Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model

Abstract

The combination of ESBL production and porin loss in E. coli can result in reduced susceptibility to ertapenem. Porin-deficient subpopulations frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics. Inappropriate use of ertapenem should be avoided to minimize the risk of selection of ESBL-producing bacteria with reduced susceptibility to carbapenems.

Structural Alteration of OmpR as a Source of Ertapenem Resistance in a CTX-M-15-Producing Escherichia coli O25b:H4 Sequence Type 131 Clinical Isolate

“…Our study showed that the Gly-63-Val substitution in OmpR renders the expression of ompC and ompF inactive. These results are in agreement with the in vitro studies of Tängdén et al and Adler et al, which demonstrated that a single-step EnvZ-or OmpR-inactivating mutation was enough to significantly increase the MIC for ertapenem due to a subsequent reduction of OmpC and/or OmpF of up to 90% (23,24). Our report provides further evidence for the clinical relevance of OmpR change in the emergence of ertapenem resistance among E. coli clinical isolates.…”

“…On the other hand, the MIC of E. coli ErtR for imipenem remained unchanged. This discrepancy, which was also evidenced in the study of Tängdén et al (23), could be attributable to the intrinsic hydrolysis spectrum of CTX-M ␤-lactamases. The full restoration of the MIC value of E. coli ErtR for meropenem by clavulanic acid supported this hypothesis.…”

“…To the best of our knowledge, this is the first time that an OmpR variant presents a structural alteration at position 63, at the extremity of the ␣-3 helix in the vicinity of the ␤-3 strand that harbors the histidine-kinase phosphorylation site Asp-55. The OmpR variants that were previously described had structural changes at different positions, such as R45S, L112R, D100E, R209C, and I83T replacements (12,23). The glycine at position 63 is well conserved among various response regulators, suggesting that it plays a crucial role in the structureactivity relationship of this protein family.…”

Modulation of Membrane Influx and Efflux in Escherichia coli Sequence Type 131 Has an Impact on Bacterial Motility, Biofilm Formation, and Virulence in a Caenorhabditis elegans Model

“…Mutants resistant to these antibiotics were obtained for all the strains with the exception of the ESC-susceptible strains S250 and CFT073, for which no increase in ETP MICs was noted after 5 months of subculture. These results were in agreement with those of Tangden and Girlich, who also observed that carbapenem resistance in E. coli was selected only among ESBL-producing strains (27,47).…”

Pharmacodynamics of Fosfomycin: Insights into Clinical Use for Antimicrobial Resistance

“…Meropenem alone resulted in increased killing relative to fosfomycin, but it did not result in extinction. We did not observe any meropenem-resistant mutants, although it is possible that a low level of mutants was present but not detectable (30). The combination of fosfomycin and meropenem resulted in a Ͼ10-log 10 CFU/ml kill and sterilization of the bacterial inoculum after 48 h of treatment.…”