title: Pharmacokinetic-pharmacodynamic analysis for efficacy of ceftaroline fosamil in patients with acute bacterial skin and skin structure infections.
abstract: Ceftaroline is a cephalosporin with broad-spectrum in vitro activity against pathogens commonly associated with acute bacterial skin and skin structure infections (ABSSSI), including methicillin-resistant Staphylococcus aureus. Ceftaroline fosamil, the prodrug of ceftaroline, is approved for the treatment of patients with ABSSSI. Using data from the microbiologically evaluable population from two phase 2 and two phase 3 randomized, multicenter, double-blind studies of patients with ABSSSI, an analysis examining the relationship between drug exposure, as measured by the percentage of time during the dosing interval that free-drug steady-state concentrations remain above the MIC (f%T>MIC), and clinical and microbiological responses was undertaken. The analysis population included 526 patients, of whom 423 had infections associated with S. aureus. Clinical and microbiological success percentages were 94.7 and 94.5%, respectively, among all of the patients and 95.3 and 95.7%, respectively, among those with S. aureus infections. Univariable analysis based on data from all of the patients and those with S. aureus infections demonstrated significant relationships between f%T>MIC and microbiological response (P < 0.001 and P = 0.026, respectively). Multivariable logistic regression analyses demonstrated other patient factors in addition to f%T>MIC to be significant predictors of microbiological response, including age and infection type for all of the patients evaluated and age, infection type, and the presence of diabetes mellitus for patients with S. aureus infections. Results of these analyses confirm that a ceftaroline fosamil dosing regimen of 600 mg every 12 h provides exposures associated with the upper plateau of the pharmacokinetic-pharmacodynamic relationship for efficacy.
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA SBhavnani@icpd.com.
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Hammel
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Van Wart
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rubino
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Reynolds
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Tampa, Florida, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
authors.affiliation: Forest Research Institute, Inc., Jersey City, New Jersey, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Khariton
authors.affiliation: Cerexa, Inc., Oakland, California, USA.
authors.forename: H David
authors.initials: HD
authors.lastname: Friedland
authors.affiliation: Forest Research Institute, Inc., Jersey City, New Jersey, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Riccobene
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002511:Cephalosporins / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D012867:Skin / Q000382:microbiology; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000382:microbiology; D016896:Treatment Outcome; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000097583:Ceftaroline