title: In vitro activity of aztreonam-avibactam against a global collection of Gram-negative pathogens from 2012 and 2013.
abstract: The combination of aztreonam plus avibactam is being developed for use in infections caused by metallo-β-lactamase-producing Enterobacteriaceae strains that also produce serine β-lactamases. The in vitro activities of aztreonam-avibactam and comparator antimicrobials were determined against year 2012 and 2013 clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii using the broth microdilution methodology recommended by the Clinical and Laboratory Standards Institute (CLSI). A total of 28,501 unique clinical isolates were obtained from patients in 190 medical centers within 39 countries. MIC90 values of aztreonam and aztreonam-avibactam against all collected isolates of Enterobacteriaceae (n = 23,516) were 64 and 0.12 μg/ml, respectively, with 76.2% of the isolates inhibited by ≤4 μg/ml of aztreonam (the CLSI breakpoint) and 99.9% of the isolates inhibited by ≤4 μg/ml of aztreonam-avibactam using a fixed concentration of 4 μg/ml of avibactam. The MIC90 was 32 μg/ml for both aztreonam and aztreonam-avibactam against P. aeruginosa (n = 3,766). Aztreonam alone or in combination with avibactam had no in vitro activity against isolates of A. baumannii. PCR and sequencing were used to characterize 5,076 isolates for β-lactamase genes. Aztreonam was not active against most Enterobacteriaceae isolates producing class A or class C enzymes alone or in combination with class B metallo-β-lactamases. In contrast, >99% of Enterobacteriaceae isolates producing all observed Ambler classes of β-lactamase enzymes were inhibited by ≤4 μg/ml aztreonam in combination with avibactam, including isolates that produced IMP-, VIM-, and NDM-type metallo-β-lactamases in combination with multiple serine β-lactamases.
authors.affiliation: International Health Management Associates, Inc., Schaumburg, Illinois, USA dbiedenbach@ihmainc.com.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Biedenbach
authors.affiliation: International Health Management Associates, Inc., Schaumburg, Illinois, USA.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Kazmierczak
authors.affiliation: International Health Management Associates, Inc., Schaumburg, Illinois, USA.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Bouchillon
authors.affiliation: International Health Management Associates, Inc., Schaumburg, Illinois, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Sahm
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Bradford
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000472:pathogenicity; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001398:Aztreonam / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004755:Enterobacteriaceae / Q000187:drug effects / Q000472:pathogenicity; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000472:pathogenicity*; D016905:Gram-Negative Bacterial Infections / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity; D001618:beta-Lactamases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; C543519:avibactam; D001618:beta-Lactamases; D001398:Aztreonam