MDR/XDR Tuberculosis and Atypical Mycobacterial Disease MDR/XDR Tuberculosis and Atypical Mycobacterial Disease Increasing Role for Surgery, Relearning.

MDR/XDR Tuberculosis and Atypical Mycobacterial Disease

Increasing Role for Surgery, Relearning Old Lessons

John D. Mitchell, M.D.Professor and ChiefSection of General Thoracic SurgeryDavis Endowed Chair in Thoracic SurgeryUniversity of Colorado School of MedicineConsultant, National Jewish Health

AATS Postgraduate Course, April 26th, 2015

No relevant financial relationships to disclose.

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

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

Case Presentation: XDR+ Tuberculosis

Drug Sensitivity Testing (CDC)

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

Case Presentation: XDR+ Tuberculosis

Treatment Course• Eventually rendered sputum culture (-)• Significant medication toxicities• Debilitated, malnourished

What is the role of surgery in this patient?

Mycobacterium TuberculosisGeneral 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

Worldwide Drug-Sensitive TB Treatment Success

2012

Worldwide Incidence of TuberculosisDecember, 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)

Multidrug and Extensively Drug Resistant Tuberculosis

Drug Susceptible Any DrugResistance

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

New Diagnostic Tests for MDRTBXpert 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

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

Worldwide MDRTB Treatment Success

2009

WHO Global Tuberculosis Report 2012. http://www.who.int/tb/publications/global_report/en/index.html

Worldwide XDRTB Treatment Success

2011

WHO Global Tuberculosis Report 2014. http://www.who.int/tb/publications/global_report/en/index.html

Drug Resistant TuberculosisPredictors of Success and Failure

• 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

Success Failure

Surgery for MDR-TB, XDR-TBFactors 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

Surgery for MDR-TBCurrent Results

Surgery for MDR-TBCurrent Results

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

Role of Surgery in MDR-TBNJH Experience

Odds Ratios for Individual Variables

Drug resistance (#)

Current drug suscept. (#)

Surgery done

FQN used

Non-extensive disease

Unfavorable Favorable

-1 -0.5 0 0.5 1 1.5 2

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

Surgery for MDR/XDR-TBRepublic of Georgia

Vashiakidze S et al. Ann Thorac Surg 2013;95:1892

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

Nontuberculous MycobacteriaComparison with Tuberculosis

TBNTM

AFB (+)

Person to person transmission

Reportable disease

Incidence increasing in US

Significant drug resistance seen

Nontuberculous MycobacteriaCommon NTM Species

• Slow growing mycobacteria– M. avium complex (MAC)– M. kansasii– M. xenopi– M. simiae

• Rapid growing mycobacteria– M. abscessus– M. fortuitum– M. chelonae

Nontuberculous MycobacteriaCommon NTM Species

• Slow growing mycobacteria– M. avium complex (MAC)– M. kansasii– M. xenopi– M. simiae

• Rapid growing mycobacteria– M. abscessus– M. fortuitum– M. chelonae

Nontuberculous MycobacteriaTherapy

• 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

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.

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.

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.

Surgery for Pulmonary NTM DiseaseResults 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

Pro

ced

ure

s

0

50

100

150

1983-1990 1991-2000 2001-

2

4

6

8

10

% M

ortality Rate

Mitchell JD et al Ann Thor Surg 2008;85(6):1887

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

Lung ResectionInfectious 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

Surgery for MDR-TB, XDR-TBSummary

• 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