Activity of aztreonam/avibactam and ceftazidime/avibactam against Enterobacterales with carbapenemase-independent carbapenem resistance

• Published in: International journal of antimicrobial agents Vol. 63; no. 3; p. 107081
• Main Authors: Mushtaq, Shazad, Vickers, Anna, Woodford, Neil, Livermore, David M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.03.2024
• Subjects: Aztreonam/avibactam; Carbapenem-resistant Enterobacterales; Ceftazidime/avibactam; CMY-42 β-lactamase; Penicillin-binding protein (PBP)3; Carbapenem-resistant Enterobacterales; CMY-42 β-lactamase; Aztreonam/avibactam; Penicillin-binding protein (PBP)3; Ceftazidime/avibactam
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2023.107081

Enterobacterales with carbapenemase-independent resistance to carbapenems are sometimes selected during therapy and, on rare occasions, cause outbreaks. Most have extended-spectrum or AmpC β-lactamases, together with changes to permeability or penicillin-binding proteins (PBPs). Newer β-lactam–β-lactamase inhibitor combinations may present useful options for infections due to these organisms. Accordingly, Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing broth-microdilution was used to measure the minimum inhibitory concentrations (MICs) of ceftazidime/avibactam and aztreonam/avibactam for 51 carbapenemase-negative Enterobacterales with resistance or reduced susceptibility to carbapenems: genomic sequencing of the least-susceptible organisms was also undertaken. MICs of the two avibactam combinations cross-correlated closely, but with fewer MICs (2/51 vs. 10/51) exceeding 8+4 mg/L in the case of ceftazidime/avibactam. Raised MICs for Escherichia coli were associated with PBP3 inserts together with CMY-42 β-lactamase; correlates among Enterobacter cloacae complex isolates remain elusive, with AmpC and PBP3 sequences found to be species specific. In the case of Klebsiella spp., no MICs exceeding 2 mg/L were seen for either combination. It appears that these avibactam combinations have potential against Enterobacterales with carbapenemase-independent carbapenem resistance or reduced susceptibility, with ceftazidime/avibactam being more reliably active than aztreonam/avibactam.