Dataset Information

Colistin-resistance gene mcr in clinical carbapenem-resistant Enterobacteriaceae strains in China, 2014-2019.

ABSTRACT: To investigate whether introduction of colistin into the clinical settings selected colistin-resistant CRE, we performed molecular epidemiological study of 1868 CRE strains collected from different geographical locales in China during the period 2014-2019. 1755 (96.18%) isolates carried the carbapenemase genes bla_KPC and bla_NDM; 14 Escherichia coli isolates (0.75%) carrying mcr-1 and bla_NDM (MCR-CREC) were also identified. Importantly, the number and relative prevalence of MCR-CREC isolates increased from 5 (0.41%) to 9 (1.38%) after introduction of polymyxin into clinical practice. Consistently, results of genetic analysis indicated that MCR-CREC strains collected before December 2017 were genetically diverse, yet those collected after that date exhibited more closely related genetic profiles, indicating that specific MCR-CREC strains were rapidly selected as a result of increased usage of colistin in clinical settings. The resistance level of MCR-CREC isolates to colistin increased after the introduction of polymyxin into clinical use with the MIC to colistin from <2 mg/L in 80% strains to 2 mg/L in 100% strains. Further dissemination of MCR-CREC strains, which exhibit resistance to the last-line drugs of carbapenems and colistin, is expected to pose a severe threat to human health.

SUBMITTER: Huang H

PROVIDER: S-EPMC7034111 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Colistin-resistance gene mcr in clinical carbapenem-resistant Enterobacteriaceae strains in China, 2014-2019.

Huang Hong H Dong Ning N Shu Lingbin L Lu Jiayue J Sun Qiaoling Q Chan Edward Wai-Chi EW Chen Sheng S Zhang Rong R

Emerging microbes & infections 20200129 1

To investigate whether introduction of colistin into the clinical settings selected colistin-resistant CRE, we performed molecular epidemiological study of 1868 CRE strains collected from different geographical locales in China during the period 2014-2019. 1755 (96.18%) isolates carried the carbapenemase genes blaKPC and blaNDM; 14 Escherichia coli isolates (0.75%) carrying mcr-1 and blaNDM (MCR-CREC) were also identified. Impor ...[more]

PMID: 31996107

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Project description:Colistin has been considered a last-line option for the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). Heterogeneous resistance to colistin leads to unexplained clinical colistin treatment failure for CRKP. Our study aimed to investigate the extent of colistin heteroresistance among CRKP strains in China. A total of 455 colistin-susceptible strains, collected from six tertiary care hospitals in China, were characterized. The overall rate of colistin heteroresistance was 6.2%, as determined by the population analysis profiles (PAPs). Genomic analysis revealed that 60.7% of the colistin-heteroresistant isolates belonged to the epidemic sequence type 11 (ST11) clone. Single-nucleotide polymorphisms (SNPs) suggested that 6 ST5216 strains shared the same origin. Each of the subpopulations had a ≥8-fold decrease in colistin MIC in the presence of carbonyl cyanide m-chlorophenylhydrazone (CCCP), which indicated that heteroresistance could be suppressed by an efflux pump inhibitor. In addition, our results suggested that the PhoPQ pathway plays an important role in the mechanisms of heteroresistance. IMPORTANCE The problem of CRKP has raised alarms concerning global health. Our study enriches the epidemiological study of colistin heteroresistance among CRKP strains in China, where the prevalence of this phenomenon was previously unknown. Importantly, colistin-heteroresistant strains may cause the failure of clinical treatment with colistin, even if the clinical laboratory reports that the strains are sensitive. The commonly used broth microdilution method is unable to detect this special phenomenon. Additionally, our results indicate that efflux pumps play a major role in colistin heteroresistance, and inhibitors can effectively reverse it. Our study is the first to provide a detailed analysis of the prevalence of colistin heteroresistance in China, as well as an analysis of the genetic mechanisms of this phenomenon.

Project description:BackgroundWith an increase in the use of colistin methansulfonate (CMS) to treat carbapenem-resistant Acinetobacter baumannii infections, colistin resistance is emerging.MethodsPatients with infection or colonization due to colistin-resistant A. baumannii were identified at a hospital system in Pennsylvania. Clinical data were collected from electronic medical records. Susceptibility testing, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. To investigate the mechanism of colistin resistance, lipid A was subjected to matrix-assisted laser desorption/ionization mass spectrometry.ResultsTwenty patients with colistin-resistant A. baumannii were identified. Ventilator-associated pneumonia was the most common type of infection. Nineteen patients had received intravenous and/or inhaled CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection prior to identification of colistin-resistant isolates. The 30-day all-cause mortality rate was 30%. The treatment regimen for colistin-resistant A. baumannii infection associated with the lowest mortality rate was a combination of CMS, a carbapenem, and ampicillin-sulbactam. The colistin-susceptible and -resistant isolates from the same patients were highly related by PFGE, but isolates from different patients were not, suggesting evolution of resistance during CMS therapy. By MLST, all isolates belonged to the international clone II, the lineage that is epidemic worldwide. Phosphoethanolamine modification of lipid A was present in all colistin-resistant A. baumannii isolates.ConclusionsColistin-resistant A. baumannii occurred almost exclusively among patients who had received CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection. Lipid A modification by the addition of phosphoethanolamine accounted for colistin resistance. Susceptibility testing for colistin should be considered for A. baumannii identified from CMS-experienced patients.

Project description:BackgroundThe current understanding of acquired chromosomal colistin resistance mechanisms in Enterobacterales primarily involves the disruption of the upstream PmrAB and PhoPQ two-component system (TCS) control caused by mutations in the regulatory genes. Interestingly, previous studies have yielded conflicting results regarding the interaction of regulatory genes related to colistin resistance in Escherichia coli, specifically those surrounding PhoPQ and PmrAB TCS.ResultsIn our study, we focused on two clinical non-mcr colistin-resistant strains of E. coli, TSAREC02 and TSAREC03, to gain a better understanding of their resistance mechanisms. Upon analysis, we discovered that TSAREC02 had a deletion (Δ27-45) in MgrB, as well as substitutions (G206R, Y222H) in PmrB. On the other hand, TSAREC03 exhibited a long deletion (Δ84-224) in PhoP, along with substitutions (M1I, L14P, P178S, T235N) in PmrB. We employed recombinant DNA techniques to explore the interaction between the PhoPQ and PmrAB two-component systems (TCSs) and examine the impact of the mutated phoPQ and pmrB genes on the minimum inhibitory concentrations (MICs) of colistin. We observed significant changes in the expression of the pmrD gene, which encodes a connector protein regulated by the PhoPQ TCS, in the TSAREC02 wild-type (WT)-mgrB replacement mutant and the TSAREC03 WT-phoP replacement mutant, compared to their respective parental strains. However, the expressions of pmrB/pmrA, which reflect PmrAB TCS activity, and the colistin MICs remained unchanged. In contrast, the colistin MICs and pmrB/pmrA expression levels were significantly reduced in the pmrB deletion mutants from both TSAREC02 and TSAREC03, compared to their parental strains. Moreover, we were able to restore colistin resistance and the expressions of pmrB/pmrA by transforming a plasmid containing the parental mutated pmrB back into the TSAREC02 and TSAREC03 mutants, respectively.ConclusionWhile additional data from clinical E. coli isolates are necessary to validate whether our findings could be broadly applied to the E. coli population, our study illuminates distinct regulatory pathway interactions involving colistin resistance in E. coli compared to other species of Enterobacterales. The added information provided by our study contribute to a deeper understanding of the complex pathway interactions within Enterobacterales.

Dataset Information

Colistin-resistance gene mcr in clinical carbapenem-resistant Enterobacteriaceae strains in China, 2014-2019.

Publications

Colistin-resistance gene <i>mcr</i> in clinical carbapenem-resistant <i>Enterobacteriaceae</i> strains in China, 2014-2019.

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