title: Pharmacodynamics of cefprozil against Haemophilus influenzae in an in vitro pharmacodynamic model.
abstract: An in vitro pharmacodynamic model was used to determine the pharmacokinetic-pharmacodynamic (PK-PD) measure and magnitude most strongly related to cefprozil activity against Haemophilus influenzae. Using 3 clinical isolates of H. influenzae, a series of dose-fractionation studies were conducted, simulating cefprozil pediatric pharmacokinetics. The studies were designed to deliver a range of free cefprozil AUC(24) given once daily, twice daily, and by continuous infusion (CI). Drug effect, characterized by computing the log(10) ratio of the area under the 24-h bacterial colony-forming unit (CFU) (AUC(CFU)) curve to drug-free control, was fit to a Hill-type model for 3 PK-PD measures of activity: AUC(24)/MIC, C(max)/MIC, and %T > MIC. Once daily regimens provided much less activity than twice daily or CI regimens. AUC(24)/MIC and %T > MIC characterized the data well, whereas C(max)/MIC did not. Based on the PK-PD model results, for cefprozil twice daily, 50% and 80% of maximum drug effect (E(max)) was achieved at a %T > MIC of approximately 52% and 75%, respectively. A 2-log(10) reduction in log(10) ratio would require free drug %T > MIC of 58% or AUC(24)/MIC of 86. Bacteriostasis was achieved at a %T > MIC and an AUC(24)/MIC of approximately 25% and 30%, respectively. An in vitro pharmacodynamic model was able to characterize the PK-PD of cefprozil against H. influenzae. Consistent with limited clinical data, a minimum %T > MIC of 40% to 50% would be suggested to achieve in vivo activity in otitis media, with maximal activity at approximately 70%T > MIC.
authors.affiliation: University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Applied Pharmacodynamics Laboratory, Department of Pharmacy Practice, Buffalo, NY 14260, USA. pfsmith@buffalo.edu
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Brian
authors.initials: B
authors.lastname: Tsuji
authors.forename: Brent M
authors.initials: BM
authors.lastname: Booker
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.forename: Sanela
authors.initials: S
authors.lastname: Bajic
authors.forename: Pamela
authors.initials: P
authors.lastname: Kelchlin
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D002511:Cephalosporins / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006192:Haemophilus Infections / Q000188:drug therapy / Q000382:microbiology; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D000097670:Cefprozil
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000097670:Cefprozil