title: Efficacy of a Ceftazidime-Avibactam combination in a murine model of Septicemia caused by Enterobacteriaceae species producing ampc or extended-spectrum β-lactamases.
abstract: Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been shown in vitro to inhibit class A, class C, and some class D β-lactamases. It is currently in phase 3 of clinical development in combination with ceftazidime. In this study, the efficacy of ceftazidime-avibactam was evaluated in a murine septicemia model against five ceftazidime-susceptible (MICs of 0.06 to 0.25 μg/ml) and 15 ceftazidime-resistant (MICs of 64 to >128 μg/ml) species of Enterobacteriaceae, bearing either TEM, SHV, CTX-M extended-spectrum, or AmpC β-lactamases. In the first part of the study, ceftazidime-avibactam was administered at ratios of 4:1 and 8:1 (wt/wt) to evaluate the optimal ratio for efficacy. Against ceftazidime-susceptible isolates of Klebsiella pneumoniae and Escherichia coli, ceftazidime and ceftazidime-avibactam demonstrated similar efficacies (50% effective doses [ED50] of <1.5 to 9 mg/kg of body weight), whereas against ceftazidime-resistant β-lactamase-producing strains (ceftazidime ED50 of >90 mg/kg), the addition of avibactam restored efficacy to ceftazidime (ED50 dropped to <5 to 65 mg/kg). In a subsequent study, eight isolates (two AmpC and six CTX-M producers) were studied in the septicemia model. Ceftazidime-avibactam was administered at a 4:1 (wt/wt) ratio, and the efficacy was compared to that of the 4:1 (wt/wt) ratio of either piperacillin-tazobactam or cefotaxime-avibactam. Against the eight isolates, ceftazidime-avibactam was the more effective combination, with ED50 values ranging from 2 to 27 mg/kg compared to >90 mg/kg and 14 to >90 mg/kg for piperacillin-tazobactam and cefotaxime-avibactam, respectively. This study demonstrates that the potent in vitro activity observed with the ceftazidime-avibactam combination against ceftazidime-resistant Enterobacteriaceae species bearing class A and class C β-lactamases translated into good efficacy in the mouse septicemia model.
authors.affiliation: Novexel SA, Romainville, France premalevasseur@sfr.fr.
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: Ludovic
authors.initials: L
authors.lastname: Lavallade
authors.affiliation: Novexel SA, Romainville, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Miossec
authors.affiliation: Novexel SA, Romainville, France.
authors.forename: John
authors.initials: J
authors.lastname: Pace
authors.affiliation: Novexel SA, Romainville, France.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Coleman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002442:Ceftazidime / Q000494:pharmacology / Q000627:therapeutic use*; D004338:Drug Combinations; D004926:Escherichia coli / Q000187:drug effects*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010878:Piperacillin / Q000494:pharmacology / Q000627:therapeutic use; D000077725:Piperacillin, Tazobactam Drug Combination; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D065093:beta-Lactamase Inhibitors; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D002442:Ceftazidime; C048795:AmpC beta-lactamases; D001618:beta-Lactamases; D010878:Piperacillin