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Probability of Target Attainment for Ceftobiprole as Derived from a Population Pharmacokinetic Analysis of 150 Subjects.

Lodise TP, Pypstra R, Kahn JB, Murthy BP, Kimko HC, Bush K, Noel G, Drusano GL

Ordway Research Institute, Albany, NY, Albany College of Pharmacy, Albany, NY, Basilea, Pharmaceutica, Basel, CH, Janssen-Ortho, Raritan, NJ, J&J Pharmaceutical Research & Development, Raritan, NJ.

Ceftobiprole is a broad-spectrum anti-MRSA cephalosporin currently undergoing phase III trials for complicated skin and skin structure infections and nosocomial pneumonia. The objectives were to describe the pharmacodynamic profiles of ceftobiprole 500mg IV Q8H (2 hour infusion) and 500mg IV Q12H (1 hour infusion), to determine the overall probability of target attainment (PTA) by weighting for the expected distributions of renal function in the populations of interests, to determine the PTA against representative pathogens encountered in clinical trials, and to determine the optimal renal dose adjustment for ceftobiprole 500mg IV q8H (2 hour infusion). A total of 150 phase I/II subjects were analyzed using BigNPOD. Monte Carlo Simulation (MCS) was performed with ADAPT II to estimate the PTA of 30-60% fT>MIC. For ceftobiprole 500mg IV Q12H, the probabilities of achieving 30% and 50% fT>MIC exceeded 90% for MICs values </= 2 mg/L and </=1 mg/L, respectively, For ceftobiprole 500mg IV Q8H, the probabilities of achieving 40 and 60% fT>MIC exceeded 90% for MICs </= 4 mg/L and </= 2 mg/L, respectively. For both ceftobiprole 500mg IV Q12H and 500mg IV Q8H, the probability of achieving a near bactericidal effect (50% fT>MIC) exceeded 90% for MSSA and MRSA. For Gram-negative pathogens, the PTA for ceftobiprole 500 mg IV Q8H in achieving a near bactericidal effect (60% fT>MIC) exceeded 90% for non-AmpC-producing Gram-negatives. Ceftobiprole 500 mg IV Q12H at CrCl </= 50 ml/min was identified as the most appropriate regimen for patients who required renal dose adjustment for mild to moderate renal impairment.

Published 27 March 2007 in Antimicrob Agents Chemother.
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