This is giving me a complex: a practical attempt to streamline nontuberculous mycobacteria nomenclature for clinical purposes

LETTER

The role of a clinical microbiology laboratory is to provide meaningful results to the health care provider. The precision of such results depends on the testing method capabilities and the reporting protocols implemented by the laboratory. For mycobacteriology laboratories that have the capability to detect, isolate, and identify nontuberculous mycobacteria (NTM), species-level identification is the goal; however, definitive species identification may not be always achievable depending on the test method used or the NTM present. As a result, there can be inconsistencies in how results are reported by various laboratories, which may create confusion for the health care provider. In this letter, we attempt to provide a practical consensus on how to report these NTM and define terms associated with the major clinically significant NTM including the recommendation of discontinuation of the collective term “group” and use of the term “complex” or determination of the species. In addition, we provide a list of the most common species and subspecies currently recognized and validly published as comprising these NTM collectives, as well as selected non-validly published taxa of clinical significance.

A 2021 taxonomic investigation of the genus Mycobacterium disputed a 2018 proposed division of the genus into five genera including the current Mycobacterium genus (1, 2). Based on these findings and most importantly to reduce confusion among clinicians, we have elected to maintain the single genus Mycobacterium designation.

The NTM reported most frequently as causes of human disease include, but are not limited to, Mycobacterium abscessus subsp. abscessus, Mycobacterium avium, Mycobacterium intracellulare subsp. intracellulare, Mycobacterium kansasii, Mycobacterium chelonae, and Mycobacterium fortuitum (3, 4). Each of these is part of a larger, phylogenetically related collective of species and subspecies (Table 1). Unfortunately, confusion can arise when laboratory reports are unclear as to whether the species, subspecies, group, or complex is being reported. For example, a report of “M. abscessus” could mean that M. abscessus subsp. abscessus has been recovered but it could also mean that either M. abscessus subsp. bolletti or M. abscessus subsp. massiliense was recovered. Knowledge of definitive subspecies is vital because the subspecies of M. abscessus varies in their macrolide susceptibility pattern due to the presence or absence of a functional, inducible erm(41), and knowing the subspecies can assist with patient management prior to obtaining phenotypic or molecular susceptibility results. The designation “M. abscessus complex” has been used most often in the literature to represent the three subspecies of M. abscessus rather than several distinct species comprising a complex (5, 6). However, according to our proposal, “M. abscessus complex” would be a misnomer because there is only one species, M. abscessus, and therefore, we recommend reporting “M. abscessus (subspecies identification not performed)” for clarity. Given the differences in macrolide susceptibility between the subspecies, laboratories reporting only the species should perform additional testing (e.g., erm(41) sequencing) or send the isolate to a reference laboratory to identify the subspecies.

TABLE 1.

Suggested nomenclature of common nontuberculous mycobacteria^a

Designation	Includes	Suggested reporting terminology	Comments
M. abscessus (7)	M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, M. abscessus subsp. massiliense	M. abscessus (subspecies identification not performed) Or as a preliminary report: M. abscessus (subspecies identification will follow) Or if the subspecies has been unambiguously identified, report as: M. abscessus subsp. abscessus, or M. abscessus subsp. bolletii, or M. abscessus subsp. massiliense	M. abscessus complex is technically erroneous when used to represent the 3 subspecies of M. abscessus because “complex“ implies more than one species. M. abscessus species may be technically correct but its use should be avoided as it is unclear to most health care providers as to whether this means ≥1 species or if it includes all 3 subspecies. If used, it should be footnoted in the report that it refers to all 3 subspecies, and subspecies identification is available upon request. M. abscessus/M. chelonae complex should not be used since available laboratory methods allow for differentiation of M. abscessus subspecies and M. chelonae, and differentiation is clinically important.
M. avium complex (8)	M. avium subsp. avium “M. avium subsp. hominissuis” M. avium subsp. paratuberculosis M. avium subsp. silvaticumb M. arosiense M. colombiense M. intracellulare subsp. intracellulare M. intracellulare subsp. chimaera M. intracellulare subsp. yongonense (re-classified)c M. marseillenseb M. timonenseb M. vulneris M. bouchedurhonense,b,d,e M. paraintracellulareb,e	M. avium complex Or if the species or subspecies has been unambiguously identified, report the individual species or subspecies (e.g., M. avium, M. intracellulare subsp. chimaera, M. vulneris) Or if the species or subspecies has not been unambiguously identified but the method has narrowed the possibilities, report the species and/or subspecies using a slash between the 2 taxa (e.g., M. intracellulare subsp. intracellulare/M. intracellulare subsp. chimaera)	M. avium complex includes all species and subspecies. M. avium is a species that can be distinguished using MALDI-TOF MS and 16S rRNA (500 bp) sequencing. Identification of M. intracellulare subsp. chimaera is important as it causes endocarditis and other infections in patients following cardiac surgery using heater/cooler units identified as contaminated in a worldwide outbreak (9).
M. chelonae complex (10)	M. chelonae subsp. chelonae M. chelonae subsp. gwakanae M. chelonae subsp. bovis M. franklinii M. immunogenum M. salmoniphilum M. saopaulense M. stephanolepidis	M. chelonae complex Or if the species has been unambiguously identified, report the individual species (e.g., M. chelonae) Or if the species has not been unambiguously identified but the method has narrowed the possibilities, report the species using a slash between the 2 taxa (e.g., M. chelonae/M. stephanolepidis)	M. salmoniphilum, M. stephanolepidis, and M. saopaulense have not been associated with human disease to date. M. chelonae subsp. bovis is validly published but is an illegitimate name which needs to be replaced. M. immunogenum is readily distinguished from the other species using MALDI-TOF MS or 16S rRNA sequencing and species-level identification should be routinely achieved.
M. fortuitum complex (11)	M. fortuitum M. alvei M. arcueilenseb M. boenickei M. brisbanense M. conceptionensed M. farcinogenes M. houstonense M. lutetienseb M. montmartrenseb M. neworleansense M. peregrinum M. porcinum M. senegalensee M. septicum M. setense M. syngnathidarum	M. fortuitum complex Or if the species has been unambiguously identified, report the individual species (e.g., M. fortuitum) Or if the species has not been unambiguously identified but the method has narrowed the possibilities, report the species using a slash between the 2 taxa (e.g., M. conceptionense/M. houstonense)	Whole genomic sequence suggests that M. senegalense and M. conceptionense are likely the same species (12) and as such should probably be reported as species using a slash between the 2 taxa (i.e., M. senegalense/M. conceptionense). M. arcueilense, M. lutetiense, M. montmartrense are environmental organisms which have not been described in human or animal disease to date. M. syngnathidarum has only been identified in syngnathid fish and has not been associated with human disease to date.
M. kansasii complex (13, 14)	M. kansasii M. persicum M. pseudokansasiib M. attenuatumb M. innocensb “M. ostraviense”b	M. kansasii complex Or if the species has been unambiguously identified, report the individual species (e.g., M. kansasii, M. persicum) Or if the species has not been unambiguously identified but the method has narrowed the possibilities, report the species using a slash to report 2 taxa (e.g., M. kansasii/M. persicum)	M. kansasii complex/M. gastri should not be reported because, although phenotypically closely related, M. kansasii complex and M. gastri can be differentiated by photochromogenicity testing and/or molecular methods and this should always be pursued due to differences in pathogenicity.
M. mucogenicum complex (12)	M. mucogenicum M. phocaicum M. aubagnense	M. mucogenicum complex Or if the species has been unambiguously identified, report the individual species (e.g., M. mucogenicum) Or if the species has not been unambiguously identified but the method has narrowed the possibilities, report the species using a slash between the 2 taxa (e.g., M. mucogenicum/M. phocaicum)
M. terrae complex (15)	M. terraeb M. algericumb M. arupense M. engbaekiib M. heraklionense M. hiberniaeb M. kumamotonenseb “M. icosiumassiliensis” b M. longobardumb “M. mephinesia”b M. minnesotenseb M. nonchromogenicumb M. senuenseb “M. sinense”b M. virginiense	M. terrae complex Or if the species have been unambiguously identified, report the individual species (e.g., M. arupense) Or if the species has not been unambiguously identified but the method has narrowed the possibilities, report the species using a slash between the 2 taxa (e.g., M. terrae/M. hiberniae)	Some members of the M. terrae complex are considered pathogenic. For isolates thought to be clinically relevant, attempts to obtain species-level identification should be pursued.

^a Taxa in quotation marks are not validly published under the International Code of Nomenclature of Prokaryotes. MALDI-TOF-MS: matrix-assisted laser desorption ionization-time-of-flight mass spectrometry and M. = Mycobacterium.

^b Unproven human or animal pathogen.

^c M. intracellulare subsp. yongonense is a heterotypic synonym; correct name is M. intracellulare subsp. chimaera.

^d The validity of this species is currently unclear.

^e Due to taxonomical reclassification, these are now considered synonyms of other taxa (https://lpsn.dsmz.de/) but may still be reported depending on methods/databases used.

Similarly, for over two decades, M. kansasii was known to contain at least seven molecular subtypes, but these have only recently been described at the species level, effectively creating a new “M. kansasii complex” with most species other than M. kansasii and M. persicum being unproven human pathogens (Table 1) (13).

Uncertainty may also stem from the lack of a definition of the differences between a “group” and a “complex.” We suggest that use of the term “group” is obsolete with molecular advances, but it can still be found in older literature where it was used largely interchangeably with the term “complex,” thus leading to confusion. In the absence of clear literature surrounding these terms, we suggest discontinuation of use of the term “group.” Instead, the term “complex” should be used to describe NTM species that are well described in the literature as genetically closely related and that may be indistinguishable using commonly available diagnostic laboratory methods [e.g., matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) or partial 16S rRNA gene sequencing].

Reporting of NTM is further complicated depending on the laboratory method used for identification. For example, partial 500 bp 16S rRNA gene sequencing can differentiate some members of the M. avium complex (MAC) (Table 1) but it cannot distinguish all species within the complex from each other. MALDI-TOF MS is similarly able to differentiate some of the species within the MAC but the species differentiated are not the same as those differentiated by partial 16S rRNA gene sequencing. In practice, species identification of MAC has not been performed routinely, so the distribution of MAC species and differences in clinical presentation and antimicrobial susceptibility (including treatment regimens) are largely unknown. An exception currently is M. intracellulare subspecies chimaera which may have specific epidemiological significance (Table 1). Most of the previously designated “MAC X” species (MAC species other than M. avium and M. intracellulare) are less commonly considered to be significant pathogens. If necessary, clinically relevant strains of MAC could be further identified to the species level if referred to a reference laboratory which may often be done for antimicrobial susceptibility testing.

For other NTM, the term “complex” is used to represent genetically closely related species such as the members of the M. fortuitum and M. mucogenicum complexes (Table 1). Again, neither partial 16S rRNA gene sequencing nor MALDI-TOF MS can definitively differentiate most of the members of these complexes.

It is incumbent on the reporting laboratory to recognize the nuances of each identification method used and to clearly report the identification to the most granular level possible but not more granular than achievable by the method utilized. In Table 1, we suggest reporting terminology for each of the major collectives of NTM and provide notes to aid clinical microbiology laboratories that perform the identification of NTM.