1. MDR/XDR Tuberculosis and Atypical Mycobacterial Disease MDR/XDR Tuberculosis and Atypical Mycobacterial Disease Increasing Role for Surgery, Relearning Old Lessons John D. Mitchell, M.D. Professor and Chief Section of General Thoracic Surgery Davis Endowed Chair in Thoracic Surgery University of Colorado School of Medicine Consultant, National Jewish Health AATS Postgraduate Course, April 26 th, 2015

2. No relevant financial relationships to disclose.

4. Case Presentation: XDR+ Tuberculosis History 38 yo male Armenian immigrant Lived in Russia 2001-2005; last visit 4 years prior No known history in Russian Prison System Ankylosing Spondylitis, prior GSW to abdomen Alcoholic, smoker 1.5 packs/day History of recurrent pneumonias, AFB (-) July 2013: Started on Remicade for AS, INH for LTBI Dec 2013: Fevers, productive cough; AFB (+) Diagnosed with drug resistant TB

5. Case Presentation: XDR+ Tuberculosis Initial Drug Regimen PZA 1500 mg po qday Moxifloxacin 600 mg po qday PAS 4 gm po bid Linezolid 600 mg po qday Ethionamide 250 mg qAM, 500 mg qPM Cycloserine 250 mg po bid Capreomycin 750 mg (12 mg/kg) IV qMon-Fri Meropenem 2 gm IV q8h Augmentin 500 mg po bid

15. Case Presentation: XDR+ Tuberculosis Drug Sensitivity Testing (CDC)

16. Case Presentation: XDR+ Tuberculosis Revised Drug Regimen Linezolid 600 mg IV q24h Cycloserine 250 mg po bid Imipenem 1 gm IV q12h Moxifloxacin 800 mg IV q24h PAS 6 gm po bid Bedaquiline 400 mg po qday Clofazimine 100 mg po qday

17. Case Presentation: XDR+ Tuberculosis Treatment Course Eventually rendered sputum culture (-) Significant medication toxicities Debilitated, malnourished What is the role of surgery in this patient?

19. Mycobacterium Tuberculosis General Principles Up to one-third of world’s population infected with mycobacterium tuberculosis Typical treatment regimens for drug-sensitive TB last 6 to 9 months –INH, rifampin, PZA, ethambutol –Duration and specific regimen depend on pattern of disease and drug sensitivities, speed of culture conversion Chemotherapy usually curative; use of surgery rare

20. Worldwide Drug-Sensitive TB Treatment Success 2012

21. Worldwide Incidence of Tuberculosis December, 2013 WHO Global Tuberculosis Report 2014. http://www.who.int/tb/publications/global_report/en/index.html Estimated number of cases, 2013 Estimated number of deaths, 2013 1.1 million* (1.0–1.3 million) 9.0 million (8.6–9.4 million) 480,000 (350,000-610,000) All forms of TB Multidrug- resistant TB HIV-associated TB 1.1 million (1.0–1.2 million) 360,000 (310,000–410,000) * Excluding deaths attributed to HIV/TB 210,000 (130,000–290,000)

22. Multidrug and Extensively Drug Resistant Tuberculosis Drug Susceptible Any Drug Resistance MDR-TB XDR- TB Resistance to at least isoniazid and rifampin (MDR) plus resistance to fluoroquinolones and one of the second-line injectable drugs (amikacin, kanamycin, or capreomycin ) 9 million TB cases

26. New Diagnostic Tests for MDRTB Xpert MTB/RIF Assay Automated PCR test that detects TB and rifampin resistance 2 hour turn around time Allows Point of Care diagnosis, treatment Funded by Gates Foundation, NIH

27. Designing a Treatment Regimen for MDRTB General Principles Early DR-TB detection/prompt initiation of therapy Regimens should be based on: the history of drugs taken by the patient drugs and regimens used in the country and the prevalence of resistance Regimens should consist ≥ 4 effective drugs When possible, once daily dosing is recommended Drug dosage should be determined by body weight WHO Guidelines for the Programmatic Management of Drug-Resistant TB2008

28. Worldwide MDRTB Treatment Success 2009 WHO Global Tuberculosis Report 2012. http://www.who.int/tb/publications/global_report/en/index.html

30. Worldwide XDRTB Treatment Success 2011 WHO Global Tuberculosis Report 2014. http://www.who.int/tb/publications/global_report/en/index.html

31. Drug Resistant Tuberculosis Predictors of Success and Fai lure Use of pyrazinamide and/or ethambutol, if susceptible Use of a fluoroquinolone Use of > 5 drugs Sputum conversion by 2 mos Surgical resection Previous therapy Number of drugs resistant Resistance to FQN Resistance to capreomycin Presence of cavitation Low BMI HIV infection Poor adherence Positive cultures at 2-3 mos XDR-TB SuccessFailure

32. Surgery for MDR-TB, XDR-TB Factors favoring Surgery A pattern of drug-resistance so extensive that it compromises the likelihood of medical cure Localized lung damage (cavitation, destroyed lung) that might be a focus of persistent disease and/or further acquired resistance Allergies or intolerance to essential medications that might afford cure Lack of access to curative chemotherapy

33. Surgery for MDR-TB Current Results

34. Xu HB, et al. J Antimicrob Chemother 2011; 66: 1687–1695

35. Role of Surgery in MDR-TB NJH Experience Odds Ratios for Individual Variables Drug resistance (#) Current drug suscept. (#) Surgery done FQN used Non-extensive disease Unfavorable Favorable -0.5 00.511.52 p<0.0001 p=0.0004 p=0.0008 p=0.02 p=0.48 log OR Chan ED, et al. AJRCCM 2004:169:1103

36. Surgery for MDR/XDR-TB Republic of Georgia Vashiakidze S et al. Ann Thorac Surg 2013;95:1892

37. Nontuberculous Mycobacteria (NTM) AKA: Atypical mycobacteria Environmental mycobacteria (EM) Mycobacteria other than tuberculosis (MOTT) Found in water, soils, food, on surfaces Resistant to chlorination, disinfectants Not obligate pathogens No person to person disease transmission

38. Nontuberculous Mycobacteria Comparison with Tuberculosis TBNTM AFB (+)   Person to person transmission  Reportable disease  Incidence increasing in US  Significant drug resistance seen  

39. Nontuberculous Mycobacteria Common NTM Species Slow growing mycobacteria –M. avium complex (MAC) –M. kansasii –M. xenopi –M. simiae Rapid growing mycobacteria –M. abscessus –M. fortuitum –M. chelonae

40. Nontuberculous Mycobacteria Common NTM Species Slow growing mycobacteria –M. avium complex (MAC) –M. kansasii –M. xenopi –M. simiae Rapid growing mycobacteria –M. abscessus –M. fortuitum –M. chelonae

41. Nontuberculous Mycobacteria Therapy Therapy directed in part by susceptibility testing, and should be continued 12 months after Culture (-) MAC: macrolide, rifampin, ethambutol, ± amikacin M kansasii: rifampin, ethambutol, INH ± macrolide M abscessus: macrolide, amikacin, cefoxitin, imipenum Indications for surgery include persistent, focal (cavitary or bronchiectatic) parenchymal disease after antimicrobial treatment

42. Surgery for Pulmonary NTM Disease Presentation Middle-aged females, thin, Caucasian, nonsmokers, right middle lobe / lingular disease Isolated large, thick-walled cavitary disease. Elderly men, smokers, ETOH abuse, underlying COPD. Resembles TB, may progress to complete lung destruction.

43. Surgery for Pulmonary NTM Disease Presentation Middle-aged females, thin, Caucasian, nonsmokers, right middle lobe / lingular disease Isolated large, thick-walled cavitary disease. Elderly men, smokers, ETOH abuse, underlying COPD. Resembles TB, may progress to complete lung destruction.

44. Surgery for Pulmonary NTM Disease Presentation Middle-aged females, thin, Caucasian, nonsmokers, right middle lobe / lingular disease Isolated large, thick-walled cavitary disease. Elderly men, smokers, ETOH abuse, underlying COPD. Resembles TB, may progress to complete lung destruction.

45. Surgery for Pulmonary NTM Disease Results of Surgical Therapy Corpe, 1981: 131 cases, mortality 6.9%, BPF 5.3%, 93% sputum conversion rate Nelson, 1998: 28 cases, mortality 7.1%, BPF 3.6%, complication rate 32%, 88% sputum conversion rate Shiraishi, 2002: 21 cases, mortality 0%, complication rate 29%, sputum conversion 100% → 90% at 2 years Mitchell, 2008: 265 cases, mortality 2.6%, complication rate 18%, BPF 4.2%, 87% sputum conversion rate

46. Procedures 0 50 100 150 1983-19901991-20002001- 2 4 6 8 10 % Mortality Rate Mitchell JD et al Ann Thor Surg 2008;85(6):1887

47. Surgery for Pulmonary NTM Disease BPF after Pneumonectomy Shiraishi, 2010: MDR-TB vs. NTM pneumonectomy No operative mortality MDR-TB: 22 patients (7 right, 15 left) –Male 72%, Sputum negative 63% –BPF rate 4.5% (1 right) NTM: 11 patients (7 right, 4 left) –Female 72%, Sputum negative 9% –BPF rate 45% (4 right, 1 left) Shiraishi Y et al. ICVTS 2010;11:429

48. Lung Resection Infectious vs. Malignant Lung Disease Adhesions Hypertrophied bronchial circulation Lymphadenopathy Dissection in hilum / around vessels Avoid spillage from cavities Space vs. no space Buttressing bronchial stump Send cultures! Anatomic complete resection is the goal

55. Surgery for MDR-TB, XDR-TB Summary Surgical resection in MDR/XDR TB and NTM disease may lead to improved outcomes in selected cases Lung resection and muscle flap use often possible using modern minimally invasive techniques Coordination of care best approached in multidisciplinary environment Resection for infectious lung disease differs from resection for cancer: experience counts