In Vivo Pharmacodynamics of Ceftobiprole against Multiple Bacterial Pathogens in Murine Thigh and Lung Infection Models

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Abstract
Ceftobiprole medocaril is the parenteral prodrug of ceftobiprole, a novel pyrrolidinone broad-spectrum cephalosporin with in vitro and in vivo bactericidal activities against methicillin-resistantStaphylococcus aureus(MRSA) and penicillin-resistantStreptococcus pneumoniae(PRSP). We have used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic (PK)-pharmacodynamic (PD) activities of ceftobiprole against multiple strains ofS. aureus(including MRSA),S. pneumoniae(including PRSP), and gram-negative bacilli. Serum levels of ceftobiprole following the administration of multiple doses were determined by a microbiological assay. In vivo bactericidal activities and postantibiotic effects (PAEs) of ceftobiprole against MRSA and PRSP strains were determined from serial CFU/thigh values following single doses of ceftobiprole (40 and 160 mg/kg of body weight). Dose fractionation studies were used to determine which PK-PD index correlated best with activity. Magnitudes of the PK-PD indices were calculated from MICs and PK parameters. A sigmoid dose-response model was used to estimate the dose (mg/kg/24 h) required to achieve a static and 2-log10kill effects over 24 h. PK results showed area under the concentration-time curve/dose values of 1.8 to 2.8 and half-lives of 0.29 to 0.51 h. MICs ranged from 0.015 to 2 μg/ml. Ceftobiprole demonstrated time-dependent killing; its in vivo PAEs varied from 3.8 h to 4.8 h for MRSA and from 0 to 0.8 h for PRSP. The time above MIC (T> MIC) correlated best with efficacy for both MRSA and PRSP. TheT> MIC values required for the static doses were significantly longer (P< 0.001) forEnterobacteriaceae(36 to 45%) than forS. aureus(14 to 28%) andS. pneumoniae(15 to 22%). The drug showed activities in the lung model similar to those in the thigh model. The presence of neutrophils significantly enhanced the activity of ceftobiprole againstS. pneumoniaebut only slightly againstKlebsiella pneumoniae. Based on its PD profile, ceftobiprole is a promising new β-lactam agent with activity against gram-negative and gram-positive organisms including MRSA and PRSP.

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