Searching for the Optimal Treatment for Metallo- and Serine-β-Lactamase Producing Enterobacteriaceae: Aztreonam in Combination with Ceftazidime-avibactam or Meropenem-vaborbactam

Abstract

Objective: Metallo-β-lactamase (MBL)-producing Enterobacteriaceae, particularly those that co-harbor serine β-lactamases, are a serious emerging public health threat given their rapid dissemination and the limited number of treatment options. Pre-clinical and anecdotal clinical data support the use of aztreonam in combination with ceftazidime-avibactam against these pathogens, but other aztreonam-based combinations have not been explored. The objective of this study was to evaluate the in vitro activity and compare synergy between aztreonam in combination with ceftazidime-avibactam and meropenem-vaborbactam against serine and MBL-producing Enterobacteriaceae via time-kill analyses. Methods: 8 clinical Enterobacteriaceae strains (4 Escherichia coli and 4 Klebsiella pneumoniae) co-producing NDM and at least one serine β-lactamase were used for all experiments. Drugs were tested alone, in dual β-lactam combinations, and in triple drug combinations against all strains. Results: All strains were resistant to ceftazidime-avibactam and meropenem-vaborbactam and 7/8 (87.5%) strains were resistant to aztreonam. Aztreonam combined with ceftazidime-avibactam was synergistic against all 7 aztreonam-resistant strains. Aztreonam combined with meropenem-vaborbactam was synergistic against all aztreonam-resistant strains with the exception of an OXA-232-producing K. pneumoniae strain. Neither triple combination was synergistic against the aztreonam-susceptible strain. Likewise, neither dual β-lactam combination was synergistic against any strain. Conclusions: These data suggest that aztreonam plus meropenem-vaborbactam has similar activity to aztreonam plus ceftazidime-avibactam against Enterobacteriaceae producing NDM and other non-OXA-48-like serine β-lactamases. Confirmation of these findings in future in vitro and in vivo models is warranted.

FIG 1

Mean log₁₀ CFU/ml versus time profiles for each drug at the highest concentration tested against the four E. coli strains. Aztreonam is shown at fC_max (A and C) and at 4× MIC (B and D). Ceftazidime and meropenem are shown at fC_max in all panels. Curves represent average concentrations from triplicate experiments.

FIG 2

Mean log₁₀ CFU/ml versus time profiles for each drug at the highest concentration tested against the four K. pneumoniae strains. (A to D) All drugs are shown at fC_max. Curves represent average concentrations from triplicate experiments.

FIG 3

Mean log₁₀ CFU/ml versus time profiles for each individual drug at the highest concentration tested that demonstrated no activity and triple-drug combinations against the four E. coli strains. (A to D) Ceftazidime-avibactam and meropenem-vaborbactam are shown at fC_max alone and in combination. (A and C) Aztreonam is shown at fC_max alone and in combination. Aztreonam is shown at 1× MIC (B) and at 0.25× MIC (D) alone and in combination. Curves represent average concentrations from triplicate experiments.

FIG 4

Mean log₁₀ CFU/ml versus time profiles for each individual drug at the highest concentration tested that demonstrated no activity and triple drug combinations against the four K. pneumoniae strains. (A to D) All drugs are shown alone and in combination at fC_max. Curves represent average concentrations from triplicate experiments.