MIC)>or=32 microg/ml) lung disease at a single referral center. Twenty-four (47%) patients had nodular disease with bronchiectasis and 27 (53%) had upper lobe cavitary disease. Most patients (77%) had M. intracellulare. Sequencing of the 23S r-RNA gene showed 49 of 51 isolates (96%) with the expected mutation in adenine 2058 or 2059. Risk factors for resistance included macrolide monotherapy or combination with a quinolone only (39/51 or 76%). Macrolide resistance developed in 12 of 303 (4.0%) patients started on the American Thoracic Society-recommended two companion drugs, with no risk difference in clarithromycin versus azithromycin and daily versus intermittent therapy. Sputum conversion with macrolide-resistant MAC occurred in 11 of 14 (79%) patients who received more than 6 mo of injectable aminoglycoside therapy and lung resection, compared with 2 of 37 (5%) who did not. The 1-yr mortality in patients who remained culture positive was 34% (13/38) compared with 0% (0/13) of patients who became culture negative (converted).
  
  
  CONCLUSIONS
  Macrolide resistance rarely occurs in patients also receiving ethambutol and a rifamycin. Macrolide-resistant MAC lung disease requires aggressive drug and surgical therapy for cure.
authors.affiliation: The University of Texas Health Center, Department of Medicine, 11937 U.S. Hwy 271, Tyler, TX 75708, USA. david.griffith@uthct.edu
authors.forename: David E
authors.initials: DE
authors.lastname: Griffith
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Brown-Elliott
authors.forename: Brett
authors.initials: B
authors.lastname: Langsjoen
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xi
authors.initials: X
authors.lastname: Pan
authors.forename: William
authors.initials: W
authors.lastname: Girard
authors.forename: Kenwyn
authors.initials: K
authors.lastname: Nelson
authors.forename: James
authors.initials: J
authors.lastname: Caccitolo
authors.forename: Julio
authors.initials: J
authors.lastname: Alvarez
authors.forename: Sara
authors.initials: S
authors.lastname: Shepherd
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wilson
authors.forename: Edward A
authors.initials: EA
authors.lastname: Graviss
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wallace
mesh_terms: D000368:Aged; D000890:Anti-Infective Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics; D018834:Chaperonin 60; D018833:Chaperonins / Q000235:genetics; D017291:Clarithromycin / Q000627:therapeutic use; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D018942:Macrolides / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015269:Mycobacterium avium Complex / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy* / Q000382:microbiology; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012329:RNA, Bacterial / Q000235:genetics; D012189:Retrospective Studies
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D018834:Chaperonin 60; D018942:Macrolides; D012329:RNA, Bacterial; C074119:heat-shock protein 65, Mycobacterium; D018833:Chaperonins; D017291:Clarithromycin