Published ahead of print on July 20, 2006, doi:10.1164/rccm.200603-450OC Am. J. Respir. Crit. Care Med., Volume 174, Number 8, October 2006, 928-934 A more recent version of this article appeared on October 15, 2006
Submitted on March 30, 2006 Clinical and Molecular Analysis of Macrolide Resistance in Mycobacterium avium Complex Lung DiseaseDavid E Griffith1*,1 Department of Medicine, University of Texas Health Center, Tyler, TX, USA, 2 Department of Microbiology, University of Texas Health Center, Tyler, TX, USA, 3 Department of Pathology, Baylor College of Medicine, Houston, TX, USA, 4 Department of Thoracic Surgery, University of Texas Health Center, Tyler, TX, USA, 5 Department of Occupational Health Sciences, University of Texas Health Center, Tyler, TX, USA, 6 Department of Medicine, University of Texas Health Center, Tyler, TX, USA; Department of Microbiology, University of Texas Health Center, Tyler, TX, USA * To whom correspondence should be addressed. E-mail: david.griffith{at}uthct.edu.
Rationale: The clinical features and outcome of macrolide-resistant Mycobacterium avium complex (MAC) lung disease are not known.
Objectives: 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.
Measurements and Main Results: We identified 51 patients over a 15 year period with clarithromycin-resistant MAC (MIC Key words: surgery, sequencing mutations, aminogylcosides
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32 µg/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 49/51 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 12/303 (4.0%) patients started on the ATS 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 11/14 (79%) of patients who received >6 months injectable aminoglycoside therapy and lung resection, compared to 2/37 (5%) that did not. The one-year mortality in patients who remained culture positive was 34% (13/38) compared to 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.
