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

• Published in: International journal of antimicrobial agents Vol. 61; no. 5; p. 106776
• Main Authors: Livermore, David M., Mushtaq, Shazad, Vickers, Anna, Woodford, Neil
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.05.2023
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Azabicyclo Compounds - pharmacology; Aztreonam - pharmacology; Aztreonam/avibactam; beta-Lactamases - genetics; beta-Lactamases - metabolism; Ceftazidime - pharmacology; Drug Combinations; Escherichia coli; Metallo-β-lactamases; Microbial Sensitivity Tests; NDM carbapenemase; PBP inserts; Penicillin-binding protein (PBP)3; Penicillin-Binding Proteins - genetics; United Kingdom; United Kingdom; Metallo-β-lactamases; Aztreonam/avibactam; NDM carbapenemase; Penicillin-binding protein (PBP)3; Escherichia coli; PBP inserts
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2023.106776

•Aztreonam/avibactam had unimodal minimum inhibitory concentrations (MICs) for Klebsiella spp. and Enterobacter spp. with metallo-β-lactamases.•Aztreonam/avibactam MICs were multi-modal for NDM-positive Escherichia coli with 15% resistance, changing little from 2015 to 2019.•Raised MICs for E. coli reflected four amino acid (YRIN or YRIK) penicillin-binding protein 3 inserts.•YRIK – or YRIN plus AmpC – was linked to MICs of 8–32 mg/L.•YRIN alone was linked to MICs of 0.5–4 mg/L. Aztreonam/avibactam is being developed on the rationale that aztreonam evades metallo-β-lactamases (MBLs) whilst avibactam protects aztreonam against co-produced serine β-lactamases. This study measured the activity of aztreonam/avibactam against MBL-producing Enterobacterales referred to the UK Health Security Agency in 2015, 2017 and 2019. Minimum inhibitory concentrations (MICs) were determined by broth microdilution, and genome sequences were determined with Illumina technology. For Klebsiella and Enterobacter spp. with NDM, IMP or VIM enzymes, the MICs of aztreonam/avibactam were distributed unimodally, 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 multi-modal 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 (defined as 0.5–4 mg/L) had YRIN inserts without acquired AmpC. Twenty-two of 24 E. coli isolates with normal MICs (defined as 0.03–0.25 mg/L) lacked PBP3 inserts. YRIK inserts were associated with E. coli ST405, and YRIN inserts with ST167; however, many isolates with high or moderately raised MICs were clonally diverse. No substantive MIC distribution shifts occurred across the three survey years; ST405 isolates with YRIK comprised more high-MIC organisms in 2019 compared with earlier years, but the apparent increase lacked significance (P>0.05).