Mycobacterium avium complex
The Mycobacterium avium complex (MAC) is a group of slowly growing, nontuberculous mycobacteria (NTM) comprising several species, primarily Mycobacterium avium (with subspecies including avium, hominissuis, paratuberculosis, and silvaticum), Mycobacterium intracellulare, Mycobacterium chimaera, and Mycobacterium paraintracellulare, which are ubiquitous environmental organisms found in soil, water, dust, and aerosols but indistinguishable by standard laboratory methods without genetic testing.[1] These bacteria are opportunistic pathogens that rarely cause disease in healthy individuals but lead to chronic infections, most commonly pulmonary disease, disseminated infections in immunocompromised hosts, and lymphadenitis in children, with increasing global incidence attributed to improved diagnostics and environmental exposure.[2] Unlike Mycobacterium tuberculosis, MAC is not contagious person-to-person and is acquired through inhalation or ingestion from natural reservoirs.[3] Epidemiologically, MAC infections have risen significantly, with U.S. prevalence of NTM pulmonary disease (of which MAC is the majority) estimated at 1.4–6.6 cases per 100,000 population as of the early 2000s and higher rates among Medicare beneficiaries (from 20 per 100,000 in 1997 to 47 per 100,000 in 2007), reaching approximately 92 per 100,000 in 2019; NTM cases were estimated at 86,000 in the U.S. in 2010, increasing to about 181,000 by 2014.[1][4][5] The disease shows a 1.6-fold predominance in women, particularly postmenopausal individuals over 65, and seasonal peaks in late winter and spring.[1] Risk factors include underlying structural lung diseases (e.g., bronchiectasis, COPD), immunosuppression (such as CD4 counts below 50 cells/μL in HIV/AIDS), genetic predispositions like alpha-1 antitrypsin deficiency, and suppressed cough reflexes in elderly women.[2] Globally, pulmonary MAC is the most common NTM lung infection, with higher burdens in regions like Southeast Asia where additional species like M. paraintracellulare have been identified.[1] Clinically, MAC manifests in diverse forms: the nodular/bronchiectatic subtype often presents as chronic cough, fatigue, weight loss, and hemoptysis in otherwise healthy older women, while the fibrocavitary form mimics tuberculosis with cavitary lesions in those with prior lung damage; disseminated disease, historically prominent in AIDS before antiretroviral therapy, involves fever, anemia, and multi-organ involvement in severely immunocompromised patients.[3] Extrapulmonary sites include cervical lymphadenitis in children under 5 and rare skin or bone infections.[2] Diagnosis follows American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria, requiring compatible clinical symptoms, radiographic evidence (e.g., high-resolution CT showing nodules or tree-in-bud patterns), and microbiologic confirmation via at least two positive sputum cultures or one positive bronchial specimen.[1] Treatment typically involves multidrug regimens, with the cornerstone being macrolides (azithromycin or clarithromycin) combined with rifampin and ethambutol, administered daily for cavitary disease or three times weekly for milder nodular forms, aiming for 12 months of culture negativity; adjunctive therapies like aminoglycosides (e.g., amikacin) are used for severe or macrolide-resistant cases, and surgery may be considered for localized disease.[2] In HIV patients, antiretroviral therapy restoration of immunity is critical to prevent dissemination.[1] Historically, M. avium was first isolated from a chicken in 1890, and recent developments include recognition of M. chimaera outbreaks linked to contaminated heater-cooler units in cardiac surgery (infections reported from surgeries since ~2004) and emerging resistance challenges necessitating novel agents like bedaquiline.[1][2]Taxonomy and Classification
Species Composition
The Mycobacterium avium complex (MAC) is a group of slowly growing, nontuberculous mycobacteria (NTM) that share phenotypic and genotypic similarities, initially defined by their ability to cause avian tuberculosis but now recognized for their opportunistic pathogenicity in humans and animals.[1] Historically, MAC was composed primarily of two species: Mycobacterium avium and Mycobacterium intracellulare, distinguished based on biochemical tests and pathogenicity in birds, with M. avium affecting fowl and M. intracellulare being less virulent in avian hosts.[6] Advances in molecular taxonomy, including 16S rRNA sequencing and whole-genome analysis, have expanded the complex to include additional species and subspecies, revealing a more diverse genetic cluster with average nucleotide identity (ANI) values often exceeding 95% among members.[7] M. avium remains a cornerstone species, subdivided into four subspecies that differ in host tropism and ecological niches: M. avium subsp. avium (serovars 1, 2, 3), which primarily causes mycobacteriosis in birds; M. avium subsp. hominissuis (serovars 4, 5, 6, 8–12, 20), an opportunistic pathogen in humans and pigs associated with pulmonary and disseminated infections; M. avium subsp. paratuberculosis (serovar 10), the etiological agent of Johne's disease in ruminants; and M. avium subsp. silvaticum (serovar 21), which affects wood pigeons and other wild birds.[1][7] These subspecies exhibit distinct genomic features, such as the presence of large sequence polymorphisms (LSPs) and insertion sequences like IS1245 in M. avium subsp. hominissuis, facilitating strain differentiation.[8] M. intracellulare, the other foundational species, encompasses subspecies including M. intracellulare subsp. intracellulare (serovars 7, 12A, 14–16, 19, 21), linked to human pulmonary disease; M. intracellulare subsp. chimaera, identified in 2004 and reclassified as a subspecies via multilocus sequence analysis, notable for causing post-surgical infections like endocarditis; and M. intracellulare subsp. yongonense, described as a novel species in 2013 and reclassified in 2018 as a synonym of subsp. chimaera based on high ANI (>99%) and DNA-DNA hybridization (DDH) values.[1][7][9] M. paraintracellulare, described in 2016 from Southeast Asian pulmonary cases showing close relatedness to M. intracellulare, has been reclassified as a synonym of M. intracellulare based on genomic confirmation.[1][10] Beyond these core members, MAC has been broadened to include several other species through genomic reclassification, such as M. colombiense (serovar 14-like), M. arosiense, M. bouchedurhonense, M. marseillense, M. timonense, and M. vulneris, which share phenotypic traits like acid-fastness and growth at 37°C but vary in clinical relevance.[7] In clinical isolates from lung disease, M. intracellulare predominates (approximately 43–44%), followed by M. avium (25%) and M. chimaera (15–16%), with mixed infections or other species comprising the remainder, as determined by whole-genome sequencing of patient samples.[11] This diversity underscores the complex's polyphyletic nature, with ongoing taxonomic refinements driven by high-throughput sequencing to better delineate transmission and pathogenicity. As of 2025, genomic analyses continue to refine MAC boundaries, with some subspecies mergers accepted under the International Code of Nomenclature of Prokaryotes (ICNP).[12][13]Type Strains and Nomenclature
The Mycobacterium avium complex (MAC) comprises a phylogenetically related group of slowly growing, nontuberculous mycobacteria primarily within the Mycobacterium avium-M. intracellulare clade, initially recognized for their shared phenotypic traits and clinical significance in opportunistic infections. The nomenclature of MAC species has evolved through classical bacteriological descriptions and modern molecular methods, including 16S rRNA gene sequencing, hsp65 analysis, and whole-genome phylogenomics, leading to the delineation of distinct species from what was once considered a single complex dominated by M. avium and M. intracellulare.[14] This taxonomic refinement began in the mid-20th century and accelerated in the 2000s with the proposal of novel species based on genetic variants within the internal transcribed spacer (ITS) region of the ribosomal operon.[15] The foundational species, Mycobacterium avium Chester 1901, was originally described from avian tuberculosis isolates, with its name deriving from the Latin "avium" (of birds), reflecting its primary association with poultry infections.[16] No type strain was designated in the original description, but ATCC 25291 (also CCUG 20992, CIP 104244, DSM 44156, NCTC 13034) serves as the neotype strain, conserved under International Code of Nomenclature of Prokaryotes (ICNP) Judicial Opinion 47.[16] Similarly, Mycobacterium intracellulare Runyon 1965 (corrig.) emerged from reclassification of "Nocardia intracellularis" Cuttino and McCabe 1949, named for its intracellular growth in macrophages; its type strain is ATCC 13950 (CCUG 28005, CIP 104243, DSM 43223, JCM 6384, NCTC 13025, TMC 1406).[17] Subsequent species were elevated from MAC genetic sequevars using multilocus sequencing. Mycobacterium chimaera Tortoli et al. 2004, named after the mythological chimera for its hybrid genetic features, was proposed from MAC-A variants; its type strain is FI-01069 (CCUG 50989, CIP 107892, DSM 44623, JCM 14737, NCTC 13781).[18] Mycobacterium colombiense Murcia et al. 2006, derived from MAC-X isolates from HIV patients in Colombia (etymology: "colombiense," pertaining to Colombia), has type strain 10B (CECT 3035, CIP 108962, DSM 45105, JCM 16228).[19] Mycobacterium yongonense Kim et al. 2013, a non-chromogenic species from pulmonary samples (etymology: honoring Korean microbiologist Bong-Jo Yong), was later reclassified as a synonym of M. intracellulare subsp. chimaera; its original type strain was 05-1390 (DSM 45126, KCTC 19555).[9] Mycobacterium vulneris Tortoli et al. 2009, isolated from a dog-bite wound (etymology: "vulneris," of a wound), has type strain NLA000700772 (CIP 109859, DSM 45247).[20]| Species | Type Strain Designation(s) | Valid Publication (DOI) |
|---|---|---|
| M. avium | ATCC 25291; CCUG 20992; CIP 104244; DSM 44156; NCTC 13034 | Chester 1901 (Approved Lists 1980) https://doi.org/10.1099/00207713-30-1-225 |
| M. intracellulare | ATCC 13950; CCUG 28005; CIP 104243; DSM 43223; JCM 6384; NCTC 13025; TMC 1406 | Runyon 1965 (Approved Lists 1980) https://doi.org/10.1099/00207713-30-1-225 |
| M. chimaera | FI-01069; CCUG 50989; CIP 107892; DSM 44623; JCM 14737; NCTC 13781 | Tortoli et al. 2004 https://doi.org/10.1099/ijs.0.02777-0 |
| M. colombiense | 10B; CECT 3035; CIP 108962; DSM 45105; JCM 16228 | Murcia et al. 2006 https://doi.org/10.1099/ijs.0.64190-0 |
| M. vulneris | NLA000700772; CIP 109859; DSM 45247 | Tortoli et al. 2009 https://doi.org/10.1099/ijs.0.008854-0 |