Diagnosing and Managing Nontuberculous Mycobacteria

Diagnostic criteria n CLINICAL - Cough, fatigue, weight loss

n RADIOGRAPH Clinical symptoms - Nodular or cavitary opacities on chest radiograph or Clinical phenotypes - High resolutation computed tomography showing n Chronic cough multifocal bronchiectasis with multiple small nodules n Fever/chills n BACTERIOLOGY n Night sweats - Positive culture results from at least two separate n Weight loss expectorated sputum samples n Shortness of breath - Positive culture results from at least one bronchial n Hemoptysis wash or lavage n Bronchiectatic n Cavitary n Fibrocavitary - Transbronchial biopsy or other lung biopsy with Nodular mycobacterial histopathologic features and positive culture for NTM or biopsy showing mycobacterial histopathologic features and one or more sputum or bronchial washings that are culture positive for NTM

M. avium Treatment Algorithm Treatment of MAC Medical treatment options in refractory MAC MAC Initial Therapy

Change from 30% additional Yes Macrolide sensitive No Nodular/bronchiectatic intermittent to culture Cavitary Disease Disease daily therapy conversion Clofazimine DAILY clarithromycin 1000 mg clarithromycin 500-1000 Cavities Present Moxifloxacin Rifampin Macrolide tiw or azithromycin mg/day or azithromycin 30% additional Ciprofloxacin 500-600 mg tiw 250-500 mg/day Ethambutol Use of Linezolid/Tedizolid culture Additional drug clofazimine No Yes Bedaquilline conversion Ethambutol 25 mg/kg tiw 15 mg/kg day

3X/WEEK DAILY Use of inhaled 30% additional Azithromycin Azithromycin Add Rifamycin rifampin 600 mg tiw rifampin 450-600 mg/day liposomal culture Rifampin Rifampin IV Amikacin amikacin conversion Ethambutol Ethambutol Consider surgery Duration of treatment: Aminoglycoside None strep or amikacin 12 months of negative cultures

Treatment of M. abscessus Interpretation of extended clarithromycin susceptibility results for M. abscessus M. abscessus M. bolletti M. abscessus M. massiliense Clarithromycin Clarithromycin Macrolide M. abscessus Genetic Macrolide susceptibility susceptibility susceptibility subspecies implication Effect days 3–5 day 14 phenotype Yes “Functional” erm 41 gene No

M. massiliense Macrolide dysfunctional

Susceptible Susceptible anti-mycobacterial Macrolide? Imipenem (IV) Macrolide M. abscessus* susceptible erm(41) gene ≥2 other drugs Cefoxitin (IV) ≥1 other drug IV Amikacin Tigecycline (IV) IV Amikacin Linezolid/Tedizolid M. abscessus Inducible macrolide functional Susceptible Resistant immunomodulatory Clofazimine M. bolletii resistance erm(41) gene 2+ mos Moxifloxacin 1-2+ mos Bedaquiline High-level 23S ribosomal Macrolide? Macrolide constitutive Any Resistant Resistant RNA point immunomodulatory 1 other drug macrolide ≥2 other drugs Consider surgery for focal disease. ≥ mutation inhaled Amikacin Duration 12 mos culture negativity. inhaled Amikacin resistance

*15-20% of M. abscessus will have a dysfunctional ERM41 gene (c28 sequevar)

Surgical Treatment of Pulmonary NTM Disease Indications to consider surgery

n Massive hemoptysis n Cavitary lesions n Failure of medical therapy n Focal severe bronchiectasis

n Intolerance to medical therapy n Focal disease with M. abscessus infection

n Macrolide resistant MAC infection

1 Am J Respir Crit Care Med Vol 175. pp 367–416, 2007. | 2 Antimicrob Agents Chemother. 2015;59(8):4994-4996. 3 CHEST 2016; 149(5):1285-1293. | 4 Am J Respir Crit Care Med 2017; 195(6): 814–823. | 5 Thorax 2017;72(Suppl 2):ii1 National Jewish