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. 2022 Nov 17;11(11):1646.
doi: 10.3390/antibiotics11111646.

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

Lisa Allander  1 , Karin Vickberg  1 , Pernilla Lagerbäck  1 , Linus Sandegren  2 , Thomas Tängdén  1
Affiliations

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

Lisa Allander et al. Antibiotics (Basel). .

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.

Keywords: Gram-negative bacteria; carbapenem resistance; combination therapy; synergy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Example of output from time-lapse microscopy experiments. The images were obtained after 6 and 24 h of antibiotic exposure against OXA-48-producing E. coli (ARU891). Antibiotic concentrations are presented in mg/L. The BCA and SESAmax (in parentheses) values are presented below each image. If BCA and SESAmax exceed the predefined cut-off values (BCA > 8.0 and SESAmax > 5.8), indicating a bacterial density of approximately > 106 CFU/mL, the image is marked with a red outline. If BCA and/or SESAmax are below the cut-off values, the image is marked with a green outline. Abbreviations: ETP—ertapenem; MEM—meropenem; DOR—doripenem.
Figure 2
Figure 2
Mean bacterial concentrations during 24 h time-kill experiments with ertapenem, meropenem, and doripenem, alone and in two-drug combinations against E. coli ATCC 25922 wild-type and constructed carbapenemase-producing strains. (a) Ertapenem and meropenem; (b) Ertapenem and doripenem; (c) Meropenem and doripenem. The lower limit of detection (dotted line) was 1 log10 CFU/mL. Abbreviations: ETP—ertapenem; MEM—meropenem; DOR—doripenem.
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