Activity of aztreonam in combination with novel β-lactamase inhibitors against metallo-β-lactamase-producing Enterobacterales from Spain.

Abstract

Metallo-β-lactamase (MBL)-producingEnterobacteralesare of particular concern because they are widely disseminated and difficult to treat, being resistant to almost all β-lactam antibiotics. Aztreonam is not hydrolysed by MBLs but is labile to serine β-lactamases (SBLs), which are usually co-produced by MBL-producing Enterobacterales. Here we report the activity of aztreonam in combination with novel β-lactamase inhibitors (BLIs) against a national multicentre study collection of strains co-producing MBLs and SBLs. Fifty-five clinical isolates co-producing MBLs (41 VIM-producers, 10 NDM-producers and 4 IMP-producers) and SBLs were selected, and whole-genomesequencing(WGS) was performed. Aztreonam, aztreonam/avibactam, aztreonam/relebactam, aztreonam/zidebactam, aztreonam/taniborbactam, aztreonam/vaborbactam and aztreonam/enmetazobactam MICs were determined. β-lactam/BLI resistance mechanisms were analysed by WGS. All BLIs decreased the aztreonam MICs for strains not susceptible to aztreonam. Aztreonam/zidebactam (MIC ≤1 mg/L for 96.4% of isolates), aztreonam/avibactam (MIC ≤1 mg/L for 92.7% of isolates) and aztreonam/taniborbactam (MIC ≤1 mg/L for 87.3 % of isolates) were the most active combinations. For other aztreonam/BLI combinations, 50-70% of the isolates yielded MICs ≤1 mg/L. WGS data revealed that mutations in PBP3, defective OmpE35/OmpK35 porins and the presence of ESBLs and class C β-lactamases were some of the resistance mechanisms involved in reduced susceptibility to aztreonam/BLIs. Combinations of aztreonam with new BLIs show promising activity against Enterobacterales co-producing MBLs and SBLs, particularly the aztreonam/zidebactam, aztreonam/avibactam and aztreonam/taniborbactam combinations. Our results show that these novel drugs may represent innovative therapeutic strategies by their use in yet unexplored combinations as solutions for difficult-to-treat infections.