Combinations of mutations inenvZ,ftsI,mrdA,acrBandacrRcan cause high-level carbapenem resistance inEscherichia coli

Adler, Marlen; Anjum, Mehreen; Andersson, Dan I.; Sandegren, Linus

doi:10.1093/jac/dkv475

Cited by 78 publications

(59 citation statements)

References 41 publications

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“…The expression of CMY-2 was not further increased in these mutants. Presumably, these mutants contain mutations in the genes for the targets of meropenem or mutations that affect the activity of drug efflux pumps (22), but this was not analyzed further. Considering the enhanced growth defect of mr42 relative to mr26 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Acquisition of Carbapenem Resistance by Plasmid-Encoded-AmpC-Expressing Escherichia coli

Boxtel

Wattel

Arenas

et al. 2017

Antimicrob Agents Chemother

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Although AmpC ␤-lactamases can barely degrade carbapenems, if at all, they can sequester them and prevent them from reaching their targets. Thus, carbapenem resistance in Escherichia coli and other Enterobacteriaceae can result from AmpC production and simultaneous reduction of antibiotic influx into the periplasm by mutations in the porin genes. Here we investigated the route and genetic mechanisms of acquisition of carbapenem resistance in a clinical E. coli isolate carrying bla CMY-2 on a plasmid by selecting for mutants that are resistant to increasing concentrations of meropenem. In the first step, the expression of OmpC, the only porin produced in the strain under laboratory conditions, was lost, leading to reduced susceptibility to meropenem. In the second step, the expression of the CMY-2 ␤-lactamase was upregulated, leading to resistance to meropenem. The loss of OmpC was due to the insertion of an IS1 element into the ompC gene or to frameshift mutations and premature stop codons in this gene. The bla CMY-2 gene was found to be located on an IncI␥ plasmid, and overproduction of the CMY-2 enzyme resulted from an increased plasmid copy number due to a nucleotide substitution in the inc gene. The clinical relevance of these genetic mechanisms became evident from the analysis of previously isolated carbapenem-resistant clinical isolates, which appeared to carry similar mutations.

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Section: Discussionmentioning

confidence: 99%

Acquisition of Carbapenem Resistance by Plasmid-Encoded-AmpC-Expressing Escherichia coli

Boxtel

Wattel

Arenas

et al. 2017

Antimicrob Agents Chemother

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“…Stepwise-carbapenem resistance in the absence of a carbapenemase or β-lactamase was reported in Sweden in 2016 when an E. coli ompC and ompF double-deletion mutant was passaged in meropenem or ertapenem for ~60 generations [Adler 2016]. Meropenem but not ertapenem passaging caused mutations in stringent response regulator enzymes, spoT , thrS , and tufA [Adler 2016].…”

Section: Non-carbapenemase Resistance Mechanismsmentioning

confidence: 99%

“…Meropenem but not ertapenem passaging caused mutations in stringent response regulator enzymes, spoT , thrS , and tufA [Adler 2016]. Increased stringent response activity is believed to contribute to carbapenem resistance but at a substantial fitness cost [Adler 2016]. …”

Section: Non-carbapenemase Resistance Mechanismsmentioning

confidence: 99%

The rapid spread of carbapenem-resistant Enterobacteriaceae

Potter

D’Souza

Dantas

2016

Drug Resistance Updates

318

211

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Carbapenems, our one-time silver bullet for multidrug resistant bacterial infections, are now threatened by widespread dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Successful expansion of Enterobacteriaceae clonal groups and frequent horizontal gene transfer of carbapenemase expressing plasmids are causing increasing carbapenem resistance. Recent advances in genetic and phenotypic detection facilitate global surveillance of CRE diversity and prevalence. In particular, whole genome sequencing enabled efficient tracking, annotation, and study of genetic elements colocalized with carbapenemase genes on chromosomes and on plasmids. Improved characterization helps detail the co-occurrence of other antibiotic resistance genes in CRE isolates and helps identify pan-drug resistance mechanisms. The novel β-lactamase inhibitor, avibactam, combined with ceftazidime or aztreonam, is a promising CRE treatment compared to current colistin or tigecycline regimens. To halt increasing CRE-associated morbidity and mortality, we must continue quality, cooperative monitoring and urgently investigate novel treatments.

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“…arbapenem resistance in Enterobacteriaceae has been reported to arise from one or a combination of the following mechanisms: carbapenemase production; reduced outer membrane permeability, often in the milieu of an extended-spectrum ␤-lactamase (ESBL), AmpC, or multiple ␤-lactamases; efflux across the outer membrane; or mutations in penicillin binding proteins (PBP) (1)(2)(3)(4)(5). Of these mechanisms, carbapenemase production is regarded as the most worrisome because many of the genes encoding carbapenemases reside on plasmids, creating the potential for hori-zontal spread.…”

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confidence: 99%

In Vitro Activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas aeruginosa Isolated by Clinical Laboratories in 40 Countries from 2012 to 2015

Karlowsky

Kazmierczak²,

Jonge

et al. 2017

Antimicrob Agents Chemother

145

107

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The combination of the monobactam aztreonam and the non-␤-lactam ␤-lactamase inhibitor avibactam is currently in clinical development for the treatment of serious infections caused by metallo-␤-lactamase (MBL)-producing Enterobacteriaceae, a difficult-to-treat subtype of carbapenem-resistant Enterobacteriaceae for which therapeutic options are currently very limited. The present study tested clinically significant isolates of Enterobacteriaceae (n ϭ 51,352) and Pseudomonas aeruginosa (n ϭ 11,842) collected from hospitalized patients in 208 medical center laboratories from 40 countries from 2012 to 2015 for in vitro susceptibility to aztreonam-avibactam, aztreonam, and comparator antimicrobial agents using a standard broth microdilution methodology. Avibactam was tested at a fixed concentration of 4 g/ml in combination with 2-fold dilutions of aztreonam. The MIC 90 s of aztreonam-avibactam and aztreonam were 0.12 and 64 g/ml, respectively, for all Enterobacteriaceae isolates; Ͼ99.9% of all isolates and 99.8% of meropenemnonsusceptible isolates (n ϭ 1,498) were inhibited by aztreonam-avibactam at a concentration of Յ8 g/ml. PCR and DNA sequencing identified 267 Enterobacteriaceae isolates positive for MBL genes (NDM, VIM, IMP); all Enterobacteriaceae carrying MBLs demonstrated aztreonam-avibactam MICs of Յ8 g/ml and a MIC 90 of 1 g/ml. Against all P. aeruginosa isolates tested, the MIC 90 of both aztreonam-avibactam and aztreonam was 32 g/ml; against MBL-positive P. aeruginosa isolates (n ϭ 452), MIC 90 values for aztreonam-avibactam and aztreonam were 32 and 64 g/ml, respectively. The current study demonstrated that aztreonam-avibactam possesses potent in vitro activity against a recent, sizeable global collection of Enterobacteriaceae clinical isolates, including isolates that were meropenem nonsusceptible, and against MBL-positive isolates of Enterobacteriaceae, for which there are few treatment options.

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Combinations of mutations inenvZ,ftsI,mrdA,acrBandacrRcan cause high-level carbapenem resistance inEscherichia coli

Cited by 78 publications

References 41 publications

Acquisition of Carbapenem Resistance by Plasmid-Encoded-AmpC-Expressing Escherichia coli

Acquisition of Carbapenem Resistance by Plasmid-Encoded-AmpC-Expressing Escherichia coli

The rapid spread of carbapenem-resistant Enterobacteriaceae

In Vitro Activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas aeruginosa Isolated by Clinical Laboratories in 40 Countries from 2012 to 2015

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