Molecular Analysis of Linezolid-Resistant Clinical Isolates of
 Mycobacterium abscessus

Ye, Meiping; Xu, Liyun; Zou, Yuzhen; Li, Bing; Guo, Qi; Zhang, Yongjie; Zhan, Mengling; Xu, Benyong; Yu, Fangyou; Zhang, Zhemin; Chu, Haiqing

doi:10.1128/aac.01842-18

Cited by 24 publications

(23 citation statements)

References 25 publications

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“…Accumulated evidence suggests that linezolid possesses elevated anti- M. abscessus activity. Recently, we reported the high activity expressed by linezolid in vitro against clinical M. abscessus isolates collected from patients with lung diseases (10). A study conducted using a Drosophila melanogaster -infection model demonstrated the anti- M. abscessus activity of linezolid in vivo (23); the successful use of linezolid in treating clinical M. abscessus infections was also reported (24).…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported a series of studies demonstrating the antibiotic susceptibility of clinical M. abscessus isolates and the treatment outcomes of patients diagnosed with M. abscessus pulmonary disease (10–13). A number of cases accumulated during the course of these studies dealt with the long-term treatment with antibiotics, including linezolid and tigecycline; the adverse effects of antibiotic treatment were well documented.…”

Section: Introductionmentioning

confidence: 99%

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Clinical Efficacy and Adverse Effects of Antibiotics Used to Treat Mycobacterium abscessus Pulmonary Disease

Chen

Zhao

Mao

et al. 2019

Preprint

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21 Treatment of Mycobacterium abscessus pulmonary infection requires long-term 22 administration of multiple antibiotics. Little is known, however, about the impact 23 of each antibiotic on treatment outcomes. A retrospective analysis was conducted to 24 evaluate the efficacy and adverse effects of antibiotics administered in 244 cases of M. 25 abscessus pulmonary disease. Only 110 (45.1%) patients met the criteria for treatment 26 success. Treatment with amikacin (AOR, 3.275; 95% CI, 1.221 -8.788), imipenem 27 (AOR, 2.078; 95% CI, 1.151 -3.753), linezolid (AOR, 2.231; 95% CI, 1.078 -4.616) 28 and tigecycline (AOR, 2.040; 95% CI, 1.079 -3.857) was successful. The incidence 29 of adverse effects was high (192/244, 78.7%). Severe adverse effects were 30 primarily: ototoxicity (14/60, 23.3%) caused by amikacin; gastrointestinal 31 (14/60, 23.3%) caused by tigecycline; and myelosuppression (5/60, 8.3%) 32 caused by linezolid. In conclusion, the rate of success in treating M. abscessus 33 pulmonary disease is still unsatisfactory; the administration of amikacin, imipenem, 34 linezolid and tigecycline correlated with increased treatment success. Adverse side 35 effects are common due to the long-term and combined antibiotic therapy. 36 Ototoxicity, gastrointestinal and myelosuppression are the most severe. 37 Keywords: Mycobacterium abscessus, pulmonary disease, drug, efficacy, adverse 38 effect. 39 40 129 radiographic improvement, adjusting for age, sex, BMI and radiographic features. 130 Statistical significance was set at a two-sided p value of less than 0.05. 131 132

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical Efficacy and Adverse Effects of Antibiotics Used to Treat Mycobacterium abscessus Pulmonary Disease

Chen

Zhao

Mao

et al. 2019

Preprint

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“…In the case of thiacetazone analogs, mutations in the TetR repressor MAB_4384 led to upregulation of the adjacent genes encoding an MmpS-MmpL efflux pump system (35,36). Increased expression of MAB_4746, encoding a member of the MmpL family, was also reported recently in LNZ-resistant isolates (37). In the case of CFZ, where CFZ-resistant strains demonstrated cross-resistance to BDQ (29), whole-genome sequencing analyses of the in vitro-selected resistors uncovered point mutations in MAB_2299c (29), a member of the TetR family of transcriptional regulators, representing the most abundant family of regulators in mycobacteria.…”

Section: Discussionmentioning

confidence: 55%

The TetR Family Transcription Factor MAB_2299c Regulates the Expression of Two Distinct MmpS-MmpL Efflux Pumps Involved in Cross-Resistance to Clofazimine and Bedaquiline in Mycobacterium abscessus

Gutiérrez

Richard

Roquet-Banères

et al. 2019

Antimicrob Agents Chemother

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Mycobacterium abscessus is a human pathogen responsible for severe respiratory infections, particularly in patients with underlying lung disorders. Notorious for being highly resistant to most antimicrobials, new therapeutic approaches are needed to successfully treat M. abscessus-infected patients. Clofazimine (CFZ) and bedaquiline (BDQ) are two antibiotics used for the treatment of multidrug-resistant tuberculosis and are considered alternatives for the treatment of M. abscessus pulmonary disease. To get insights into their mechanisms of resistance in M. abscessus, we previously characterized the TetR transcriptional regulator MAB_2299c, which controls expression of the MAB_2300-MAB_2301 genes, encoding an MmpS-MmpL efflux pump. Here, in silico studies identified a second mmpS-mmpL (MAB_1135c-MAB_1134c) target of MAB_2299c. A palindromic DNA sequence upstream of MAB_1135c, sharing strong homology with the one located upstream of MAB_2300, was found to form a complex with the MAB_2299c regulator in electrophoretic mobility shift assays. Deletion of MAB_1135c-1134c in a wild-type strain led to increased susceptibility to both CFZ and BDQ. In addition, deletion of these genes in a CFZ/BDQ-susceptible mutant lacking MAB_2299c as well as MAB_2300-MAB_2301 further exacerbated the sensitivity of this strain to both drugs in vitro and inside macrophages. Overall, these results indicate that MAB_1135c-1134c encodes a new MmpS-MmpL efflux pump system involved in the intrinsic resistance to CFZ and BDQ. They also support the view that MAB_2299c controls the expression of two separate MmpS-MmpL efflux pumps, substantiating the importance of MAB_2299c as a marker of resistance to be considered when assessing drug susceptibility in clinical isolates.

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“…One hundred and nighty-four clinical isolates were collected as described previously from the sputum and bronchoalveolar lavage fluid samples of patients with lung infections in Shanghai Pulmonary Hospital. 11,14 Isolates were initially screened for non-tuberculosis mycobacteria by growth in MGIT960 culture medium and resistance to p-nitrobenzoic acid. M. abscessus was identified by sequencing the rpoB and erm(41) genes.…”

Section: Bacteriamentioning

confidence: 99%

Zinc Chelator N,N,N′,N′-Tetrakis(2-Pyridylmethyl)Ethylenediamine Reduces the Resistance of Mycobacterium abscessus to Imipenem

Zou

Zhan

et al. 2020

IDR

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Imipenem is one of the very few effective options for treating Mycobacterium abscessus (M. abscessus) infections; the development of imipenem resistance is a major health concern. Materials and Methods: The susceptibility of 194 clinical M. abscessus isolates to imipenem was determined. The ability of imipenem to synergize with N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN), a zinc chelator and a metallo-β-lactamases (MBLs) inhibitor, to inhibit M. abscessus growth was also assessed. Results: M. abscessus exhibited an elevated resistance to imipenem (MIC 50 = 16 mg/L, MIC 90 = 64 mg/L). A combination of TPEN and imipenem synergized to inhibit the growth of 100% of imipenem-resistant and 79.2% of imipenem-resistance intermediate isolates; no synergy was observed treating imipenem-sensitive isolates. A remarkable decrease in the MIC 50 (from 16 to 4 mg/L) and MIC 90 (from 64 to 8 mg/L) of imipenem was observed when it was combined with TPEN; the portion of imipenem-resistant isolates also decreased (from 48.4% to 0%). Consistent with these results demonstrating synergy, a time-kill assay showed the addition of TPEN significantly improved the bactericidal activity of imipenem toward M. abscessus. Similarly, EDTA (a potent MBLs inhibitor) promoted the anti-M. abscessus activity of imipenem in a disk assay, corroborating the effect of TPEN and supporting the role of MBLs in imipenem resistance exhibited by some isolates. Conclusion: These findings demonstrate that TPEN can reduce the resistance of M. abscessus to imipenem and suggest that the inhibition of MBLs activity is the underlying mechanism.

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Molecular Analysis of Linezolid-Resistant Clinical Isolates of Mycobacterium abscessus

Abstract: A total of 194 Mycobacterium abscessus isolates were collected from patients, and the whole genomes were sequenced. Eighty-five (43.8%) isolates showed linezolid (LZD) resistance.

Cited by 24 publications

References 25 publications

Clinical Efficacy and Adverse Effects of Antibiotics Used to Treat Mycobacterium abscessus Pulmonary Disease

Clinical Efficacy and Adverse Effects of Antibiotics Used to Treat Mycobacterium abscessus Pulmonary Disease

The TetR Family Transcription Factor MAB_2299c Regulates the Expression of Two Distinct MmpS-MmpL Efflux Pumps Involved in Cross-Resistance to Clofazimine and Bedaquiline in Mycobacterium abscessus

<p>Zinc Chelator N,N,N′,N′-Tetrakis(2-Pyridylmethyl)Ethylenediamine Reduces the Resistance of <em>Mycobacterium abscessus</em> to Imipenem</p>

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