Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48- and NDM-Producing Escherichia coli and Klebsiella pneumoniae

Abstract

Double-carbapenem combinations have shown synergistic potential against carbapenemase-producing Enterobacterales, but data remain inconclusive. This study evaluated the activity of double-carbapenem combinations against 51 clinical KPC-2-, OXA-48-, NDM-1, and NDM-5-producing Escherichia coli and Klebsiella pneumoniae and against constructed E. coli strains harboring genes encoding KPC-2, OXA-48, or NDM-1 in an otherwise isogenic background. Two-drug combinations of ertapenem, meropenem, and doripenem were evaluated in 24 h time-lapse microscopy experiments with a subsequent spot assay and in static time-kill experiments. An enhanced effect in time-lapse microscopy experiments at 24 h and synergy in the spot assay was detected with one or more combinations against 4/14 KPC-2-, 17/17 OXA-48-, 2/17 NDM-, and 1/3 NDM-1+OXA-48-producing clinical isolates. Synergy rates were higher against meropenem- and doripenem-susceptible isolates and against OXA-48 producers. NDM production was associated with significantly lower synergy rates in E. coli. In time-kill experiments with constructed KPC-2-, OXA-48- and NDM-1-producing E. coli, 24 h synergy was not observed; however, synergy at earlier time points was found against the KPC-2- and OXA-48-producing constructs. Our findings indicate that the benefit of double-carbapenem combinations against carbapenemase-producing E. coli and K. pneumoniae is limited, especially against isolates that are resistant to the constituent antibiotics and produce NDM.

Antimicrobial combination effects against multidrug‐resistant Acinetobacter baumannii and Pseudomonas aeruginosa strains: A cross‐sectional study

“…The synergistic effect of double‐carbapenem combination has been reported against K. pneumoniae and P. aeruginosa . 30 Although a previous study showed a considerable decrease in MICs of MER in combination with doripenem, 31 the low frequency of significant amounts of FICI in our study demonstrates that using double‐carbapenem combination as a treatment choice for carbapenem‐resistant Gram‐negative bacteria is not always appropriate. However, FICI amounts of MER‐IMI were significant in isolates lacking MBL enzymes.…”

Genomic characterization of a WHO critical priority isolate Enterobacter kobei ST2070 harboring OXA-10, KPC-2, and CTX-M-12 recovered from a water irrigation channel in Ecuador

“…The isolate UTA41 co-harbor the OXA-10-type class D β-lactamase and the KPC-2-type class A β-lactamase. This co-carriage was observed on different studies of Klebsiella pneumoniae from clinical origin on Sweden, Taiwan, and Russia [ [34] , [35] , [36] ]. KPC-2 has become the most clinically important carbapenemases enzyme due to its prevalence in enteric bacteria from human, animal and environmental origin [ [37] , [38] , [39] ].…”