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Genetic Evolution of Mycobacterium abscessus Conferring Clarithromycin Resistance during Long-Term Antibiotic Therapy.

ABSTRACT: 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.

SUBMITTER: Li B

PROVIDER: S-EPMC7142343 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genetic Evolution of <i>Mycobacterium abscessus</i> Conferring Clarithromycin Resistance during Long-Term Antibiotic Therapy.

Li Bing B Guo Qi Q Mao Yanhua Y Zou Yuzhen Y Zhang Yongjie Y Zhang Zhemin Z Chu Haiqing H

Canadian respiratory journal 20200328

<h4>Objectives</h4>Clarithromycin is recommended as the core agent for treating <i>M. abscessus</i> 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 <i>in vivo</i> development of clarithromycin resistance in <i>M. abscessus</i> clinical isolates.<h4>Methods</h4><i>M. abscessus</i> isolates from patients with lung infections during long-term antibiotic therapy were longit ...[more]

PMID: 32300380

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Project description:PURPOSE:Clarithromycin was considered the cornerstone for the treatment of Mycobacterium abscessus complex infections. Genetic resistance mechanisms have been described and many experts propose amikacin as an alternative. Nevertheless, clarithromycin has several advantages; therefore, it is necessary to identify the non-functional erm(41) allele to determine the most suitable treatment. The aims of this study were to characterize the molecular mechanisms of clarithromycin resistance in a collection of Mycobacterium abscessus complex isolates and to verify the relationship between these mechanisms and the antibiogram. MATERIALS AND METHODS:Clinical isolates of M. abscessus complex (n = 22) from 16 patients were identified using four housekeeping genes (rpoB, secA1, sodA and hsp65), and their genetic resistance was characterized by studying erm(41) and rrl genes. Nine strains were recovered from the clinical isolates and subjected to E-test and microdilution clarithromycin susceptibility tests, with readings at 3, 7 and 14 days. RESULTS:We classified 11/16 (68.8%) M. abscessus subsp. abscessus, 4/16 (25.0%) M. abscessus subsp. bolletii, and 1/16 (6.3%) M. abscessus subsp. massiliense. T28 erm(41) allele was observed in 8 Mycobacterium abscessus subps. abscessus and 3 Mycobacterium abscessus subsp. bolletii. One strain of M. abscessus subsp. bolletii had an erm(41) gene truncated and was susceptible to clarithromycin. No mutations were observed in rrl gene first isolates. In three patients, follow-up of initial rrl wild-type strains showed acquired resistance. CONCLUSIONS:Most clinical isolates of M. abscessus complex had inducible resistance to clarithromycin and total absence of constitutive resistance. Our findings showed that the acquisition of resistance mutations in rrl gene was associated with functional and non-functional erm(41) gene. Caution is needed when using erm(41) sequencing alone to identify M. abscessus subspecies. This study reports an acquired mutation at position 2057 of rrl gene, conferring medium-low clarithromycin constitutive resistance.

Dataset Information

Genetic Evolution of Mycobacterium abscessus Conferring Clarithromycin Resistance during Long-Term Antibiotic Therapy.

Publications

Genetic Evolution of <i>Mycobacterium abscessus</i> Conferring Clarithromycin Resistance during Long-Term Antibiotic Therapy.

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