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

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)-producingEnterobacteriaceae , a difficult-to-treat subtype of carbapenem-resistantEnterobacteriaceae for which therapeutic options are currently very limited. The present study tested clinically significant isolates ofEnterobacteriaceae (n = 51,352) andPseudomonas aeruginosa (n = 11,842) collected from hospitalized patients in 208 medical center laboratories from 40 countries from 2012 to 2015 forin vitro 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 MIC90 s of aztreonam-avibactam and aztreonam were 0.12 and 64 μg/ml, respectively, for allEnterobacteriaceae isolates; >99.9% of all isolates and 99.8% of meropenem-nonsusceptible isolates (n = 1,498) were inhibited by aztreonam-avibactam at a concentration of ≤8 μg/ml. PCR and DNA sequencing identified 267Enterobacteriaceae isolates positive for MBL genes (NDM, VIM, IMP); allEnterobacteriaceae carrying MBLs demonstrated aztreonam-avibactam MICs of ≤8 μg/ml and a MIC90 of 1 μg/ml. Against allP. aeruginosa isolates tested, the MIC90 of both aztreonam-avibactam and aztreonam was 32 μg/ml; against MBL-positiveP. aeruginosa isolates (n = 452), MIC90 values for aztreonam-avibactam and aztreonam were 32 and 64 μg/ml, respectively. The current study demonstrated that aztreonam-avibactam possesses potentin vitro activity against a recent, sizeable global collection ofEnterobacteriaceae clinical isolates, including isolates that were meropenem nonsusceptible, and against MBL-positive isolates ofEnterobacteriaceae , for which there are few treatment options.