Nontuberculous Mycobacterioses (overview) A31.9

Pinner, 1931

Nontuberculous mycobacteria (NTMs) have been known almost as long as M. tuberculosis itself, but their clinical significance was not recognized until the 1950s. NTMs are facultatively humpathogenic and can become clinically relevant as opportunistic pathogens, under certain conditions, some nosocomial, even in immunocompetent individuals.

The term "nontuberculous mycobacterioses", or "NTM" for short, refers to diseases caused by infections with nontuberculous mycobacteria. This is a heterogeneous group of more than 190 environmental mycobacteria (Daley CL et al. 2020) characterized by a wide diversity in terms of their occurrence, pathogenicity, adaptations to environmental conditions. Their relationship to the obligate pathogens of the tuberculosis complex and leprosy is reflected in the antipodal naming "nontuberculous mycobacteria." The older name "atypical mycobacteria is outdated. It was most often understood as synonymous with Mycobacterium avium complex (MAC) infection.

Most NTM live as apathogenic prokaryotes in soil or water (Adjemian J et al. 2012). They also reach household plumbing via water, where they can occur in biofilms in high bacterial counts (Schulze-Röbbecke R et al. 1992). Furthermore, NTMs can also be detected in foods such as pasteurized milk and cheese, but not in homogenized milk, among others (Leite CQ et al. 2003; Jordão Junior CM et al. 2009). The implication of these studies is that humans have constant contact with ubiquitous mycobacteria. Versch. Studies show that humans have several times more contact with NTMs than with M. tuberculosis. Nevertheless, NTMs are responsible for only 1-3% of mycobacterial disease cases. Thus, special local conditions, or defects of the local or systemic immune defense (see NTM in HIV infections) are necessary prerequisites for an infection with NTMs.

Mycobacteria that do not produce either tuberculosis or leprosy are now referred to as non-tuberculous mycobacteria, or NTM for short. Their transmission from person to person is discussed, but is not certain.

NTMs occur mainly in dust, dirt, fresh and salt water, in birds, pigs, sheep, cattle, in milk and eggs.

The most important representative of NTM for Central Europe is M. marinum, the pathogen of swimming pool granuloma.

So far, more than 190 different NTM species have been discovered. In addition to NTMs that have also been detected in environmental samples, there are species, such as M. ulcerans, M. genavense, or M. haemophilum, that are significantly more host-specific than other species. M. haemophilum can cause scleritis in addition to skin afflictions (Pisitpayat P et al. 2020). Infections of birds have been described for M. genavense, but there is no evidence of spread outside this host. Mycobacterium ulcerans has been diagnosed in over 33 countries worldwide, not only in tropical areas of West Africa but also in areas with temperate non-tropical climates, including Australia and Japan. (Johnson PD et al. 2007). For M. haemophilum, water reservoirs are considered a likely source of infection.

Basically, according to the Runyon classification, NTM are divided into:

Slow-growing NTM: The list of clinically important slow-growing nontuberculous mycobacteria (NTM) is constantly expanding as new species are identified and older ones are recognized as pathogenic. Because the pathogens are ubiquitous in nature, many NTM have been isolated from ground or tap water, soil, house dust, domestic and wild animals, and birds. Most infections occur by inhalation or direct inoculation from environmental sources.

In addition to their cultural growth rate, NTMs can be classified as photochromogenic, scotochromogenic, or nonpigmented based on their pigment production. The following pathogens are of clinical relevance:

• M. arupense
• M. asiaticum
• M. avium and M. avium complex: Based on molecular biology criteria, the MAC complex is defined as a grouping of slow-growing mycobacteria. It currently consists of 12 validly published species: Mycobacterium avium*, Mycobacterium intracellulare*, Mycobacterium chimaera, Mycobacterium colombiense, Mycobacterium arosiense, Mycobacterium vulneris*, Mycobacterium boucheduronense, Mycobacterium timonens, Mycobacterium marseillnse, Mycobacterium yongoense, Mycobacterium paraintracellulare, Mycobacterium lepraemurium (van Ingen J et al. 2018).
• M. bohemicum
• M. branderi
• M. celatum (mainly pulmonary infections in immunocompetent individuals; local infections of the skin)
• M. chimaera
• M. europaeum
• M. florentinum
• M. genavense (nosocomial infections in HIV infection)
• M. gordonae (typically detected in tap water, mainly pulmonary infections, occasional skin involvement)
• M. haemophilum (nodular, also ulcerative lesions, in immunocompetents as well as in immunoincompetents).
• M. heckeshornense
• M. interjectum
• M. intermedium (chronic granulomatous dermatitis, associated with exposure to a hot tub)
• M. intracellulare*(chronic granulomatous/lupoid dermatitis/Pampaloni A et al. 2020).
• M. kansasii (Pulmonary infections with M. kansasii resemble infections with M. tuberculosis in their clinical presentation. In rare cases, M. kansasii is also the etiologic agent of infantile lymphadenitis. Skin involvement is rare).
• M. cubicae
• M. lentiflavum (preferred causative agent of cervical lymphadenitis in children; complicating cosmetic surgery)
• M. malmoense (tuberculoid granuloma on the dorsum of the hand/Schmoor P et al. 2001)
• M. marinum (verrucous plaques and nodules, also sporotrichoid dissemination; swimming pool granuloma)
• M. nebraskense
• M. palustre
• M. saskatchewanse
• M. scrofulaceum (clustered in pediatric cervical lymphadenitis)
• M. shimodei
• M. simiae (usually pulmonary infections, rarely disseminated, papular or nodular skin infiltrates in bacteremia).
• M.smegmatis (artificial infections in cosmetic procedures/filler materials).
• M. szulgai (very rarely, disseminated skin lesions have been described in the setting of bacteremia in immunosuppressed patients; cervical lymphadenitis in children)
• M. terrae complex (no known dermatological relevance)
• M. ulcerans (Buruli ulcer, localized skin infection with torpid ulcers common in tropical zones; also reported in temperate Australia/Bairnsdale Ulcer and Japan. In Australia, M.ulcerans has also been detected in mosquitoes (Aedes camptorhynchus).
• M. vulneris*(belongs to the MAC complex, dermatologically not relevant)
• M. xenopi (along with MAC complex and M. kansasii, belongs to the frequent NTM in pulmonary infections; also detected in tap water)

* Belonging to the MAC complex.

Examples of:

• Photochromogenic NTM (pigment formation under light): M. marinum, M. kansasii .
• Scotochromogenic N TM (pigment formation without light): M. scrofulaceum, M. szulgai.
• Non-chromogenic NTM (no pigment formation): M. ulcerans ( Buruli ulcer), M. avium-intracellulare complex, M. malmoense, M. xenopi.

Fast-growing NTM: The eponymous characteristic of fast-growing mycobacteria is that they show marked growth in less than 7 days at their optimal growth temperature. This statement refers to standard culture conditions only. Fast-growing mycobacteria are clearly resistant to a wide variety of environmental conditions. Therefore, they are widely distributed (Falkinham 3rd JO 2009). In larger series of studies, fast growing NTM (RGM) from skin and soft tissue infections were found to have the following distribution pattern (Kumar C et al 2021):

• M. abscessus 38.7 %
• M. fortuitum 31.5 %
• M. chelonae 15 %
• M. chelonae/abscessus complex 9.6 %.

_______________________

• M. abscessus**(outbreaks of M. abscessus complex associated with cosmetic procedures and nosocomial transmission are not uncommon).
• M. alvei
• M. aurum
• M. boenickei
• M. brumae
• M. chelonae (M. chelonae and M. fortuitum/localized clinical pictures with sprotrichoid arranged skin and soft tissue granulomas after inoculation are possible/more frequent are disseminated courses with granuloma or abscess formations with immunodeficiency)
• M. confluentis
• M.fortuitum complex**(Infection with the pathogens occurs after minor trauma, but also after medical procedures: injections, indwelling cannulas, liposuction, tattoos, acupuncture, etc . Mycobacterium fortuitum infections have also been observed after face-lift surgery).
• M. goodii (catheter-associated bacteremia has been demonstrated).
• M. holsaticum
• M. immunogenum (mainly skin infections e.g. after cosmetic procedures and surgery)
• M. iranicum
• M. margeritense
• M. mucogenicum
• M. peregrinum
• M. phocaicum
• M. septicum (skin infections caused by M. septicum have been reported after cosmetic surgery)
• M. smegmatis (described in association with various cosmetic procedures, among others. Wang CJ et al. 2022)
• M. thermoresistible

While NTM may be detectable in the sputum or stool of asymptomatic individuals (colonization), almost only patients with massive immunodeficiency and less than < 50 CD4 cells/µl become ill. In the pre-HAART era, this was as high as 40% of AIDS patients.

In the meantime, NTM infections in HIV-infected patients have become rather rare as a result of sufficient thefrapic measures of HIV infection. In the past, NTM infections in HIV-infected patients were almost always disseminated.

NTM infections in immunocompetent persons mostly occur as localized forms. Thus as pulmonary infections, as osteomyelitides (spine! Joints!), as lymphadenopathies, as skin manifestations in the form of inflammatory plaques and nodules (see below swimming pool granuloma) or melting, subcutaneously localized "scrophular" abscesses.

Of etiopathogenetic note are NTMs that occur in patients with primary immunodeficiencies that affect intrinsic imm unity. These immunodeficiency syndromes are grouped under the term MSMD, "Mendelian susceptibility to mycobacterial diseases" (MSDM). MSMD refer to rare, autosomal dominant or autosomal recessive or X-linked recessive (monogenic) immunodeficiency syndromes caused by molecular defects in the IL12 / IFNγ-dependent signaling pathway (Casanova JL 2001).

Histology, PCR, culture from tissue biopsy.

The AP is often elevated. In case of newly occurring anemia and constitutional symptoms, infection with atypical mycobacteria should always be considered.

Tuberculoid and sarcoid palisade granulomas, with multinucleated giant cells, accompanied by a diffuse infiltrate of lymphocytes, gronulocytes, and histiocytic foam cells are demonstrable. Usually signs of acute and chronic panniculitis.

Individual skin lesions can be excised; in the case of uncomplicated lymph node involvement, lymph node extirpation may be performed. If deep infections and fistula tracts develop, incision and drainage, usually combined with antibiosis.

The individual mycobacteria respond differently to the tuberculostatic drugs (see Tuberculostatics), prior determination of resistance is therefore essential. Long-term treatment (sometimes up to 2 years) necessary. The duration of therapy should be continued for some time even after clinical healing.

In case of disseminated infestation, antibiotic combination treatments are necessary. Since patients are often immunosuppressed, these cases are life-threatening.

For general therapy regimens, see Tables 2 and 3. For specific dosages in chemotherapeutic treatment, see below, depending on the clinical picture. Appropriate drugs include:

Imipenem 1 g i.v. every 6 h.

Levofloxacin 500 mg i.v. or p.o. 1x/day.

Clarithromycin 500 mg p.o. 2x/day.

Trimethoprim/sulfamethoxazole ke

Doxycycline 100 to 200 mg p.o. 1x/day

Cefoxitin 2 g i.v. every 6 to 8 h

Amikacin 10 to 15 mg/kg i.v. 1x/day.

Combination therapy with at least 2 drugs that have in vitro activity is recommended. Duration of therapy averages 24 months and may be longer if the infected foreign body remains in the body. Amikacin is usually included for the first 3 to 6 months of therapy. Infections caused by M. abscessus and M. chelonae are usually resistant to most antibiotics and have been shown to be extremely difficult or impossible to cure.

Differentiation of common ubiquitous mycobacteria according to their treatability with conventional tuberculostatics (according to Fätkenheuer/Diehl/Schrappe).

Clinic and therapy of common infections with atypical mycobacteria

S.a. Newsletter March 2023

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