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Double-carbapenem combinations have shown synergistic potential against carbapenemase-producing <i>Enterobacterales,</i> 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 <i>Escherichia coli</i> and <i>Klebsiella pneumoniae</i> and against constructed <i>E. coli</i> 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 <i>E. coli</i>. In time-kill experiments with constructed KPC-2-, OXA-48- and NDM-1-producing <i>E. coli</i>, 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 <i>E. coli</i> and <i>K. pneumoniae</i> is limited, especially against isolates that are resistant to the constituent antibiotics and produce NDM.