Molecular characterization of clinical isolates of Enterobacterales with elevated MIC values for aztreonam-avibactam from the INFORM global surveillance study, 2012-2017

Objectives: While aztreonam-avibactam is a potent β-lactam-β-lactamase-inhibitor combination, reduced in vitro activity against some Enterobacterales isolates has been reported. In this study, globally collected clinical isolates of Enterobacterales with elevated minimum inhibitory concentrations (MICs) for aztreonam-avibactam were examined for potential resistance mechanisms.

Methods: Isolates with aztreonam-avibactam MICs ≥8 μg/mL (n = 55: Escherichia coli, n = 38; Enterobacter cloacae, n = 10; Klebsiella pneumoniae, n = 3; others, n = 4) and <8 μg/mL (n = 18) collected for the INFORM global surveillance programme were characterized by short read whole-genome sequencing. Sequences were inspected for the presence of β-lactamase genes, penicillin-binding protein (PBP) mutations, and disruptions in the coding sequences of porin genes.

Results: All isolates of E. coli testing with aztreonam-avibactam MIC values ≥8 μg/mL carried a previously documented four-amino-acid insertion in PBP3 at position 333 of YRI(K/N/P). Such mutations were absent in isolates with MICs <2 μg/mL (n = 6). Among other species, carriage of PER- or VEB-type β-lactamases was identified in 10/17 (58.8%) of isolates testing with aztreonam-avibactam MICs ≥8 μg/mL, but no isolates with lower MIC values (n = 11).

Conclusions: PBP3 mutations are known to confer resistance to aztreonam in E. coli, providing a rationale for the elevated MIC values for aztreonam-avibactam in these isolates. Elevated MICs in other isolates were associated with the carriage of PER-type β-lactamases, which have been previously shown to be inhibited less effectively by avibactam than other Class A β-lactamases and may contribute to this phenotype. Other resistance mechanisms contributing to poor in vitro activity for aztreonam-avibactam in some of these isolates are not yet elucidated.