Nontuberculous Mycobacteria Epidemiology and Clinical Management Kevin L. Winthrop, MD, MPH Associate Professor, Divisions of Infectious Diseases, Public Health and Preventive Medicine Oregon Health & Science University Disclosures NTM Research funding Insmed NIH American Lung Association NTMir Nontuberculous Mycobacterium (NTM) MOTT Environmental organisms Soil, lakes, rivers Municipal water systems (yes, including your tap at home) Biofilm where water flows Live with amoeba, legionella, others 1
Nontuberculous Mycobacterium (NTM) Slow growers MAC, M. kansasii, M. marinum, M. xenopi Rapid growers (RGM) M. abscessus, M. chelonae, M. fortuitum 100+ species and growing 16s rdna gene sequencing Too many PhD candidates My favorite Proposed name: M. jacuzzii Surgical outbreak of skin infections 15 cases following breast augmentation Linked to one surgeon Cultures Surgeon s hair, face, eyebrows, nose, ears, and groin Surgeon s home jacuzzi All grew identical NTM isolates similar to M. smegmatis Rahav et al. CID 2006 Environment? Host? Killer showerheads? Related to publication by Feazel et al: Opportunistic pathogens enriched in showerhead biofilms. PNAS 2009: 38: 16393-16399 2
Pulmonary NTM? 16,810 NTM Disease Manifestations (Larger image on next page) Henkle E, et al. (abstract) ATS 2014 77% of NTM disease is pulmonary 3
NTM Disease Manifestations Henkle E, et al. (abstract) ATS 2014 77% of NTM disease is pulmonary
Pulmonary NTM Most common in US M. avium complex (MAC), M. kansasii, M. abscessus 2007 ATS/IDSA diagnostic criteria Patient with radiographic evidence of disease and pulmonary symptoms AND At least 2 sputum cultures positive, or One BAL or tissue specimen with positive culture, or Tissue with granulomatous histopathology in conjunction with positive culture (BAL or sputum) Griffith D et al. AJRCCM 2007 Marras T, et al. EID 2013 Increasing Rates with Age Prevots et al. AJRCCM 2010 4
Distribution of Disease Hoefsloot W, et al Eur Respir J 2013
Distribution of Disease (Larger image on previous page) Hoefsloot W, et al Eur Respir J 2013 Two Disease Types Older male, smoker, COPD Apical cavitary or fibronodular disease More rapidly progressive Older female ( Lady-Windermere ) Scoliosis, thin, pectus deformities*, hypomastia, mitral valve prolapse Nodular and interstitial nodular infiltrate Bronchiectasis right middle lobe / lingula Bronchiolitis ( tree and bud ) on HRCT Slowly progressive *Iseman MD et al. Am Rev Respir Dis. 1991 Disease Characteristics Differ by Sex Winthrop et al. AJRCCM 2010 5
Risk Factors for Pulmonary NTM Primarily from case series level data Underlying lung architectural abnormalities Bronchiectasis, cystic fibrosis Alpha-one antitrypsin, emphysema Prior TB or other infection GERD with micro-aspiration Exposure/transmission information lacking Gardening? Hot tubs? 6
MAC Therapeutic Options Diagnosis decision to treat Observation vs. suppression vs. cure Treatment best defined for MAC Macrolide, rifampin, ethambutol Amikacin (parenteral or inhaled PRN) 18-24 months (12 month culture negative) No macrolide monotherapy TIW okay if non-cavitary or not re-infection Griffith DG, et al. AJRCCM 2007 TIW vs. Daily Therapy Institutional-based series 180 pulmonary MAC patients Retrospective review of treatment outcomes 94% bronchiectatic and 98% non-cavitary 85% converted culture Similar between regimens (most switched to TIW) No difference between macrolides 48% relapses with positive culture post-treatment Wallace R, et al Chest 2014 (Larger image on next page) Wallace R, et al Chest 2014 7
Wallace R, et al Chest 2014
Wallace R, et al Chest 2014
(Larger image on previous page) Wallace R, et al Chest 2014 M. kansasii M. Kansasii clinical presentation more like TB Thin-walled cavities and upper lobe disease common Treatment with INH, RIF, EMB TIW therapy probably fine 12 months culture negativity High treatment success rates (90%+) Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. ATS/CDC/IDSA AJRCCM 2007 Rapidly Progressive Disease 10 weeks while on therapy 8
M. abscessus Therapy Cure = rare (often treat off and on forever) More rapidly progressive or relentless than MAC 3-4 drugs for 18-24 months 4-6 months induction phase suppressive strategy thereafter Rotational parenteral based regimen Parenteral Drugs Limited antibiotic options based upon susceptibility testing Parenteral agents Tigecycline 50mg daily Cefoxitin 2gm TID, Imipenam 500-1000mg BID Amikacin 10mg/kg TIW M. abscessus Oral antibiotics---also very limited options Rarely macrolides Clofazimine Rarely moxifloxacin/ciprofloxacin Rarely linezolid Surgery for limited disease Jarand et al. CID 2011 9
Erythromycin Methylase Gene erm(41) Koh et al. AJRCCM 2011
Erythromycin Methylase Gene erm(41) (Larger image on previous page) Koh et al. AJRCCM 2011 M. Abscessus (massiliense) Person-to-Person Transmission Repetitive unit-sequence based polymerase chain reaction Aitken ML, et al Am J Respir Crit Care Med 2012 Pulmonary Hygiene 10
Extrapulmonary NTM Immunocompetent settings Most infections occur 1-6 weeks after contact with contaminated water Nail salon, trauma, surgical or injection procedures, fishtank or other acquatic exposure Rapid or slow growing NTM Pediatric lymphadenitis Males > females, age 1-2 years old Children under 5 years NTM > TB 11
M. chelonae post plastic surgery M. marinum---fishtank granuloma Treatment Macrolides, sulfonamides, doxycycline, rifampin, ethambutol. Treat with 2 agents X 3-4 months. Surgical debridement if necessary. 12
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IMID Biologic Therapies TNF- inhibition Infliximab, adalimumab, golimumab, certolizumab (monoclonal antibodies) Etanercept (soluble p75 receptor) Other Biologics CD4 co-stimulation modulator: abatacept B-cell (CD20+) antibody: rituximab Anti-IL-6 receptor antibody: tocilizumab Anti- IL12/IL23 antibody: ustekinumab Small molecules: tofacitinib Winthrop KL et al. Ann Rheum Dis 2013; Winthrop KL Nat Rheum Rev 2013 14
Acknowledgements Close colleagues and friends at variety of institutions including: NJMC Mayo UT Tyler NIH Univ. Ontario U Florida CDC ATS/IDSA Cystic Fibrosis Registry (Larger image on next page) Nested case-control study Incident positive AFB culture in 2011 Controls with negative cultures 2010 and 2011 Binder A, et al American J of Clin Microbiology 2013 Chronic Macrolide Use Protective Against NTM (Larger image on next page) Binder A, et al American J of Clin Microbiology 2013 15
Cystic Fibrosis Registry Nested case-control study Incident positive AFB culture in 2011 Controls with negative cultures 2010 and 2011 Binder A, et al American J of Clin Microbiology 2013
Chronic Macrolide Use Protective Against NTM Binder A, et al American J of Clin Microbiology 2013