title: Assessment of the In Vitro Activity of Ceftazidime-Avibactam against Multidrug-Resistant Klebsiella spp. Collected in the INFORM Global Surveillance Study, 2012 to 2014.
abstract: Increasing resistance in Gram-negative bacilli, including Klebsiella spp., has reduced the utility of broad-spectrum cephalosporins. Avibactam, a novel non-β-lactam β-lactamase inhibitor, protects β-lactams from hydrolysis by Gram-negative bacteria that produce extended-spectrum β-lactamases (ESBLs) and serine carbapenemases, including Ambler class A and/or class C and some class D enzymes. In this analysis, we report the in vitro activity of ceftazidime-avibactam and comparators against multidrug-resistant (MDR) Klebsiella spp. from the 2012-2014 INFORM surveillance study. Isolates collected from 176 sites were sent to a central laboratory for confirmatory identification and tested for susceptibility to ceftazidime-avibactam and comparator agents, including ceftazidime alone. A total of 2,821 of 10,998 (25.7%) Klebsiella species isolates were classified as MDR, based on resistance to three or more classes of antimicrobials. Among the MDR isolates, 99.4% had an ESBL screen-positive phenotype, and 27.4% were not susceptible to meropenem as an example of a carbapenem. Ceftazidime-avibactam was highly active against MDR isolates, including ESBL-positive and serine carbapenemase-producing isolates, with MIC50/90 values of 0.5/2 μg/ml and 96.6% of all MDR isolates and ESBL-positive MDR isolates inhibited at the FDA breakpoint (MIC value of ≤8 μg/ml). Ceftazidime-avibactam did not inhibit isolates producing class B enzymes (metallo-β-lactamases) either alone or in combination with other enzymes. These in vitro results support the continued investigation of ceftazidime-avibactam for the treatment of MDR Klebsiella species infections.
authors.affiliation: International Health Management Associates, Schaumburg, Illinois, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Hackel
authors.affiliation: International Health Management Associates, Schaumburg, Illinois, USA kkazmierczak@ihmainc.com.
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Kazmierczak
authors.affiliation: International Health Management Associates, Schaumburg, Illinois, USA.
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Hoban
authors.affiliation: International Health Management Associates, Schaumburg, Illinois, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Biedenbach
authors.affiliation: International Health Management Associates, Schaumburg, Illinois, USA.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Bouchillon
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
authors.forename: Boudewijn L M
authors.initials: BL
authors.lastname: de Jonge
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Stone
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D002442:Ceftazidime / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D006801:Humans; D007709:Klebsiella / Q000187:drug effects* / Q000378:metabolism; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000378:metabolism; D008826:Microbial Sensitivity Tests / Q000379:methods; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; D002511:Cephalosporins; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D065093:beta-Lactamase Inhibitors; D002442:Ceftazidime; D001618:beta-Lactamases; C063912:carbapenemase