2. Danger in the Water Theodore Marras MD FRCPC University of Toronto & University Health Network

3. Potential conflicts of interest Financial – none Other – clinical and academic interest in pulmonary NTM disease (especially epidemiology, long term outcomes) Off label use of therapies None of the medications mentioned have a formal indication for the treatment of pulmonary NTM disease Declarations

4. 1.Identify relevant potential infective exposures 2.Review management of pMAC: –Recommended drug treatment –Approach to comprehensive management 3.Review data on treatment outcomes 4.Combining knowledge of: –Environment / interventions (relevance, uncertainty) –Treatment outcomes … to better inform clinical decisions Objectives - Pulmonary Mycobacterium avium complex (pMAC)

5. Background

6. Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly Diagnosis

7. Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly Diagnosis

8. Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly Diagnosis

9. Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly Diagnosis

10. Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly DiagnosisMicro +Micro

11. Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly DiagnosisMicro / Clin / RadMicro

12. “Disease” Criteria ClinicalPulmonary symptoms, or Nodules or cavities on CXR, or Multifocal bronchiectasis & multiple small nodules on HRCT (and exclusion of other diagnoses) MicroWith > 2 sputa  2 cultures + With 1 BAL/wash  1 BAL/wash + With biopsy  1 biopsy culture +, or 1 culture + and bx evidence of disease Pulmonary NTM Disease - ATS / IDSA 2007

13. Age and sex distribution

14. Increasingly common disease of the elderly in Ontario

15. Where does it come from?

16. Moist environments –Natural and treated water –Soils Very disinfectant resistant The Water we Drink - MAC

18. Hot Tub Lung: Hypersensitivity Pneumonitis to NTM Embil et al.Chest 19975 Kahana et al.Chest 19971 Mangione et al.Emerg Inf Dis 20015 Case recordNEJM 20001 Khoor et al.Am J Clin Pathol 200110 Rickman et al.Mayo Clin Proc 20022 Cappelluti et al.Arch Intern Med 20031 Pham et al.J Thoracic Imaging 20031 Grimes et al.Respiration 20011 AksamitRespir Infect 20039 Lumb et al.Appl Environ Micro 20044 Systrom & WittramNEJM 20051 TOTAL41

21. Study Design Pulmonary NTM Source of infection … Multiple respiratory samples and shower and bathtub specimens grew MAC, with matching PFGE patterns… Hypersensitivity Pneumonitis Reaction to Mycobacterium avium in Household Water* Theodore K. Marras, MD; Richard J. Wallace, Jr., MD, FCCP; Laura L. Koth, MD; Michael S. Stulbarg, MD;† Clayton T. Cowl, MD, FCCP; and Charles L. Daley, MD (CHEST 2005; 127:664–671)

22. Pulmonary NTM Source of infection … M. avium isolated from showerhead water and biofilm in the home of a woman with M. avium disease. DNA fingerprinting demonstrated identical M. avium isolates from showerhead and patient … Mycobacterium avium in a shower linked to pulmonary disease Joseph O. Falkinham III, Michael D. Iseman, Petra de Haas and Dick van Soolingen J Water Health 06(2):209–213

24. Study Design Occupational soil exposure - risk factor for MAC skin test reactivity MAC skin testing - Soil exposure

25. Study Design Occupational soil exposure - risk factor for MAC skin test reactivity MAC skin testing - Soil exposure StudyPopulationRisk Factor Odds Ratio (95% CI) P value Reed Am J Epi 2006 Random sample, West Palm Beach FL (N=447) Soil occupation (> 6 years) 2.7 (1.3-6.0) 0.01 Khan AJRCCM 2007 Representative sample, USA (N=7,384) Farming / Construction 1.43 (1.07-1.92) 0.02

26. Study Design Occupational soil exposure - risk factor for MAC skin test reactivity MAC skin testing - Soil exposure StudyPopulationRisk Factor Odds Ratio (95% CI) P value Reed Am J Epi 2006 Random sample, West Palm Beach FL (N=447) Soil occupation (> 6 years) 2.7 (1.3-6.0) 0.01 Khan AJRCCM 2007 Representative sample, USA (N=7,384) Farming / Construction 1.43 (1.07-1.92) 0.02

27. Study Design Occupational soil exposure - risk factor for MAC skin test reactivity MAC skin testing - Soil exposure StudyPopulationRisk Factor Odds Ratio (95% CI) P value Reed Am J Epi 2006 Random sample, West Palm Beach FL (N=447) Soil occupation (> 6 years) 2.7 (1.3-6.0) 0.01 Khan AJRCCM 2007 Representative sample, USA (N=7,384) Farming / Construction 1.43 (1.07-1.92) 0.02

28. High numbers of … M. avium, M. intracellulare, and M. chelonae, recovered from aerosols produced by pouring commercial potting soil and potting soil samples provided by patients with pulmonary mycobacterial infections. Dominant mycobacteria in soil samples corresponded to dominant species implicated clinically. Pulsed-field gel electrophoresis demonstrated a closely related pair of M. avium isolates recovered from a patient and from that patient’s own potting soil. App Env Microbiol 2006; 72:7602-6. Pulmonary NTM Source of infection

29. Management of pMAC

30. “Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients” - ATS / IDSA 2007 ATS / IDSA guidelines - Diagnosis  Treatment Symptoms + Imaging + Cultures = NTM Disease

31. “Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients” - ATS / IDSA 2007 ATS / IDSA guidelines - Diagnosis  Treatment Symptoms + Imaging + Cultures = NTM Disease

32. When to treat? Micro – R epeated isolates / AFB smear + Symptoms –Systemic* – fatigue, fever/sweat, weight loss –Local – cough, sputum, hemoptysis, dyspnea Significant burden on imaging –Consolidation, nodules, cavities … –Progression Pulmonary NTM - Diagnosis  Treatment

33. Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

34. Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

35. Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

36. Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

37. Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

38. ATS / IDSA guidelines - Drug treatment – MAC Drug / class Disease type FibronodularCavitary or Advanced / recurrent MACROLIDE Clari 1000 tiw or Azi 500-600 tiw Clari 500-1000 qd or Azi 250-300 qd Ethambutol20-25 mg/kg tiw15 mg/kg/d RifamycinRMP 600 tiw RMP 450-600 qd or RFB 150-300 qd Amikacin (SM, KM) Not recommended Consider / recommended (10-15 mg/kg/d)

39. ATS / IDSA guidelines - Drug treatment – MAC Drug / class Disease type FibronodularCavitary or Advanced / recurrent MACROLIDE Clari 1000 tiw or Azi 500-600 tiw Clari 500-1000 qd or Azi 250-300 qd Ethambutol20-25 mg/kg tiw15 mg/kg/d RifamycinRMP 600 tiw RMP 450-600 qd or RFB 150-300 qd Amikacin (SM, KM) Not recommended Consider / recommended (10-15 mg/kg/d) Other agents - Fluoroquinolones, clofazimine, linezolid

40. When to stop? Sputum cultures negative for 12 months Pulmonary NTM - Treatment duration

41. Comprehensive management

42. Start with guidelines Expect drug intolerance (staggered start) Macrolides whenever possible Amikacin for advanced cases* Fluoroquinolones, clofazimine, linezolid as needed / tolerated Aim for >3 drugs* –More drugs, higher doses  greater efficacy Tailor therapy –Switch drugs to minimize AE’s –Re-evaluate objectives based on response, toxicity * When treating intensively Pulmonary MAC - Drugs

43. Other interventions Nutrition Bronchodilators / Inhaled steroids? Pulmonary hygiene Surgery Avoid exposure –Hot tubs –Shower? Pulmonary MAC - Treatment – Other

44. Other interventions Nutrition Bronchodilators / Inhaled steroids? Pulmonary hygiene Surgery Avoid exposure –Hot tubs –Shower? Pulmonary MAC - Treatment – Other

45. Other interventions Nutrition Bronchodilators / Inhaled steroids? Pulmonary hygiene Surgery Avoid exposure –Hot tubs –Shower? Pulmonary MAC - Treatment – Other

46. Other interventions Nutrition Bronchodilators / Inhaled steroids? Pulmonary hygiene Surgery (?) Pulmonary MAC - Treatment – Other

47. Pulmonary MAC - Following patients on therapy Assess response Microbiologic – sputum q 2-4 months Clinical – periodic Radiographic – LDCT scan 4-6 mo, then q 6-12 mo Follow for drug toxicities Education  important toxicity stop drugs Clinical Rifamycin  CBC, liver tests Ethambutol  visual acuity, colour etc. Amikacin  ‘lytes, creatinine, serum level, audiograms

48. Outcomes

49. Clinical practice (geographic region) Leeds, UK; MAC 1999-2001 41% disease recurrence or mortality at 2 years post treatment Henry, ERJ 2004 pNTM – a chronic disease? - Clinical practice

50. Clinical practice (specialty clinic) 50% didn’t achieve sputum culture conversion 60% didn’t tolerate initial antibiotics 85% remain symptomatic Huang, Chest 1999 pNTM – a chronic disease? - Clinical practice

51. StudyRx (months) NSputum convert (%)Success (%) PPITTPPITT Dautzenberg ’95123977657765 Wallace ’96> 54897758667 Roussel ‘98152967485741 Griffith ’98> 66866566656 Tanaka ’9964672616348 Huang ’99>122771373619 Griffith ‘00> 65978547854 Griffith ‘011210361546154 Field ’02> 530100878170 Kobashi ‘03127158 32 Fujikane ’05>613797798266 Lam ’06129121138353 Kobashi ’07247357511412 Kobashi ’072414661 18 Jenkins ’082417090 33 Total (weighted)-1,13772%62%50%43% pNTM – a chronic disease? - Clinical studies

52. Study Follow-up (months) N Recurrence N% Huang ’99<72273/1030 Kobashi ’0736-487321/3757 Kobashi ’073614629/8933 Total (weighted)-24653/13639% pNTM – a chronic disease? - Recurrence

53. Treatment –Poorly tolerated –Suboptimal efficacy Pulmonary MAC (NTM) - Chronicity

54. Treatment –Poorly tolerated –Suboptimal efficacy Cause(s) not identified or reversible –Host defect –Exposure remains… Pulmonary MAC (NTM) - Chronicity

55. Am J Resp Crit Care Med 2007, 175:367-416 Canadian Tuberculosis Standards, 6 th ed www.ntminfo.org