<i>In Vitro</i> Activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas aeruginosa Isolated by Clinical Laboratories in 40 Countries from 2012 to 2015

Abstract

The combination of the monobactam aztreonam and the non-β-lactam β-lactamase inhibitor avibactam is currently in clinical development for the treatment of serious infections caused by metallo-β-lactamase (MBL)-producing <i>Enterobacteriaceae</i>, a difficult-to-treat subtype of carbapenem-resistant <i>Enterobacteriaceae</i> for which therapeutic options are currently very limited. The present study tested clinically significant isolates of <i>Enterobacteriaceae</i> (<i>n</i> = 51,352) and <i>Pseudomonas aeruginosa</i> (<i>n</i> = 11,842) collected from hospitalized patients in 208 medical center laboratories from 40 countries from 2012 to 2015 for <i>in vitro</i> susceptibility to aztreonam-avibactam, aztreonam, and comparator antimicrobial agents using a standard broth microdilution methodology. Avibactam was tested at a fixed concentration of 4 μg/ml in combination with 2-fold dilutions of aztreonam. The MIC₉₀s of aztreonam-avibactam and aztreonam were 0.12 and 64 μg/ml, respectively, for all <i>Enterobacteriaceae</i> isolates; >99.9% of all isolates and 99.8% of meropenem-nonsusceptible isolates (<i>n</i> = 1,498) were inhibited by aztreonam-avibactam at a concentration of ≤8 μg/ml. PCR and DNA sequencing identified 267 <i>Enterobacteriaceae</i> isolates positive for MBL genes (NDM, VIM, IMP); all <i>Enterobacteriaceae</i> carrying MBLs demonstrated aztreonam-avibactam MICs of ≤8 μg/ml and a MIC₉₀ of 1 μg/ml. Against all <i>P. aeruginosa</i> isolates tested, the MIC₉₀ of both aztreonam-avibactam and aztreonam was 32 μg/ml; against MBL-positive <i>P. aeruginosa</i> isolates (<i>n</i> = 452), MIC₉₀ values for aztreonam-avibactam and aztreonam were 32 and 64 μg/ml, respectively. The current study demonstrated that aztreonam-avibactam possesses potent <i>in vitro</i> activity against a recent, sizeable global collection of <i>Enterobacteriaceae</i> clinical isolates, including isolates that were meropenem nonsusceptible, and against MBL-positive isolates of <i>Enterobacteriaceae</i>, for which there are few treatment options.