title: Activities of ceftazidime and avibactam against β-lactamase-producing Enterobacteriaceae in a hollow-fiber pharmacodynamic model.
abstract: Avibactam is a novel non-β-lactam β-lactamase inhibitor that is currently undergoing phase 3 clinical trials in combination with ceftazidime. Ceftazidime is hydrolyzed by a broad range of β-lactamases, but avibactam is able to inhibit the majority of these enzymes. The studies described here attempt to provide insight into the amount of avibactam required to suppress bacterial growth in an environment where the concentrations of both agents are varying as they would when administered to humans. Following the simulation of a single intravenous dose of the drug, ceftazidime alone had no effect on any test organism, but a ceftazidime-avibactam combination resulted in rapid killing of all of the strains, with growth suppressed for the 8 h of the study. For seven of eight strains, this was achieved with a 1-g-250-mg profile, but a 2-g-500-mg profile was necessary to completely suppress a high-level-AmpC-producing isolate. When ceftazidime was infused continuously for 24 h with a single bolus dose of avibactam, rapid killing of all of the strains was again observed, with growth suppressed for 10 to >24 h. Regrowth appeared to commence once the avibactam concentration dropped below a critical concentration of approximately 0.3 μg/ml. In a third series of studies, ceftazidime was administered every 8 h for 24 h with avibactam administered at fixed concentrations for short periods during each ceftazidime dose profile. Simulating a 1-g dose of ceftazidime, an avibactam pulse of >0.25 and <0.5 μg/ml was required to suppress growth for 24 h.
authors.affiliation: Novexel SA, Romainville, France.
authors.forename: Ken
authors.initials: K
authors.lastname: Coleman
authors.affiliation: Novexel SA, Romainville, France.
authors.forename: Premavathy
authors.initials: P
authors.lastname: Levasseur
authors.affiliation: Novexel SA, Romainville, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Girard
authors.affiliation: Novexel SA, Romainville, France.
authors.forename: Monica
authors.initials: M
authors.lastname: Borgonovi
authors.affiliation: Novexel SA, Romainville, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Miossec
authors.affiliation: Novexel SA, Romainville, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Merdjan
authors.affiliation: Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA.
authors.forename: George
authors.initials: G
authors.lastname: Drusano
authors.affiliation: Anti-infectives Consulting, LLC, Stonington, Connecticut, USA.
authors.forename: David
authors.initials: D
authors.lastname: Shlaes
authors.affiliation: AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA wright.nichols@astrazeneca.com.
authors.forename: Wright W
authors.initials: WW
authors.lastname: Nichols
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D002442:Ceftazidime / Q000008:administration & dosage / Q000494:pharmacology*; D016971:Citrobacter freundii / Q000187:drug effects / Q000201:enzymology; D004359:Drug Therapy, Combination; D016972:Enterobacter cloacae / Q000187:drug effects / Q000201:enzymology; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology; D004756:Enterobacteriaceae Infections / Q000382:microbiology*; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D065093:beta-Lactamase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; C543519:avibactam; D002442:Ceftazidime; D001618:beta-Lactamases