Mycobacteriological characteristics and treatment outcomes in extrapulmonary Mycobacterium abscessus complex infections
Suk Hyeon JeongSu‐Young KimHee Jae HuhChang‐Seok KiNam Yong LeeCheol‐In KangDoo Ryeon ChungKyong Ran PeckSung Jae ShinWon‐Jung Koh
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Abstract:
The differentiation between Mycobacterium abscessus subspecies abscessus (M. abscessus) and Mycobacterium abscessus subspecies massiliense (M. massiliense) and determination of the presence of inducible resistance to macrolide antibiotics are important factors in the management of patients with Mycobacterium abscessus complex (MABC) infections. Unlike pulmonary MABC infections, little information on extrapulmonary MABC infections is available.The molecular identification of clinical isolates was performed, and the clinical characteristics and treatment outcomes of 20 consecutive patients with extrapulmonary MABC infections were assessed.M. abscessus and M. massiliense each caused 10 (50%) of the cases. Eight (80%) M. abscessus isolates that had inducible resistance to clarithromycin harbored an intact erm(41) gene of the T28 variant, whereas two (20%) M. abscessus isolates had the C28 erm(41) variant and were susceptible to clarithromycin. All M. massiliense isolates had a truncated erm(41) gene and were susceptible to clarithromycin. The drug susceptibility profiles other than clarithromycin were similar for the M. abscessus and M. massiliense isolates. Of the 20 patients, 17 (85%) showed a favorable outcome, including all patients with M. massiliense infection and 70% (7/10) of patients with M. abscessus infection. Favorable outcomes were associated with M. massiliense and M. abscessus isolates with a non-functional erm(41) gene (p=0.049).Precise species and subspecies identification and the determination of macrolide susceptibility are recommended for the optimal treatment of extrapulmonary MABC infections.Keywords:
Mycobacterium abscessus
Subspecies
Nontuberculous Mycobacteria
Mycobacterium abscessus
Mycobacterium chelonae
Mycobacterium fortuitum
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The differentiation between Mycobacterium abscessus subspecies abscessus (M. abscessus) and Mycobacterium abscessus subspecies massiliense (M. massiliense) and determination of the presence of inducible resistance to macrolide antibiotics are important factors in the management of patients with Mycobacterium abscessus complex (MABC) infections. Unlike pulmonary MABC infections, little information on extrapulmonary MABC infections is available.The molecular identification of clinical isolates was performed, and the clinical characteristics and treatment outcomes of 20 consecutive patients with extrapulmonary MABC infections were assessed.M. abscessus and M. massiliense each caused 10 (50%) of the cases. Eight (80%) M. abscessus isolates that had inducible resistance to clarithromycin harbored an intact erm(41) gene of the T28 variant, whereas two (20%) M. abscessus isolates had the C28 erm(41) variant and were susceptible to clarithromycin. All M. massiliense isolates had a truncated erm(41) gene and were susceptible to clarithromycin. The drug susceptibility profiles other than clarithromycin were similar for the M. abscessus and M. massiliense isolates. Of the 20 patients, 17 (85%) showed a favorable outcome, including all patients with M. massiliense infection and 70% (7/10) of patients with M. abscessus infection. Favorable outcomes were associated with M. massiliense and M. abscessus isolates with a non-functional erm(41) gene (p=0.049).Precise species and subspecies identification and the determination of macrolide susceptibility are recommended for the optimal treatment of extrapulmonary MABC infections.
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Objectives . Clarithromycin is recommended as the core agent for treating M. abscessus infections, which usually calls for at least one year of treatment course, facilitating the development of resistance. This study aimed to identify the underlying mechanism of in vivo development of clarithromycin resistance in M. abscessus clinical isolates. Methods . M. abscessus isolates from patients with lung infections during long-term antibiotic therapy were longitudinally collected and sequenced. PFGE DNA fingerprinting was used to confirm the genetic relationships of the isolates. Whole genome comparative analysis was performed to identify the genetic determinants that confer the clarithromycin resistance. Results . Three pairs of initially clarithromycin-susceptible and subsequently clarithromycin-resistant M. abscessus isolates were obtained. We found that the clarithromycin-resistant isolates emerged relatively rapidly, after 4–16 months of antibiotic therapy. PFGE DNA fingerprinting showed that the clarithromycin-resistant isolates were identical to the initial clarithromycin-susceptible ones. Whole genome sequencing and bioinformatics analysis identified several genetic alternations in clarithromycin-resistant isolates, including genes encoding efflux pump/transporter, integral component of membrane, and the tetR and lysR family transcriptional regulators. Conclusion . We identified genes likely encoding new factors contributing to clarithromycin-resistance phenotype of M. abscessus , which can be useful in prediction of clarithromycin resistance in M. abscessus .
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Mycobacterium abscessus is a ubiquitous, rapidly growing species of nontuberculous mycobacteria that colonizes organic surfaces and is frequently associated with opportunistic infections in humans. We report here the draft genome sequence of Mycobacterium abscessus strain M139, which shows genomic features reported to be characteristic of both Mycobacterium abscessus subsp. abscessus and Mycobacterium abscessus subsp. massiliense.
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Background: Mycobacterium abscessus is the most pathogenic and drug-resistant rapid-growing mycobacterium.Clarithromycin or azithromycin are the only regular oral antimycobacterial agents that have an effect on M. abscessus.We tried to detect the clarithromycin-resistant strains from the clinical isolates of M. abscessus.Methods: We tried to isolate the clarithromycin-resistant strains from 220 clinical isolates of M. abscessus by performing using reverse hybridization assay (RHA) and the broth microdilution test (BMT).Results: Seven resistant strains (3.2%) from all the tested clinical isolates were detected by BMT.Three of these resistant strains were also detected by RHA and it was confirmed that they had point mutants.Conclusion: These results showed that clarithromycin resistance in M. abscessus clinical isolates is related to a point mutation and other unknown mechanisms.(
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Mycobacterium abscessus accounts for a large proportion of lung disease cases caused by rapidly growing mycobacteria. The association between clarithromycin sensitivity and treatment outcome is clear. However, M. abscessus culture and antibiotic susceptibility testing are time-consuming. Clarithromycin susceptibility genotyping offers an alternate, rapid approach to predicting the efficacy of clarithromycin-based antibiotic therapy. M. abscessus lung disease patients were divided into two groups based upon the clarithromycin susceptibility genotype of the organism isolated. A retrospective analysis was conducted to compare the clinical features, microbiological characteristics, and treatment outcomes of the two groups. Several other potential predictors of the response to treatment were also assessed. Sixty-nine patients were enrolled in the clarithromycin-resistant genotype group, which included 5 infected with rrl 2058-2059 mutants and 64 infected with erm(41)T28-type M. abscessus; 31 were in the clarithromycin-sensitive group, i.e., 6 and 25 patients infected with genotypes erm(41)C28 and erm(41) M type, respectively. The results showed that lung disease patients infected with clarithromycin-sensitive and -resistant M. abscessus genotypes differed significantly in clarithromycin-based combination treatment outcomes. Patients infected with the clarithromycin-sensitive genotype exhibited higher initial and final sputum-negative conversion and radiological improvement rates and better therapeutic outcomes. Multivariate analysis demonstrated that genotyping was a reliable and, more importantly, rapid means of predicting the efficacy of clarithromycin-based antibiotic treatment for M. abscessus lung disease.
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Abstract Nontuberculous Mycobacteria (NTM) are a group of emerging bacterial pathogens that have been identified in cystic fibrosis (CF) patients with microbial lung infections. The treatment of NTM infection in CF patients is challenging due to the natural resistance of NTM species to many antibiotics. Mycobacterium abscessus is one of the most common NTM species found in the airways of CF patients. In this study, we characterized the extracellular vesicles (EVs) released by drug‐sensitive M. abscessus untreated or treated with clarithromycin (CLR), one of the frontline anti‐NTM drugs. Our data show that exposure to CLR increases mycobacterial protein trafficking into EVs as well as the secretion of EVs in culture. Additionally, EVs released by CLR‐treated M. abscessus increase M. abscessus resistance to CLR when compared to EVs from untreated M. abscessus . Proteomic analysis further indicates that EVs released by CLR‐treated M. abscessus carry an increased level of 50S ribosomal subunits, the target of CLR. Taken together, our results suggest that EVs play an important role in M. abscessus resistance to CLR treatment.
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Abstract Background Mycobacterium abscessus group belongs to a group of rapidly growing mycobacteria (RGM) and, following Mycobacterium avium complex, is the second most common pathogen responsible for lung disease caused by nontuberculous mycobacteria (NTM). Clarithromycin is known to be the key drug in the treatment of M. abscessus group disease, but a high failure rate of treatment response is reported due to clarithromycin inducible resistance. Methods Using the results from a clarithromycin susceptibility test we examined the proportion of clarithromycin inducible resistant M. abscessus (sensu stricto; hereafter referred to as M. abscessus) clinical strains. Also, we attempted to detect the clarithromycin resistant strains, using the amplification refractory mutation system-PCR (ARMS-PCR) and real-time PCR methods for rapid detection of single-nucleotide polymorphisms (SNPs) at position 28 (T or C) of the erm(41) gene of M. abscessus leading to resistance to clarithromycin. Results Of the 157 M. abscessus clinical strains, clarithromycin susceptible, resistant, and inducible resistant strains accounted for 10.83% (n = 17), 22.29% (n = 35), and 66.88% (n = 105), respectively. Clarithromycin resistant strains were able to separate from clarithromycin susceptible strains by ARMS-PCR and real-time PCR identical to DNA sequence analysis. Conclusion Most M. abscessus clinical strains in Korea are resistant to clarithromycin, and ARMS-PCR and real-time PCR are useful tools for the rapid detection of single-nucleotide polymorphisms (SNPs) at position 28 of the erm(41) gene.
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The ribosomal methylase Erm(41) confers inducible resistance to macrolides in Mycobacterium abscessus. The aim of this work was to systematically study and compare drug susceptibility to clarithromycin and azithromycin in M. abscessus and Mycobacterium chelonae clinical isolates with a particular focus on inducible drug resistance. Clinical isolates of M. abscessus subsp. abscessus (n = 21), M. abscessus subsp. bolletii (n = 16), M. abscessus subsp. massiliense (n = 10) and M. chelonae (n = 22) were characterized regarding their erm(41) and rrl genotypes and subjected to drug susceptibility testing (DST) for clarithromycin and azithromycin. Microdilution DST was performed in cation-adjusted Mueller–Hinton broth (pH 7.4) with readings at days 3, 7 and 12 and with pre-incubation at subinhibitory macrolide concentrations for erm(41) induction. In addition, the influence of variations in pH and growth medium on DST results was examined. MICs of azithromycin were consistently higher than those of clarithromycin. In strains with an inducible erm(41) gene, high median MICs of ≥256 mg/L on day 12 were observed for both clarithromycin and azithromycin. Inducible resistance was at least as pronounced for azithromycin as for clarithromycin. Our findings do not support the suggestion of a preferential use of azithromycin over clarithromycin in order to limit inducible macrolide resistance. Both compounds provoked a comparable resistance phenotype in M. abscessus. Caution is needed when using either azithromycin or clarithromycin for treatment of M. abscessus infections.
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