title: Efficacy of human simulated exposures of ceftaroline against phenotypically diverse Enterobacteriaceae isolates.
abstract: Ceftaroline fosamil, a new broad-spectrum cephalosporin, exhibits potent bactericidal activity against common Gram-negative pathogens, including Enterobacteriaceae, and Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The purpose of this study was to evaluate the efficacy of a human simulated dose of ceftaroline fosamil against clinical Enterobacteriaceae in both neutropenic and immunocompetent mouse thigh infection models. Thirty-five Enterobacteriaceae isolates with ceftaroline MICs ranging from 0.25 to 32 μg/ml were selected for the neutropenic model, and five Escherichia coli isolates were also tested in the immunocompetent model. Two hours after inoculation, the ceftaroline fosamil human simulated regimen of 600 mg intravenously (i.v.) every 12 h was administered. The change in log(10) CFU after 24 h was compared to that in 0 h controls. The human simulated regimen produced predictable efficacy against 18 of 20 isolates with a MIC of ≤ 1 μg/ml. Similar efficacy was seen in the immunocompetent model against isolates with a MIC of ≤ 2 μg/ml, and enhanced efficacy was observed against the isolate with a MIC of 4 μg/ml. Human simulated exposures to ceftaroline fosamil at 600 mg every 12 h provided predictable efficacy against Enterobacteriaceae with MICs of ≤ 1 μg/ml and enhanced efficacy within the immunocompetent model, supporting the clinical utility of ceftaroline fosamil against these organisms.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Seth T
authors.initials: ST
authors.lastname: Housman
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Keel
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.forename: Gregory
authors.initials: G
authors.lastname: Williams
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002511:Cephalosporins / Q000008:administration & dosage / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D004334:Drug Administration Schedule; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D004756:Enterobacteriaceae Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D007121:Immunocompetence; D007275:Injections, Intravenous; D007709:Klebsiella / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D010641:Phenotype; D013848:Thigh / Q000382:microbiology; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000097583:Ceftaroline