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Nontuberculous Mycobacterial Infections

Charles L. Daley, MDNational Jewish Health

University of Colorado, Denver

Disclosures

• Insmed – site investigator for Phase II trial of inhaled liposomal amikacin in pulmonary NTM

Nontuberculous Mycobacterial Infections 

• What are nontuberculous mycobacteria (NTM)?

• Are NTM infections increasing?

• How do we diagnose NTM infections?

• How do we treat NTM infections?

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Taxonomy of Mycobacteria

• BacteriaKingdomKingdom

• ActinobacteriaPhylumPhylum

• ActinomycetalesOrderOrder

• CorynebacterineaeSuborderSuborder

• MycobacteriaceaeFamilyFamily

• MycobacteriumGenusGenus

• > 150 speciesSpeciesSpecies• M. tuberculosis complex

• M. leprae

• Nontuberculous mycobacteria 

NTM That Have Been Reported to Cause Lung Disease

Slowly Growing Mycobacteria Rapidly Growing Mycobacteria*

M. arupense M. kubicae M. abscessus M. holsaticum

M asiaticum M. lentiflavum M. alvei M. fortuitum

M. avium M. malmoense M. boenickei M. mageritense

M. branderi M. palustre M. bolletii M. massiliense

M. celatum M. saskatchewanse M. brumae M. mucogenicum

M. chimaera M. scrofulaceum M. chelonae M. peregrinum

M. florentinum M. shimodei M. confluentis M. phocaicum

M. heckeshornense M. simiae M. elephantis M. septicum

M. intermedium M. szulgai M. goodii M. thermoresistible

M. interjectum M. terrae

M. intracellulare M. triplex

M. kansasii M. xenopi

* Growth in subculture within 7 days

Nontuberculous Mycobacterial Infections Environmental Pathogens

• What are nontuberculous mycobacteria (NTM)?

• Are NTM infections increasing?

• How do we diagnose NTM infections?

• How do we treat NTM infections?

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Increasing rates of NTM

• The isolation of prevalence of pulmonary NTM isolates increased from 9.1/100,000 in 1997 to 14.1/100,000 in 2003 in Ontario, CA (Marras T, et al, Thorax 2007) 

• Annual prevalence of NTM pulmonary disease in hospitalized patients in the US increased at a rate of 6.5% for women, 3.2% for men (Adjemian et al, 2012, AJRCCM).

• The incidence of clinically significant pulmonary disease rose from 2.2/100,000 in 1999 to 3.2/100,000 in 2005 in Queensland, Australia (Thomson R, 2010, EID)

Prevalence of Pulmonary NTM Among Medicare Part B Enrollees by State

• A national representative 5% sample of Medicare Part B beneficiaries, 1997-2007• All subjects were ≥ 65 yrs

Adjemian J, et al. Am J Respir Crit Care Med 2012, epub

Incidence of Pulmonary NontuberculousMycobacterial Infection Over Time

Adjemian J, et al. Am J Respir Crit Care Med 2012, epub

8.2%/year

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Incidence of Pulmonary NTM Infections in Oregon, by Gender

Henkle E, et al. Annals ATS 2015;12:642

Why are NTM increasing?

• Exposure– Great exposure to aerosols

– Change in plumbing (copper to PVC, lower water temperatures)

• Diagnostics– More sensitive culture methods

– More CT scans

• Organism– Increased virulence?

• Host factors– Aging population, more lung disease

– More immunosuppressed patients

– Decreasing cross‐immunity to M. tuberculosis

NTM incidence

TB Incidence

Percentage of NTM/Myco

Brode SK, et al, IJTLD 2014

Systematic review n = 22 studies

Temporal trends in NTM• 75% had increasing rates• 12.5% had stable rates• 12.5% had declining rates

Proportion of myco disease due to NTM• Rising in 94% of

geographic areas

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Nontuberculous Mycobacterial Infections Environmental Pathogens

• What are nontuberculous mycobacteria (NTM)?

• Are NTM infections increasing?

• How do we diagnose NTM infections?

• How do we treat NTM infections?

Diagnosis of NTM Infections

Think about it!

Collect a specimen

Microscopic examination

Culture

Identification

Drug susceptibility

Diagnosis!8-12 weeks

Clinical Presentation

• Cough (chronic)

• Fatigue

• Weight loss

• Hemoptysis

• Dyspnea

• Bronchiectasis 

• COPD

• Pneumoconiosis

• Alveolar proteinosis

• Esophageal disorders

• Autoimmune disorders

• Immunocompromised

Symptoms/Signs Underlying Conditions

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Demographic and Clinical Characteristics of TB and NTM

• Younger age1,2

• Male2

• Foreign‐born2

• Constitutional symptoms2

• Older age1,2

• Female2

• Non smoker1

• Previous TB treatment1

• COPD2

• Immunosuppressive medications2

Associated with TB Associated with NTM

1Koh WJ, et al. Int J Tuber Lung Dis 2006:10:1001

2Kendall BA, et al. Emerg Infect Dis 2011;17:506

Age ≤ 50, not US born98% PPV for TB

Age > 50, US born, COPD92% PPV for NTM

Radiographic Presentation

Nodular Bronchiectatic Fibrocavitary

Chest CT Findings Consistent with TB or NTM Lung Disease

Study Number Findings c/w NTM Findings c/w TB

Lynch DA, 1995

15 TB55 MAC

Bronchiectasis (RML, lingula)

_

Primack SL,1995

45 TB32 MAC

Bronchiectasis Interlobular septal thickening

Chung MJ, 2006

113 DS TB35 MDR‐TB68 NTM

Bronchiectasis (extensive) Multiple cavities, MDR>NTM> TBPleural effusions

Koh WJ, 2006

229 TB70 NTM

Middle/lower zone distributionBilateral

Pleural effusionsUpper zone distributionUnilateral

Kahkouee S, 2013

43 MDR‐TB23 NTM

Thin walled cavities with satellite nodules

Thick walled cavities in background of consolidation“Fibrodestructive”Calcified parenchymaPleural effusions

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Mycobacterial Culture

• Cultures for mycobacteria should include both solid and liquid media

• Broth media have a higher yield and provide results more rapidly

• Solid media allow observation of colony morphology, growth rates, recognition of mixed cultures, and quantitation

• Drug susceptibility testing– MAC – test macrolide– M. kansasii – test rifampin– Rapid growers – multiple drugs ATS/IDSA AJRCCM 2007;175:367

Identification/Speciation

Line Probe

NAAT(MAC, M. avium, M. intracellulare, M. gordonae, M. kansasii, Mtb)

Sequencing

ATS Diagnostic Criteria For NTM Lung Disease

Clinical Cough, fatigue, weight loss

Radiograph • Nodular or cavitary opacities on chest radiograph or• High resolutation computed tomography showing multifocal bronchiectasis with multiple small nodules

Bacteriology • Positive culture results from at least two separate expectorated sputum samples• Positive culture results from at least one bronchial wash or lavage• Transbronchial biopsy or other lung biopsy with 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

ATS/IDSA AJRCCM 2007;175:367

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Case

• 35 year old Caucasian woman from Florida with cough for several weeks

Proportion of M. tuberculosis and NTM in AFB Smear + Specimens

Jeon K, et al. Int J Tuberc Lung Dis 2005;9:1046

NTM Among Suspected TB and MDR‐TB Cases in High Incidence Setting

Culture Confirmed

Study Location No. TB NTM

Aliyu G, 2013

Nigeria 1603 TB suspects

375 (85%) 69 (15.0%)

Xu K, 2014 China 13,882 TB suspects

1332 (94.5%) 78 (5.5%)

Tabarsi P, 2009

Iran 105 MDR‐TB suspects

? 12 (11.4%)

Shahraki A, 2015

Iran 117 MDR‐TB suspects

82* (70.0%) 35 (30.0%)

*63 had MDR-TB

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NTM Isolated in Culture‐confirmed Pulmonary TB

Study Location TB Patients

NTM  Met ATS Criteria*

Jun HJ, 2009

Seoul, Korea 958  113 (7.1%)

20 (17.7%)

Huang CT, 2009

Taipei, Taiwan 2133 154 (7.3%)

48 (31.1%)

Damaraju D, 2013

Ontario, Canada 369 40 (11.0%)

14 (35.0%)

* ≥ 2 cultures

NTM isolated during TB treatment may need to be treated

Nontuberculous Mycobacterial Infections Environmental Pathogens

• What are nontuberculous mycobacteria (NTM)?

• Are NTM infections increasing?

• How do we diagnose NTM infections?

• How do we treat NTM infections?

NTM Pulmonary InfectionsWhen to Treat?

• The Patient– Increased susceptibility?– Clinical symptoms and overall condition of patient– Extent of radiograph abnormalities and whether there

is evidence of progression

• The Organism– Species that has been isolated– Bacteriologic load (smear + vs. smear -)

• Overall goal of therapy?– Cure, bacteriologic conversion, relief of symptoms,

prevention of progression

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Clinical Relevance of Different Species: Netherlands and S. Korea

Van Ingen J, Koh WJ, Daley CL, unpublished

Treatment M. avium complex

MAC

Macrolide sensitive NoYes

DAILYRifampin

EthambutolOther drug

ClofazimineMoxifloxacinCiprofloxacinNew drug?

Add IV Amikacin

Duration :12 mos culture negativity

DAILYAzithromycin

RifampinEthambutol

3X/WEEKAzithromycin

RifampinEthambutol

Cavities Present

YesNo

Treatment Outcomes for MAC

Culture Conversion

Recurrence on Treatment

Recurrence after Treatment

Macrolide susceptible 14% (73% reinfection)

48% (75% reinfection)

Non cavitaryCavitary

80%<50%

Macrolide resistant NA NA

Surgery + aminoglycoside*No surgery/aminoglycoside

80%5%

NA – not available* ≥ 6 months IV aminoglycoside

Griffith DE, et al. AJRCCM 2006;174:928Wallace R, et al. Chest 2014:146:276-282Jeong BH, et al. AJRCCM 2015:191:96-103

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Case

• 68 year old woman with chronic cough and fatigue

M. abscessus

“Functional” erm41 gene NoYes

Macrolide?≥2 other drugs

Amikacin

Macrolide≥1 other drug

Amikacin

Imipenem (IV)Cefoxitin (IV)Tigecycline (IV)LinezolidClofazimineMoxifloxacinNew drug?

Macrolide?≥2 other drugs

Inhaled Amikacin

Macrolide≥1 other drug

Inhaled Amikacin

Treatment of M. abscessus complex

2+ mos 2+ mos

Duration 12 mos culture negativity

M. abscessusM. bolletii

M. massiliense

Treatment Outcomes for Pulmonary M. abscessus

Study Treatment N Success Failure Relapse

Griffith, 1993

TotalMedMed/surg

1541477

10 (6%)––

–––

–––

Jeon, 2009

TotalMed Med/surg

65–8

38 (58%)–

7 (88%)

18 (28%)––

9 (14%)––

Jarand, 2011

TotalMedMed/surg

694623

33 (48%)18 (39%)15 (65%)

20 (29%) 16 (23%)

Lyu,2011

TotalMedMed/surge

412417

33 (81%)23 (82%)10 (77%)

5 (12%)––

4 (12%)––

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Treatment Responses for Patients with M. abscessus and M. massiliense

Koh WJ, et al. Am J Respir Crit Care Med 2011;183:405-10

• Patients with M. massiliense are more likely to improve:– Symptoms: 97% vs.75%, p = 0.04– Radiographs: 82% vs. 42%, p = 0.003– Culture conversion: 88% vs. 25%, p < 0.001

• Why the difference in outcomes?– M. abscessus has erm(41) which results in acquired macrolide

resistance– M. massiliense has a deletion in erm(41) which renders it

nonfunctional

• Incubation of M. abscessus with clarithromycin led to rapid increase in MICs but not with M. massiliense

Case

45 year old African-American woman with SLE and chronic cough who relocated to Denver after Hurricane Katrina

Mycobacterium kansasiiTreatment Regimens

Drug Dose

Isoniazid 300 mg/dayRifampin 600 mg/dayor rifabutin 300 mg/day

Ethambutol 15mg/kg/day

Duration: At least 12 mos of negative sputum cultures

ATS/IDSA. AJRCCM 2007

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Mycobacterium kansasiiOutcomes of Treatment

Study N Regimen Duration mos

Conversion Cure* Failure Relapse

Ahn, 1983

40 H/R/ESM biw for 3 mo

12 Median – 5.5 weeks

ND 0 2.5%

BTS, 1994

173 R/E 9 89% by 3 mo 89% 1 9.7%

Sauret, 1995

1414

H/R/EH/R/E

1218

100%, mean-4.5±2.0

93%100%

0 3.5%0

Evans, 1996

47 H/R/E±Z Mean-10.3

ND 79% ND 0

Santin,2009

75 H/R/ESM for 2-3 mo

12 ND 83% 0 6.6%

Park, 2010

31 H/R/E Median-16 Median – 1 mo95% by 12 mo

52% 0 6%

*Cure was nearly 100% when non-mycobacterial deaths and lost to follow-up patients are excluded

Video‐assisted Thoracic SurgeryVATS

Treatment of M. avium complexSurgery

Surgery

35 year old Caucasian woman from Florida with cough for several weeks who grew M. avium complex

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Treatment of M. abscessusSurgery

56 year old Caucasian woman who developed hemoptysis in December 2004. Grew MAC and M. abscessus.

Video‐assisted Thoracoscopic Surgery for Pulmonary NTM

• Site: University of Colorado Denver

• 134 NTM patients

• VATS resection

• Outcomes

– Operative mortality – 0%

– Conversion to thoracotomy – 3%

– Post‐op complications – 7%

– Mean length of stay – 3.3 days

Yu JA, et al. Eur J Cardio-Thorac Surg 2011:40:671

Summary

• NTM infections appear to be increasing in many countries

• Diagnosis should consider the clinical and radiographic presentation –it may be difficult to distinguish NTM from TB

• The decision to treat should be based on at least three factors; patient, organism (species and bacterial load) and goals of treatment

• Treatment is complex and outcomes remain suboptimal

• New drugs and treatment regimens are needed