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

Overview & Synopsis

BackgroundAztreonam is currently in Phase III clinical trials in combination with the β-lactamase inhibitor (BLI) avibactam. Avibactam allows the recovery of aztreonam activity against strains that co-produce metallo-β-lactamases (MBLs) and serine-β-lactamases (SBLs), which are able to hydrolyse this antibiotic (such as ESBLs or AmpC-type enzymes). MBLs have replaced KPC as the most common carbapenemase in some hospitals due to the recent increased use of ceftazidime-avibactam. The aim of this work was to evaluate the activity of aztreonam in combination with avibactam and other novel β-lactamase inhibitors in current clinical trials (such as relebactam, vaborbactam, zidebactam, taniborbactam and enmetazobactam) against MBL and SBL co-producing Enterobacterales strains from a Spanish multicentre collection.MethodsTwenty-three completely sequenced MBLs and SBLs co-producing Enterobacterales clinical isolates were included in the study (11 VIM-producers, 8 NDM-producers, and 4 IMP-producers, MBLs with global distribution). The most prevalent SBLs were CTX-M-15 (12 strains), OXA-1 (12 strains), and TEM-1 (7 strains). MICs for aztreonam, aztreonam/avibactam, aztreonam/relebactam, aztreonam/vaborbactam, aztreonam/zidebactam, aztreonam/taniborbactam and aztreonam/enmetazobactam were performed. The antimicrobial activity of all inhibitors was also tested. A concentration of 4 mg/L was used for all inhibitors in the aztreonam/BLI combinations and EUCAST MIC breakpoints to aztreonam were considered for all combinations.ResultsAztreonam/zidebactam combination showed the highest activity against all strains, 95.7% of strains displayed MIC≤1 mg/L and only 4.3% showed MIC≥8 mg/L (MIC breakpoints for susceptibility and resistance to aztreonam, respectively), even improving the activity shown by aztreonam/avibactam. Zidebactam, in contrast to the other inhibitors, showed antimicrobial activity alone (43.5% of strains showed MIC≤1 mg/L). The aztreonam/avibactam and aztreonam/taniborbactam combinations also showed high activity, more than 70% of the strains showed a MIC≤1 for both combinations, and more importantly, aztreonam-resistant strains decreased from 95% to less than 15%. The other combinations, although they improved the activity of aztreonam alone, showed more moderate results (Table).ConclusionsCombinations of aztreonam with new BLIs allow the recovery of the antibiotic's activity against MBL- and SBL co-producing Enterobacterales. Aztreonam/zidebactam, aztreonam/avibactam, and aztreonam/taniborbactam are the most active combinations against these strains. Further studies of these promising combinations aztreonam/novel BLIs are needed to know theirs in vitro and in vivo activity.