title: Supporting the ceftaroline fosamil/avibactam Enterobacteriaceae breakpoint determination using humanised in vivo exposures in a thigh model.
abstract: Previous in vivo studies using a human-simulated regimen of ceftaroline/avibactam 600/600mg every 8h (q8h) showed activity against extended-spectrum β-lactamase-, AmpC- and KPC-producing Enterobacteriaceae with minimum inhibitory concentrations (MICs) ≤ 1 μg/mL. Here we sought to determine the efficacy of this human-simulated regimen against organisms with MICs ≥ 1 μg/mL to help determine a breakpoint value that would reliability predict efficacy in humans. In total, 31 isolates (1 Escherichia coli, 9 Klebsiella pneumoniae, 9 Enterobacter cloacae, 1 Citrobacter koseri, 2 Serratia marcescens, 1 Klebsiella oxytoca and 8 Pseudomonas aeruginosa) with ceftaroline/avibactam MICs of 1 to 16 μg/mL were tested in a murine immunocompromised thigh infection model; 15 isolates were also tested in an immunocompetent model. Doses were given to simulate human free drug exposures of ceftaroline fosamil/avibactam 600/600 mg q8h over 24h as a 1-h infusion by targeting the fT>MIC profile. Efficacy was evaluated as the change in log10 CFU compared with 0-h controls after 24h. Reductions in bacterial CFU in the neutropenic model were seen against a majority of isolates tested with MICs ≤ 4 μg/mL, where fT>MIC was >55%. More variable efficacy was seen in isolates with MICs ≥ 8 μg/mL, where fT>MIC drops below 40%. Overall activity was enhanced in the immunocompetent model. The humanised regimen of ceftaroline fosamil/avibactam 600/600 mg q8h as a 1-h infusion showed predictable efficacy against isolates with various genotypic and phenotypic profiles and MICs ≤ 4 μg/mL. These data provide valuable information to help determine a ceftaroline/avibactam breakpoint for Enterobacteriaceae.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: Amira A
authors.initials: AA
authors.lastname: Bhalodi
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.affiliation: Cerexa, Inc., Oakland, CA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Williams
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA; Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA. Electronic address: David.Nicolau@hhchealth.org.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D053961:Azabicyclo Compounds / Q000008:administration & dosage*; D002511:Cephalosporins / Q000008:administration & dosage*; D004195:Disease Models, Animal; D016972:Enterobacter cloacae / Q000187:drug effects; D004755:Enterobacteriaceae / Q000187:drug effects*; D004756:Enterobacteriaceae Infections / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects; D005260:Female; D006801:Humans; D007710:Klebsiella Infections / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D015203:Reproducibility of Results; D013848:Thigh; D001618:beta-Lactamases; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D002511:Cephalosporins; D001618:beta-Lactamases; D000097583:Ceftaroline; C543519:avibactam
keywords: Avibactam; Breakpoint; Ceftaroline fosamil; Enterobacteriaceae