Pharmacokinetic-Pharmacodynamic Analysis for Efficacy of Ceftaroline Fosamil in Patients with Acute Bacterial Skin and Skin Structure Infections

Ceftaroline is a cephalosporin with broad-spectrumin vitro activity against pathogens commonly associated with acute bacterial skin and skin structure infections (ABSSSI), including methicillin-resistantStaphylococcus 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 withS. 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 withS. aureus infections. Univariable analysis based on data from all of the patients and those withS. aureus infections demonstrated significant relationships betweenf %T >MIC and microbiological response (P < 0.001 andP = 0.026, respectively). Multivariable logistic regression analyses demonstrated other patient factors in addition tof %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 withS. 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.