Non-tuberculous mycobacteria (NTMs) and lung disease

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• Non-tuberculous mycobacteria (NTMs) and lung
  disease
• Turkish Thoracic Society
• 16th Annual Conference

Philip Hopewell, MD Curry International
Tuberculosis Center University of California, San
Francisco
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Non-tuberculous mycobacteria (NTMs)

• At least 140 species identified
• Pathogenicity is highly variable
• Isolated from many environmental sources,
  generally moist sites
• Can cause disease in almost any structure or
  tissue
• At least 40 reported as a cause of lung disease
• Distribution differs by geography
• Incidence/prevalence appears to be increasing
• Diagnosis of disease (vs. colonization) may be
  difficult
• Response to treatment is slow and often incomplete

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NTMs and lung disease
gt 7 days
lt 7 days
3
frequent
more pathogenic
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MAC
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2
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Daley CL, Griffith DE. IJTLD 201014
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NTMs gross appearance
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NTMs in Izmir
Isolates in 31 of 77 patients thought to be
causative agents of lung disease.

• MAC 13 (42) M. Szulgai 2
  (6.5)
• M. abcessus 5 (16) M. Simiae 2
  (6.5)
• M. Kansasii 5 (16) M. scrofulaceum
  1 (3.2)
• M. fortuitum 2 (6.5) M. not
  speciated 1 (3.2)

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NTMs in Istanbul
Unidentified 43 (57) M.
fortuitum 3(8) M. Abcessus 9 (28)
M. Szulgai 3 (8) M. Avium complex 8
(25) M. neonarum 1 (2) M.
Kansasii 5 (16) M. Gordonae 6(16)
Total 75
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ATS/IDSA diagnostic criteria

• Clinical (both required)
• 1. Pulmonary symptoms, nodular or cavitary
  opacities on chest radiograph, or a
  high-resolution CTscan with multifocal
  bronchiectasis and multiple small nodules and
• 2. Appropriate exclusion of other diagnoses
• Microbiological
• 1. Positive cultures from at least two sputum
  samples. or
• 2. Positive culture result from at least one
  bronchial wash or lavage or

Griffith DE et al AJRCCM. 2007175
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ATS/IDSA diagnostic criteria

• Histological ( microbiological)
• 1. Transbronchial or other lung biopsy with
  mycobacterial histopathologic features
  (granulomatous inflammation or AFB) and positive
  culture for NTM or
• 2. Biopsy showing mycobacterial histopathologic
  features (granulomatous inflammation or AFB) and
  one or more sputum or bronchial washings that are
  culture positive for NTM

Griffith DE et al AJRCCM. 2007175
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NTMs and lung disease Risk factors

• Structural defects
• Bronchiectasis
• COPD
• Cystic fibrosis
• Previous TB
• Lady Windermere syndrome (?)
• Impaired systemic immunity
• Inherited deficiency
• Acquired deficiency HIV, immunosupressive therapy

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MAC disease Clinical patterns

• Bronchiectatic/cavitary disease
• Middle lobe/lingular bronchiectasis (Lady
  Windermere syndrome)
• Disseminated MAC
• Hypersensitivity pneumonitis (hot tub lung)

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M. avium disease and COPD
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M. avium middle lobe/lingular bronchiectasis
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M. avium progression
18 months
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Disseminated MAC in HIV
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MAC in HIV lymph node biopsy
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M. Avium hypersensitivity pneumonitis
Marras TK, et al. Chest. 2005 127
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MAC hot tub lung findings
Marras TK, et al. Chest. 2005 127
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Treatment of MAC pulmonary disease

• Nodular/bronchiectatic (mild) disease
• clarithromycin (1,000 mg) or azithromycin (500
  mg),
• rifampin (600 mg), and
• ethambutol (25 mg/kg)
• Fibrocavitary or severe nodular/bronchiectatic
  disease
• clarithromycin (5001,000 mg) or azithromycin
  (250 mg),
• rifampin (600 mg) or rifabutin (150300 mg),
• ethambutol (15 mg/kg)
• consider three times-weekly amikacin or
  streptomycin early in therapy
• Patients should be treated until culture negative
  on therapy for 1 year.
• Hypersensitivity
• Macrolide and rifampin corticosteroid (?)

three times weekly
daily
Griffith DE et al AJRCCM. 2007175
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Treatment and prevention of disseminated MAC
disease in HIV

• Disseminated MAC disease
• clarithromycin (1,000 mg/d) or azithromycin (250
  mg/d) and ethambutol (15 mg/kg/d) with or without
  rifabutin (150350 mg/d) daily.
• Prophylaxis (AIDS with CD4 counts less than 50)
• Azithromycin 1,200 mg/week or clarithromycin
  1,000 mg/day
• Rifabutin 300 mg/day (effective, less well
  tolerated)

Griffith DE et al AJRCCM. 2007175
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MAC surgical treatment

• There are no established criteria for patient
  selection.
• There are potentially severe perioperative
  complications.
• There are few centers with extensive experience
  with mycobacterial surgery.
• Surgical resection of limited (focal) disease in
  a patient with adequate cardiopulmonary reserve
  to withstand partial or complete lung resection
  can be successful in combination with multidrug
  treatment regimens for treating MAC lung disease
• Surgical resection of a solitary pulmonary nodule
  due to MAC is considered curative.
• Mycobacterial lung disease surgery should be
  performed in centers with expertise in both
  medical and surgical management of mycobacterial
  diseases.

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San Francisco General Hospital
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Treatment of M. kansasii and M. abcessus
pulmonary disease

• M. kansasii
• isoniazid (300 mg), rifampin (600 m), ethambutol
  (15 mg/kg) daily
• Treat until culture negative on therapy for 1
  year.
• M. abcessus
• no proven antibiotic regimen.
• only predictably curative therapy of limited lung
  disease is surgical resection combined with
  multidrug chemotherapy
• administration of multidrug therapy, including a
  macrolide and one or more parenteral agents
  (amikacin, cefoxitin, or imipenem) or a
  combination of parenteral agents may help control
  symptoms and progression.

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Treatment M. Malmoense and M.xenopipulmonary
disease

• Optimum regimens are not established for either
  agent.
• M. Malmoense
• rifampicin, ethambutol isoniazid, macrolide,
  fluoroquinolone
• M. xenopi
• rifampicin, ethambutol, macrolide

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NTMs environmental sources

• Natural waters
• Drinking water distribution systems
• Biofilms in drinking water distribution systems
• Building, hospital, and household plumbing
• Hot tubs and spas
• Natural and household / building aerosols
• Boreal forest soils and peats
• Acidic, brown-water swamps
• Potting soils
• Metal removal fluid systems

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NTM microbiological evaluation

• NTM should be identified to the species level.
• Methods of rapid species identification include
• commercial DNA probes (MAC, M. kansasii, and M.
  gordonae)
• high-performance liquid chromatography (HPLC).
• For some NTM isolates, especially rapidly growing
  mycobacterial isolates (M. fortuitum, M
  abscessus, and M. chelonae), other identification
  techniques may be necessary (extended antibiotic
  in vitro susceptibility testing, DNA sequencing

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NTMs Drug susceptibility testing

• Routine susceptibility testing of MAC isolates is
  recommended for clarithromycin only.
• Routine susceptibility testing of M. kansasii
  isolates is recommended for rifampin only.
• Routine susceptibility testing, for both
  taxonomic identification and treatment of M.
  fortuitum, M abscessus, and M. chelonae) should
  be with amikacin, imipenem (M. fortuitum only),
  doxycycline, fluoroquinolones, a sulfonamide or
  trimethoprim-sulfamethoxazole, cefoxitin,
  clarithromycin, linezolid, and tobramycin (M.
  chelonae)

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Diagnosis of NTM disease (simplified)

• Compatible illness with clinical and/or
  radiographic progression
• Bacterial load
• Species
• M. kansasii
• M. malmonese
• M. szulgai
• M. xenopi

most pathogenic
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Isolation prevalence of NTMs, Ontario
Marras TK, et al. Thorax 20074