title: Pharmacodynamic profiling of ceftobiprole for treatment of complicated skin and skin structure infections.
abstract: Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin (meticillin)-resistant staphylococci, was statistically noninferior to a combination of vancomycin plus ceftazidime in patients with complicated skin and skin structure infections (cSSSI). This analysis used data from this clinical trial to determine the relationship between therapeutic outcome and the percentage of time that the unbound ceftobiprole concentration exceeds the MIC (percent T>MIC). From the trial of ceftobiprole (500 mg every 8 h, 2-h infusion) for cSSSI due to gram-positive and/or gram-negative bacteria, data from 309 patients in the microbiological intent-to-treat analysis set with measured ceftobiprole concentrations and baseline MICs were used to assess the relationship between percent T>MIC and therapeutic outcome. Individual pharmacokinetic (PK) profiles were obtained from a three-compartment population PK model. The relationship between percent T>MIC and a clinical cure was determined. For the clinical trial dosing regimen, individual percent T>MICs were used to calculate fractional target attainment rates (TARs) for >or=30 and >or=50% T>MIC targets at various MICs. There was a statistically significant relationship between achieving a >or=30 or >or=50% T>MIC and a clinical cure (P = 0.003 and P = 0.007, respectively; Pearson's chi(2) test). The fractional TAR was greater than 90% at a MIC of <or=4 mg/liter for patients with normal renal function. A relationship between percent T>MIC and a clinical cure with ceftobiprole was demonstrated. A ceftobiprole regimen of 500 mg every 8 h as a 2-h infusion has a high probability of achieving a target of >or=30 or >or=50% T>MIC for patients with cSSSI due to gram-positive and gram-negative pathogens.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, LLC, 920 Route 202 South, Raritan, NJ 08869, USA. HKimko@its.jnj.com
authors.forename: Holly
authors.initials: H
authors.lastname: Kimko
authors.forename: Xu
authors.initials: X
authors.lastname: Xu
authors.forename: Partha
authors.initials: P
authors.lastname: Nandy
authors.forename: Mahesh N
authors.initials: MN
authors.lastname: Samtani
authors.forename: Richard S
authors.initials: RS
authors.lastname: Strauss
authors.forename: Partha
authors.initials: P
authors.lastname: Bagchi
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Noel
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002442:Ceftazidime / Q000627:therapeutic use; D002511:Cephalosporins / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D012874:Skin Diseases, Infectious / Q000188:drug therapy* / Q000382:microbiology*; D016896:Treatment Outcome; D014640:Vancomycin / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C443755:ceftobiprole; D014640:Vancomycin; D002442:Ceftazidime