In Vitro Activity of Ceftazidime-Avibactam and Aztreonam-Avibactam against OXA-48-Carrying Enterobacteriaceae Isolated as Part of the International Network for Optimal Resistance Monitoring (INFORM) Global Surveillance Program from 2012 to 2015

Abstract

Enterobacteriaceae producing the Ambler class D OXA-48 carbapenemase, combined with additional resistance mechanisms, such as permeability defects or cocarriage of class A, B, or C β-lactamases, can become highly resistant to most β-lactams currently in use, including carbapenems. A total of 45,872 Enterobacteriaceae clinical isolates collected in 39 countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance study in 2012 to 2015 were tested for susceptibility to β-lactams and comparator agents using the Clinical and Laboratory Standards Institute broth microdilution methodology and screened for the presence of β-lactamases. The bla_OXA-48 and bla_OXA-48-like genes were detected in 333 isolates across 14 species of Enterobacteriaceae collected in 20 countries across the globe. Few agents tested were effective in vitro against the overall collection of OXA-48-producers (n = 265), with tigecycline (MIC₉₀, 2 µg/ml; 92.5% susceptible), ceftazidime-avibactam (MIC₉₀, 4 µg/ml; 92.5% susceptible), and aztreonam-avibactam (MIC₉₀, 0.5 µg/ml; 99.6% of isolates with MIC ≤8 µg/ml) demonstrating the greatest activity. Similarly, colistin (MIC₉₀, 1 µg/ml; 94.2% susceptible), tigecycline (MIC₉₀, 2 µg/ml; 92.6% susceptible), ceftazidime-avibactam (MIC₉₀, >128 µg/ml; 89.7% susceptible), and aztreonam-avibactam (MIC₉₀, 4 µg/ml; 100% of isolates with MIC ≤8 µg/ml) were most active against OXA-48-like-positive isolates (n = 68). The in vitro activity of ceftazidime-avibactam was improved against the subset of metallo-β-lactamase (MBL)-negative, OXA-48- and OXA-48-like-positive isolates (99.2% and 100% susceptible, respectively). The data reported here support the continued investigation of ceftazidime-avibactam and aztreonam-avibactam for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae carrying OXA-48 and OXA-48-like β-lactamases in combination with serine- or metallo-β-lactamases.