Molecular Characterization of Clinical Isolates of Enterobacterales with Elevated MIC Values for Aztreonam-Avibactam from the INFORM Global Surveillance Study, 2012-2017.

Abstract

OBJECTIVES\nWhile 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.\n\n\nMETHODS\nIsolates with aztreonam-avibactam MICs ≥8\u2009µg/ml (n\u2009=\u200955: Escherichia coli, n\u2009=\u200938; Enterobacter cloacae, n\u2009=\u200910; Klebsiella pneumoniae, n\u2009=\u20093; others, n\u2009=\u20094) and <8\u2009µg/ml (n\u2009=\u200918) collected for the INFORM global surveillance program 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.\n\n\nRESULTS\nAll isolates of E. coli testing with aztreonam-avibactam MIC values ≥8\u2009µg/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\u2009µg/ml (n\u2009=\u20096). 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\u2009µg/ml, but no isolates with lower MIC values (n\u2009=\u200911).\n\n\nCONCLUSIONS\nPBP3 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.