title: Pharmacodynamic characterization of ceftobiprole in experimental pneumonia caused by phenotypically diverse Staphylococcus aureus strains.
abstract: Ceftobiprole (BPR) is an investigational cephalosporin with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains. The pharmacodynamic (PD) profile of BPR against S. aureus strains with a variety of susceptibility phenotypes in an immunocompromised murine pneumonia model was characterized. The BPR MICs of the test isolates ranged from 0.25 to 2 mug/ml. Pharmacokinetic (PK) studies were conducted with infected neutropenic BALB/c mice; and the BPR concentrations were measured in plasma, epithelial lining fluid (ELF), and lung tissue. PD studies with these mice were undertaken with eight S. aureus isolates (two methicillin-susceptible S. aureus strains, three hospital-acquired MRSA strains, and three community-acquired MRSA strains). Subcutaneous BPR doses of 2 to 125 mg/kg of body weight/day were administered, and the change in the number of log(10) CFU/ml in lungs was evaluated after 24 h of therapy. The PD profile was characterized by using the free drug exposures (f) determined from the following parameters: the percentage of time that the concentration was greater than the MIC (T > MIC), the maximum concentration in serum/MIC, and the area under the concentration-time curve/MIC. The BPR PK parameters were linear over the dose range studied in plasma, and the ELF concentrations ranged from 60 to 94% of the free plasma concentration. fT > MIC was the parameter that best correlated with efficacy against a diverse array of S. aureus isolates in this murine pneumonia model. The 80% effective dose (ED(80)), ED(50), and stasis exposures appeared to be similar among the isolates studied. BPR exerted maximal antibacterial effects when fT > MIC ranged from 6 to 22%, regardless of the phenotypic profile of resistance to beta-lactam, fluoroquinolone, erythromycin, clindamycin, or tetracycline antibiotics.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA.
authors.forename: Somvadee
authors.initials: S
authors.lastname: Laohavaleeson
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Tessier
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002511:Cephalosporins / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D017714:Community-Acquired Infections / Q000188:drug therapy / Q000382:microbiology; D003428:Cross Infection / Q000188:drug therapy / Q000382:microbiology; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D016106:Methicillin Resistance; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D011023:Pneumonia, Staphylococcal / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C443755:ceftobiprole