title: In vivo efficacy of a human-simulated regimen of ceftaroline combined with NXL104 against extended-spectrum-beta-lactamase (ESBL)-producing and non-ESBL-producing Enterobacteriaceae.
abstract: Ceftaroline exhibits in vitro activity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producing Enterobacteriaceae when combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 against Enterobacteriaceae in a murine thigh infection model. Twelve Enterobacteriaceae isolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log(10) CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to ≥ 2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤ 1 μg/ml and could be useful in combating the growing threat of resistant Enterobacteriaceae.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA.
authors.forename: Dora E
authors.initials: DE
authors.lastname: Wiskirchen
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.forename: Guilherme H
authors.initials: GH
authors.lastname: Furtado
authors.forename: Gregory
authors.initials: G
authors.lastname: Williams
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002511:Cephalosporins / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology* / Q000472:pathogenicity; D004756:Enterobacteriaceae Infections / Q000188:drug therapy*; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D013848:Thigh / Q000382:microbiology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism*; D000097583:Ceftaroline
chemical_list: D053961:Azabicyclo Compounds; D002511:Cephalosporins; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D000097583:Ceftaroline; C543519:avibactam