title: In vivo efficacy of humanized ceftaroline fosamil-avibactam exposures in a polymicrobial infection model.
abstract: Although Gram-positive cocci are the most common pathogens in diabetic foot infections, these infections often are polymicrobial. The objective of this study was to assess the efficacy of a simulated human dose of 600 mg ceftaroline fosamil-600 mg avibactam every 8 h as a 1-h infusion in a polymicrobial in vivo murine model. Seven isolates were used (3 methicillin-resistant Staphylococcus aureus [MRSA] isolates, 1 methicillin-susceptible S. aureus [MSSA] isolate, 1 Escherichia coli isolate, 1 Enterobacter cloacae isolate, and 1 Bacteroides fragilis isolate) in various combinations in an immunocompromised polymicrobial tissue infection to assess the efficacy of the simulated regimen. Each infection was comprised of at least one S. aureus isolate with a MIC of 0.25 to 1 μg/ml and one Enterobacteriaceae isolate with a MIC of 1 or 4 μg/ml. Eight of 16 infections also included B. fragilis, with a MIC of 0.5 μg/ml, as a third organism. Efficacy was evaluated after 24 h as the change in log10 CFU from the level of 0-h controls. Efficacy was seen against all isolate combinations, with at least a 1-log kill against Enterobacteriaceae and a minimum of a 2-log kill against S. aureus and B. fragilis isolates. These bacterial reductions correlate with free drug concentration above the MIC (fT>MIC) produced by the humanized regimen of 100, 86, and 56% at MICs of 1, 2, and 4 μg/ml, respectively. The humanized regimen of 600 mg ceftaroline fosamil-600 mg avibactam every 8 h as a 1-h infusion showed predictable efficacy against all infections tested in this model. These data support further clinical investigation of ceftaroline fosamil-avibactam for the treatment of polymicrobial tissue infections.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Amira A
authors.initials: AA
authors.lastname: Bhalodi
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 / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001441:Bacteroides fragilis / Q000187:drug effects / Q000254:growth & development; D002511:Cephalosporins / Q000494:pharmacology*; D060085:Coinfection; D004334:Drug Administration Schedule; D004338:Drug Combinations; D016972:Enterobacter cloacae / Q000187:drug effects / Q000254:growth & development; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D016867:Immunocompromised Host; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D016896:Treatment Outcome; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D002511:Cephalosporins; D004338:Drug Combinations; D000097583:Ceftaroline; C543519:avibactam
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