Non-tuberculous mycobacteria

Background

• Mycobacteria that excludes tuberculosis and leprosy

Microbiology

• Acid-fast bacilli, free-living in the environment
  • Direct microscopy with auremine rodhamine fluorochrome stain (better than Ziehl-Neelsen)
• Broadly divided into slow-growers and fast-growers
  • Fast-growers produce colonies within 7 days on solid media
    • Grows optimally at 28-30º C, with some preferring 35 ºC
    • May grow in blood culture if mycobacteremic
  • Slow-growers produce colonies after more than 7 days on solid media
    • MAC, M. xenopi, and M. kansasii are the three most important
    • Grows optimally at 35-37º C except M. haemophilum (28-30 ºC) and M. xenopi (42-45 ºC)
• Media includes blood or chocolate agar, MTBC media, etc
• Species-level identifiation requires molecular tests

Species

• More than 200 species of Mycobacterium spp. that are not in M. tuberculosis complex or M. leprae
• Often divided into rapid growers (visible in culture in less than 5-7 days) and slow growers (more than 7 days)
• Slow-growers are further classified by production of yellow-orange pigment
  • Photochromagens produce pigment when exposed to light
  • Scotochromogens produce pigment regardless of light
  • Nonchromogens do not produce pigment

Slow or Rapid	Pigmentation	Complex	Species	Notes
rapid	nonchromogen	M. fortuitum complex	M. fortuitum
			M. peregrinum
			M. porcinum
			M. chelonae
			M. abscessus
		M. abscessus	M. abscessus subsp. abscessus
		M. abscessus	M. abscessus subsp. bolletii
		M. abscessus	M. abscessus subsp. massiliense
			M. smegmatis
			M. mucogenicum
slow	photochromogen		M. kansasii	Always assumed to be pathogenic, never colonizer.
			M. marinum	Intermediate-grower (7-10 days).
	scotochromogen		M. gordonae	Intermediate-grower (7-10 days). Common tap-water contaminant.
			M. scrofulaceum
	nonchromogen	M. avium complex	M. avium complex	In HIV, rarely pulmonary and almost always disseminated.
			M. avium	Most common subspecies.
			M. intracellulare
			M. chimaera	Associated with contaminated heater-cooler units in cardiac bypass machines.
		M. terrae complex	M. terrae complex
			M. ulcerans
			M. xenopi	Grows optimally at 42-45 ºC.
			M. simiae
			M. malmoense
			M. szulgai
			M. asiaticum
			M. haemophilum	Grows optimally at 28-30 ºC.

Pathophysiology

• Inhalation ± microaspiration, likely from water source
  • Environmental organisms that are essentially unavoidable
• Response is cell-mediated with pulmonary macrophages, with assistance from CD4, IL-2, and IFN-γ

Epidemiology

• NTMs are distributed worldwide, present in soil, household water, vegetable matter, animals, and birds
  • Also tap water (especially M. gordonae, M. kansasii, M. xenopi, M. simiae, MAC, and M. mucogenicum)
• 90% of patients with NTM infections have underlying pulmonary disease
• No person-to-person transmission
• In Ontario: M. avium complex (25%), M. xenopi (10%), M. abscessus/M. chelonae, M. fortuitum

Species	Distribution
Pulmonary Disease
M. abscessus	Worldwide; may be found concomitant with MAC
M. avium complex	Worldwide; most common NTM pathogen in US
M. kansasii	US, Europe, South Africa, and coal-mining regions
M. malmoense	UK, northern Europe; uncommon in US
M. xenopi	Europe, Canada; uncommon in US; associated with pseudoinfection
Lymphadenitis
M. avium complex	Worldwide; most common NTM pathogen in US
M. malmoense	UK, northern Europe (especially Scandinavia)
M. scrofulaceum	Worldwide; previously common, now rarely isolated in US
Disseminated Disease
M. avium complex	Worldwide; AIDS; most common NTM pathogen in US
M. chelonae	US; non-AIDS immunosuppressed skin lesions
M. haemophilum	AIDS; US, Australia; non-AIDS immunosuppressed
M. kansasii	AIDS; US, South Africa
SSTI and MSK
M. abscessus	Penetrating injury
M. chelonae	US, associated with keratitis and disseminated disease
M. fortuitum	Penetrating injury, footbaths
M. marinum	Worldwide, fresh- and saltwater
M. ulcerans	Australia, tropics, Africa, Southeast Asia, not US
Contaminant
M. gordonae	Most common NTM contaminant
M. haemophilum
M. mucogenicum
M. nonchromogenicum
M. terrae complex

Clinical Manifestations

Syndrome	Species	Description
Pulmonary disease	MAC, M. kansasii, M. xenopi, M. abscessus
Upper lobe cavitary	MAC, M. kansasii	Male smokers, often alcohol use, usually early 50s
RML/lingular nodular bronchiectasis	MAC, M. abscessus, M. absessus subsp. massiliense	Female nonsmokers, usually older than 60
Localized alveolar/cavitary	M. abscessus, MAC	Prior granulomatous dz (usually TB) with bronchiectasis
Reticulonodular or alveolar bilateral lower lobe	M. fortuitum	Achalasia, chronic vomiting, exogenous lipoid pneumonia
Reticulonodular	MAC, M. abscessus subsp. abscessus, M. abscessus subsp. massiliense	Adolescents with CF, HIV-positive patients, prior bronchiectasis
Hypersensitivity pneumonitis	M. immunogenum, M. avium	Metal workers, indoor hot tubs
Cervical lymphadenitis	MAC
SSTI	M. fortuitum, M. marinum, M. chelonae, M. ulcerans
MSK	M. marinum, MAC, M. kansasii, M. fortuitum, M. abscessus, M. chelonae
Disseminated	HIV-positive: M. avium and M. kansasii, HIV-negative: M. abscessus and M. chelonae
Catheter-related	M. fortuitum, M. abscessus, M. chelonae

Pulmonary Disease

• Risk factors include COPD and CF1
• Most common clinical manifestation of NTM
• Most commonly caused by MAC, M. kansasii, M. xenopi, and M. abscessus
• Nonspecific chronic or subacute respiratory syndrome with prominent cough

Fibrocavitary Disease

• Usually preexisting lung disease (COPD etc), men
• Upper-lobe predominant, focal, cavitary
• DDx includes TB and lung cancer

Nodular Bronchiectatic Disease

• Lady Windermere syndrome
• RML/lingula with discrete nodules and bronchiectasis
• Usually no preexisting lung disease, non-smoker, women

Investigations

• Almost always needs CT; may repeat to monitor for progression
• 3 sputums for AFB; may treat M. kansasii based on only a single colony but everything else needs 2-3 positives
  • Rule out tuberculosis

Skin and Soft Tissue Infection

• From direct inoculation
• M. abscessus, M. fortuitum, M. chelonae, M. marinum, M. ulcerans
• Dx: tissue biopsy culture (best) or culture of discharge

M. marinum

• "Fish tank granuloma"
• Incubation 2 to 3 weeks
• Small violet papular lesions on hands, which can ulcerate
• Can also cause sporotrichoid disease

Other Infections

Superficial Lymphadenitis

• Children, usually submandibular
• May be from eating dirt

Disseminated Disease

• Usually in AIDS or other significant cell-mediated immunosuppression

M. chimaera Infection

• Outbreaks associated with heater units used in cardiac surgery
• Present with IE, sternal wound infections, mediastinitis, etc.

Diagnosis

• Sputum smear and culture for AFB
  • Spontaneous, induced, or BAL
  • PCR/NAAT can be done for TB and MAC, but only done on smear positive samples unless specifically requested

Diagnostic Criteria for Pulmonary Disease

• Diagnosis requires clinical, radiologic, and microbiologic criteria
• Clinical: pulmonary or systemic symptoms
• Radiologic: nodular or cavitary opacities on chest radiograph, or a high-resolution cCT scan that shows bronchiectasis with multiple small nodules
• Microbiologic:
  • Positive cultures from at least 2 separate expectorate sputums, or
  • One positive culture from bronchial wash or lavage
  • Transbronchial or other lung biopsy with mycobacterial histologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for NTM
• Exclusion of other diagnoses

Management

• Treatment decisions
  • First is to decide whether or not to treat; must weigh the risks and benefits
  • NTM can represent contamination, colonization, or infection/invasion
  • The mycobacteria are inherently resistant to many bacteria, sometimes require IV therapy, multiple agents with toxicity, prolonged treatment
  • Treatment often ineffective
  • Recurrence is common; 50% of patients need a second course within 5 years of the first one
  • Decide to start based on shared decision-making model, reviewing:
    • Meets diagnostic criteria
    • Comorbidities
    • Toxicities
    • Goals of care
• All rapid-growers are resistant to first-line TB treatment (RIPE), and have aspiration as an underlying risk factor
  • Need susceptibilities for macrolides in MAC; needs to be specifically requested

Pulmonary Disease

Mycobacterium avium Complex

• MAC is the prototype
• Macrolide (azithro/clarithro) backbone, with 2 to 3 other agents depending on the disease type and severity
• Rifampin and clarithromycin interact, so prefer rifamycin
• Treat until 12 months after negative cultures

Class	Nodular	Cavitary or Advanced
Macrolide	Clarithromycin 1000 tiw or azithromycin 500 tiw	Clarithromycin 500 bid or azithromycin 250 daily
Ethambutol	25 mg/kg tiw	15 mg/kg/day
Rifamycin	TMP 600 tiw	RMP 450-600 mg OD, or RFB 150-300 mg daily
Amikacin	—	Consider 10-15 mg/kg/day IV

M. kansasii

• M. kansasii pulmonary disease: daily isoniazid (300 mg/d), rifampin (600 mg/d), and ethambutol (15 mg/kg/d)
• Patients should be treated until culture negative on therapy for 1 year
• Could consider treating based on a single positive colony, as it is rarely a colonizer

M. abscessus

• There are no drug regimens of proven or predictable efficacy for treatment of M. abscessus lung disease
• Multidrug regimens that include clarithromycin 1,000 mg/day may cause symptomatic improvement and disease regression
• Surgical resection of localized disease combined with multidrug clarithromycin-based therapy offers the best chance for cure of this disease

Non-Pulmonary Disease

Rapid Growers (M. abscessus, M. chelonae, M. fortuitum)

• Based on in vitro susceptibilities
• For M. abscessus, a macrolide-based regimen is frequently used
• Surgical debridement may be necessary

Skin and Soft Tissue Infection

• 3 to 6 months for M. marinum, 6 to 12 months for MAC

Cervical Lymphadenitis

• Mostly due to MAC
• Treated primarily by surgical excision, with a greater than 90% cure rate
• A macrolide-based regimen should be considered for patients with extensive MAC lymphadenitis or poor response to surgical therapy

Monitoring

• Depends on the antibiotics used
• Audiology for aminoglycosides
• Liver enzymes monthly for many others