Exploring Aztreonam in Combination with Ceftazidime-Avibactam or Meropenem-Vaborbactam as Potential Treatments for Metallo- and Serine-β-Lactamase-Producing Enterobacteriaceae

Metallo-beta-lactamase (MBL)-producing Enterobacteriaceae, particularly those that coharbor serine beta-lactamases, are a serious emerging public health threat given their rapid dissemination and the limited number of treatment options. Preclinical 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. Eight clinical Enterobacteriaceae strains (4 Escherichia coli and 4 Klebsiella pneumoniae) coproducing NDM and at least one serine beta-lactamase were used for all experiments. Drugs were tested alone, in dual beta-lactam combinations, and in triple-drug combinations against all strains. 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. 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 beta-lactamases. Confirmation of these findings in future in vitro and in vivo models is warranted.