Comparing Mycobacterium massiliense and Mycobacterium abscessus lung infections in cystic fibrosis patients

Patients with lung disease caused by Mycobacterium abscessus subsp. abscessus (here M. abscessus) typically have poor treatment outcomes. Although clofazimine (CFZ) has been increasingly used in the treatment of M. abscessus lung disease in clinical practice, there are no reported data on its effectiveness for this disease. This study sought to evaluate the clinical efficacy of a CFZ-containing regimen for the treatment of M. abscessus lung disease. We performed a retrospective review of the medical records of 42 patients with M. abscessus lung disease who were treated with CFZ-containing regimens between November 2013 and January 2015. CFZ was administered in combination with other antibiotics as an initial antibiotic regimen in 15 (36%) patients (initial treatment group), and it was added to an existing antibiotic regimen for refractory M. abscessus lung disease in 27 (64%) patients (salvage treatment group). Overall, there was an 81% treatment response rate based on symptoms and a 31% response rate based on radiographic findings. Conversion to culture-negative sputum samples was achieved in 10 (24%) patients after CFZ-containing antibiotic treatment, and during treatment, there were significant decreases in the positivity of semiquantitative sputum cultures for acid-fast bacilli in both the initial (P ϭ 0.018) and salvage (P ϭ 0.001) treatment groups. Our study suggests that CFZ-containing regimens may improve treatment outcomes in patients with M. abscessus lung disease and that a prospective evaluation of CFZ in M. abscessus lung disease is warranted.

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confidence: 99%

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Yang

Jhun

Moon

et al. 2017

“…Despite treatment combining clarithromycin, amikacin, and cefoxitin or imipenem, failures were still observed in 20 to 73% of cases (24)(25)(26). These failures can be attributed to inducible production of 23S RNA methylase encoded by erm (41) or to the acquisition of resistance due to rrl mutations or other mechanisms.…”

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confidence: 99%

Selection of Resistance to Clarithromycin in Mycobacterium abscessus Subspecies

Mougari

Bouziane

Crockett

et al. 2017

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Mycobacterium abscessus is an emerging pathogen against which clarithromycin is the main drug used. Clinical failures are commonly observed and were first attributed to acquired mutations in rrl encoding 23S rRNA but were then attributed to the intrinsic production of the erm(41) 23S RNA methylase. Since strains of M. abscessus were recently distributed into subspecies and erm(41) sequevars, we investigated acquired clarithromycin resistance mechanisms in mutants selected in vitro from four representative strains. Mutants were sequenced for rrl, erm(41), whiB, rpIV, and rplD and studied for seven antibiotic MICs. For mutants obtained from strain M. abscessus subsp. abscessus erm(41) T28 sequevar and strain M. abscessus subsp. bolletii, which are both known to produce effective methylase, rrl was mutated in only 19% (4/21) and 32.5% (13/40) of mutants, respectively, at position 2058 (A2058C, A2058G) or position 2059 (A2059C, A2059G). No mutations were observed in any of the other genes studied, and resistance to other antibiotics (amikacin, cefoxitin, imipenem, tigecycline, linezolid, and ciprofloxacin) was mainly unchanged. For M. abscessus subsp. abscessus erm(41) C28 sequevar and M. abscessus subsp. massiliense, not producing effective methylase, 100% (26/26) and 97.5% (39/40) of mutants had rrl mutations at position 2058 (A2058C, A2058G, A2058T) or position 2059 (A2059C, A2059G). The remaining M. abscessus subsp. massiliense mutant showed an 18-bp repeat insertion in rpIV, encoding the L22 protein. Our results showed that acquisition of clarithromycin resistance is 100% mediated by structural 50S ribosomal subunit mutations for M. abscessus subsp. abscessus erm(41) C28 and M. abscessus subsp. massiliense, whereas it is less common for M. abscessus subsp. abscessus erm(41) T28 sequevar and M. abscessus subsp. bolletii, where other mechanisms may be responsible for failure.

“…The response rates for macrolide-based antibiotic therapy are much higher among patients with M. massiliense lung disease than among those with M. abscessus lung disease (8)(9)(10). This is likely due to the presence of a functional ribosomal methyl transferase erm (41) gene in M. abscessus, which results in inducible macrolide resistance, observed as susceptibility to macrolides at day 3 but resistance at day 14 of drug susceptibility testing (DST).…”

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confidence: 99%

Clinical Characteristics and Treatment Outcomes of Patients with Macrolide-Resistant Mycobacterium massiliense Lung Disease

Choi

Kim

Lee

et al. 2017

Macrolide antibiotics are cornerstones in the treatment of Mycobacterium massiliense lung disease. Despite the emergence of resistance, limited data on macrolide-resistant M. massiliense lung disease are available. This study evaluated the clinical features and treatment outcomes of patients and the molecular characteristics of macrolide-resistant M. massiliense isolates. We performed a retrospective review of medical records and genetic analyses of clinical isolates from 15 patients who had macrolide-resistant M. massiliense lung disease between September 2005 and February 2015. Nine patients (60%) had the nodular bronchiectatic form of the disease, and six (40%) had the fibrocavitary form. Before the detection of macrolide resistance, three patients (20%) were treated with macrolide monotherapy, four (27%) with therapy for presumed Mycobacterium avium complex infections, and eight (53%) with combination antibiotic therapy for M. massiliense lung disease. The median treatment duration after the detection of resistance was 18.7 months (interquartile range, 11.2 to 39.8 months). Treatment outcomes were poor, with a favorable outcome being achieved for only one patient (7%), who underwent surgery in addition to antibiotic therapy. The 1-, 3-, and 5-year mortality rates were 7, 13, and 33%, respectively. Of the 15 clinical isolates, 14 (93%) had point mutations at position 2058 (n ϭ 9) or 2059 (n ϭ 5) of the 23S rRNA gene, resulting in macrolide resistance. Our study indicates that treatment outcomes are poor and mortality rates are high after the development of macrolide resistance in patients with M. massiliense lung disease. Thus, preventing the development of macrolide resistance should be a key consideration during treatment.KEYWORDS nontuberculous mycobacteria, Mycobacterium massiliense, macrolides, drug resistance P ulmonary disease caused by nontuberculous mycobacteria (NTM) is increasing worldwide (1, 2); for patients with chronic lung diseases, such as bronchiectasis or cystic fibrosis, the Mycobacterium abscessus complex (MABC) is the most important cause of pulmonary infections due to rapidly growing mycobacteria (3, 4). Currently, the MABC can be divided into three subspecies, i.e., M. abscessus subsp. abscessus (hereafter M. abscessus), M. abscessus subsp. massiliense (hereafter M. massiliense), and M. abscessus subsp. bolletii (hereafter M. bolletii) (5, 6). Of the three subspecies, M.