Activity of aztreonam/avibactam against metallo-β-Lactamase-producing Enterobacterales from the UK: Impact of penicillin-binding protein-3 inserts and CMY-42 β-lactamase in Escherichia coli

Aztreonam/avibactam is being developed on the rationale that aztreonam evades metallo-β-lactamases (MBLs) whilst avibactam protects against co-produced serine β-lactamases. We measured the activity of aztreonam/avibactam against MBL-producing Enterobacterales referred to the UKHSA in 2015, 2017, 2019. MICs were determined by broth microdilution, genome sequences with Illumina technology. For Klebsiella and Enterobacter spp. with NDM, IMP or VIM enzymes, the MICs of aztreonam/avibactam were unimodally distributed, with >90% of isolates inhibited at 1+4 mg/L, and all inhibited at 8+4 mg/L. Over 85% of Escherichia coli with NDM carbapenemases were inhibited at 8+4 mg/L, but their MIC distribution was multimodal, with major peaks at 0.12 and 8 mg/L. Forty-eight of 50 NDM E. coli with ‘high’ aztreonam/avibactam MICs (defined as ≥8 mg/L) had YRIK inserted after amino-acid 333 of penicillin-binding protein (PBP)3 or had a YRIN insert plus an acquired AmpC β-lactamase, commonly CMY-42. Ten of 15 E. coli with ‘moderately-raised’ aztreonam/avibactam MICs (0.5-4 mg/L) had YRIN inserts without acquired AmpC. Twenty-two of 24 E. coli isolates with ‘normal’ MICs (0.03-0.25 mg/L) lacked PBP3 inserts. YRIK inserts were associated with E. coli ST405 and YRIN with ST167; however, many isolates with high or moderately-raised MICs were clonally diverse. No substantive MIC distribution shifts occurred across the 3 survey years; ST405 isolates with YRIK comprised more high-MIC organisms in 2019 versus earlier years, but the apparent excess lacked significance (P >0.05).