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, Mycobacterium xenopi, and Mycobacterium kansasii are the three most important
  - Grows optimally at 35-37º C except Mycobacterium haemophilum (28-30 ºC) and Mycobacterium xenopi (42-45 ºC)
Media includes blood or chocolate agar, MTBC media, etc
Species-level identification requires molecular tests

Species

More than 200 species of Mycobacterium spp. that are not in Mycobacterium tuberculosis complex or Mycobacterium 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	Mycobacterium fortuitum complex	Mycobacterium fortuitum
			Mycobacterium peregrinum
			Mycobacterium porcinum
			Mycobacterium chelonae
		Mycobacterium abscessus complex	Mycobacterium abscessus
			Mycobacterium abscessus subsp. abscessus
			Mycobacterium abscessus subsp. bolletii
			Mycobacterium abscessus subsp. massiliense
			Mycobacterium smegmatis
			Mycobacterium mucogenicum
slow	photochromogen		Mycobacterium kansasii	Always assumed to be pathogenic, never colonizer.
	photochromogen		Mycobacterium marinum	Intermediate-grower (7-10 days).
	scotochromogen		Mycobacterium gordonae	Intermediate-grower (7-10 days). Common tap-water contaminant.
	scotochromogen		Mycobacterium scrofulaceum
	nonchromogen	Mycobacterium avium complex	Mycobacterium avium complex	In HIV, rarely pulmonary and almost always disseminated.
			Mycobacterium avium	Most common subspecies.
			Mycobacterium intracellulare
			Mycobacterium chimaera	Associated with contaminated heater-cooler units in cardiac bypass machines.
		Mycobacterium terrae complex	Mycobacterium terrae complex
			Mycobacterium ulcerans
			Mycobacterium xenopi	Grows optimally at 42-45 ºC.
			Mycobacterium simiae
			Mycobacterium malmoense
			Mycobacterium szulgai
			Mycobacterium asiaticum
			Mycobacterium 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 Mycobacterium gordonae, Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium simiae, MAC, and Mycobacterium mucogenicum)
90% of patients with NTM infections have underlying pulmonary disease
No person-to-person transmission
In Ontario: Mycobacterium avium complex (25%), Mycobacterium xenopi (10%), Mycobacterium abscessus/Mycobacterium chelonae, Mycobacterium fortuitum

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

Clinical Manifestations

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

Pulmonary Disease

Risk factors include COPD and CF1
Most common clinical manifestation of NTM
Most commonly caused by MAC, Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium 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 Mycobacterium 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
Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium marinum, Mycobacterium ulcerans
Dx: tissue biopsy culture (best) or culture of discharge

Mycobacterium 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

Mycobacterium 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 (azithromycin/clarithromycin) 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

Mycobacterium kansasii

Mycobacterium 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

Mycobacterium abscessus

There are no drug regimens of proven or predictable efficacy for treatment of Mycobacterium 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 (Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum)

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

Skin and Soft Tissue Infection

3 to 6 months for Mycobacterium 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

References

^ Jennifer R. Honda, Vijaya Knight, Edward D. Chan. Pathogenesis and Risk Factors for Nontuberculous Mycobacterial Lung Disease. Clinics in Chest Medicine. 2015;36(1):1-11. doi:10.1016/j.ccm.2014.10.001.