Mycobacteroides abscessus complexEpidemiology and Clinical Manifestations of M. abscessus in Lung Transplant Recipients

Mycobacteroides abscessus complex, separated from the mycobacteria genus in 2018 based on phylogenomics, is a rapid-growing mycobacteria (RGM) species complex composed of three subspecies: M. abscessus subspecies abscessus, subsp. massiliense, and subsp. bolletii [47, 48]. In lung transplant recipients, M. abscessus is the most common cause of NTM disease [11, 45]. Transmission is primarily thought to be aerosolization from water sources, but there is emerging evidence of possible person-to-person spread, particularly between cystic fibrosis patients [49]. The complex typically causes pulmonary disease, but also commonly causes skin and soft tissue infections, similar to other rapid-growing mycobacteria [48, 49].

Previous data suggested that infection with M. abscessus portended a higher mortality rate post-lung transplant [50]. However, emerging studies have suggested that M. abscessus infection can be controlled after lung transplant, shifting the framework of M. abscessus as an absolute contraindication to a relative contraindication [29, 30, 51]. One study in 2015 found a higher mortality rate after solid organ transplant in patients with NTM infections but did not see a difference between M. abscessus and other NTM [44]. More recent data suggest that lung transplant recipients with M. abscessus infection have excellent survival when aggressive surveillance strategies are employed by transplant centers [52]. AST, BTS, and ISHLT no longer consider M. abscessus to be contraindications to lung transplant but do recommend transplanting only at centers with mycobacteria experience [10, 31, 32].

Susceptibility Testing for M. abscessus complex

The CLSI has established breakpoints for RGM for amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline or minocycline, imipenem, linezolid, moxifloxacin, and trimethoprim-sulfamethoxazole [41, 42]. Of note, RGM can have inducible macrolide resistance via the erm gene, which requires extended incubation for 14 days [40,41,42]. M. abscessus subspecies bolletii should have clarithromycin reported as resistant due to its known functional erm gene, whereas M. abscessus subspecies abscessus and massiliense should have clarithromycin broth dilution performed [40,41,42]. Therefore, it is important for reference laboratories to perform subspecies level identification.

Treatment of M. abscessus complex

The AST recommends azithromycin plus two parenteral agents (amikacin, imipenem, tigecycline, or cefoxitin) and to start therapy prior to availability of susceptibility testing [10]. The BTS recommends an initial 4-week course of intravenous amikacin, tigecycline, and imipenem plus oral clarithromycin or azithromycin [31]. Following that, BTS recommends the patient should have a continuation phase consisting of oral antibiotics (macrolide plus one to three of the following: clofazimine, linezolid, minocycline or doxycycline, moxifloxacin, and co-trimoxazole) plus inhaled amikacin [31]. IDSA recommends susceptibility-based testing for M. abscesssus for macrolides and amikacin [35]. IDSA recommends using macrolides if susceptible and using at least three active drugs (based on susceptibility testing, which may include cefoxitin, amikacin, imipenem, linezolid, or tigecycline). BTS recommends continuing therapy for at least 12 months after sputum conversion, but IDSA does not offer duration recommendations given lack of supportive clinical studies [31, 35].

Omadacycline, a novel agent in the aminomethylcycline class, has in vivo and in vitro activity against M. abscessus [53]. Several case series have suggested efficacy and safety of this agent in treating M. abscessus infections [54,55,56]. Other agents that can be considered for RGM include bedaquiline, tedizolid, and clofazimine [40]. Reference laboratories, such as National Jewish Health, now offer omadacycline susceptibility testing from rapid-growing mycobacteria.

Mycobacterium avium complexEpidemiology and Clinical Manifestations of Mycobacterium avium complex in Lung Transplant Recipients

Mycobacterium avium complex (MAC) comprises eleven slow-growing mycobacterial species, the most common being M. avium and M. intracellulare, and constitutes the most common clinically relevant NTM in the United States, North America, and Australia [57, 58]. Notably, MAC is the second most common NTM infection after lung transplantation [45]. MAC has been isolated from municipal water systems, owing in part to its high resistance to chlorination, and acquisition is thought to be mostly due to aerosolization of water reservoirs [59, 60]. MAC typically manifests with pulmonary infection, but the organism can also cause disseminated infection, skin/soft tissue infections, bone/joint infections, and gastrointestinal infection [57, 58].

Susceptibility Testing for MAC

The CLSI recommends in vitro susceptibility testing of clinically relevant MAC isolates as baseline testing as well as repeat testing on those who relapse on macrolide therapy or who have had prior macrolide therapy [40,41,42]. The only antibiotics that have demonstrated a correlation between in vitro test result and clinical response in controlled trials for MAC are macrolides and amikacin, and CLSI breakpoints have been established for clarithromycin, amikacin (intravenous and inhaled), moxifloxacin, and linezolid [42]. Rifamycins and ethambutol show poor correlation of in vitro susceptibility testing and clinical response, and the CLSI offers no breakpoints for either antibiotic [41, 42]. Moxifloxacin and linezolid have CLSI breakpoints for MAC but have unestablished efficacy [41, 42].

Treatment of MAC

The AST recommends triple therapy with azithromycin, rifabutin, and ethambutol, substituting rifampin with rifabutin to lessen the interaction with calcineurin or mTOR inhibitors [10]. The BTS recommends triple therapy with azithromycin (or clarithromycin), rifampin, and ethambutol [31]. IDSA recommends triple therapy with azithromycin, ethambutol, and a third antimycobacterial, with thrice weekly dosing preferred for noncavitary nodular or bronchiectatic disease [35]. For cavitary disease, IDSA recommends parenteral aminoglycoside therapy for 2–3 months in addition to daily oral therapy [35]. The IDSA recommends monthly sputum AFB cultures during treatment for MAC [35]. IDSA recommends considering addition of inhaled liposomal amikacin if patient has persistent sputum cultures positive after 6 months of initial therapy [35]. All three societies recommend continuing therapy for 12 months post-sputum conversion.

Mycobacterium kansasii Epidemiology and Clinical Manifestations of M. kansasii in Lung Transplant Recipients

M. kansasii is a slow growing photochromogenic NTM that typically causes pulmonary infection, cited as the sixth most common NTM isolate from clinical samples worldwide [61]. Surveillance studies have shown the organism in water systems, suggesting that transmission occurs via drinking contaminated water or inhaling aerosols [61]. Some evidence suggests it may be the most common NTM species in heart transplant recipients [46]. Data on lung transplant recipients with M. kansasii is scarce, but it is thought to be a less common cause of NTM infection than M. abscessus and M. avium complex [45].

Susceptibility Testing for M. kansasii

The CLSI has established breakpoints for M. kansasii against clarithromycin, rifampin, amikacin, ciprofloxacin, doxycycline, linezolid, minocycline, moxifloxacin, rifabutin, and trimethoprim-sulfamethoxazole [41, 42]. The CLSI recommends that all clinically relevant M. kansasii isolates be tested for rifampin (and that rifabutin testing is typically not necessary, as rifampin is a reliable surrogate in this situation) [40, 42]. Isoniazid and ethambutol, while used to treat this infection, are not recommended for testing given lack of correlation between MIC result and clinical response [41, 42]. The CLSI does recommend testing the isolate for additional antibiotics if rifampin is resistant (including amikacin, ciprofloxacin, linezolid, moxifloxacin, doxycycline, trimethoprim-sulfamethoxazole) [41, 42].

Treatment of M. kansasii

The AST recommends triple therapy with rifabutin, ethambutol, and isoniazid or azithromycin [10]. The BTS recommends triple therapy with rifampin, ethambutol, and isoniazid or a macrolide (azithromycin or clarithromycin [31]. IDSA recommends rifampin, ethambutol and isoniazid or a macrolide [39]. Aminoglycosides are not recommended by IDSA for M. kansasii, regardless of severity, given excellent outcomes with triple oral therapy [35]. Of note, M. kansasii is naturally resistant to pyrazinamide due to reduced activity of pyrazinamidase, an enzyme required to activate pyrazinamide [62]. AST and BTS recommend continuing treatment until 12 months after sputum conversion, but IDSA recommends a fixed duration of 12 months (given lack of evidence of benefit for continuing treatment 12 months after sputum conversion) [10, 31, 35].

Mycolicibacterium fortuitum group.

Epidemiology and Clinical Manifestations of M. fortitum group in Lung Transplant Recipients

The Mycolicbacterium fortuitum group, also separated from the mycobacteria genus in 2018 based on phylogenomics, is a RGM group of 17 species, most commonly M. fortuitum, M. perigrinum, and M. septicum in humans [47, 63]. The species have been isolated from water systems, soil, and dust [63]. Clinically, M. fortuitum group typically causes subacute to chronic skin and soft tissue infections and can be associated with surgical procedures, trauma, cosmetic procedures, and tattoos [64]. Its role in pulmonary infection is less clear, as evidence suggests it is more like to be a transient colonizer than a true cause of pulmonary disease, and most cases of lung isolation do not require antibiotic therapy [65, 66]. In lung transplant recipients, M. fortuitum infections are typically limited to case reports due to their low pathogenicity in the lung.

Susceptibility Testing for M. fortuitum group

The CLSI has established breakpoints for RGM for amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline or minocycline, imipenem, linezolid, moxifloxacin, and trimethoprim-sulfamethoxazole [41, 42]. M. fortuitum is known to have the erm gene and should be presumed macrolide resistant, but CLSI still recommends broth dilution with clarithromycin to confirm [41, 42].

Treatment of M. fortuitum group

The AST recommends dual therapy with fluoroquinolone, sulfonamide, or amikacin [10]. For skin and soft tissue diseases, treatment is generally continued for at least four months, often up to six months for bone infections [22]. For pulmonary infections, treatment is often continued for at least 12 months post-sputum conversion, though neither the AST, BTS, or IDSA