Pharmacodynamics of cefprozil against Haemophilus influenzae in an in vitro pharmacodynamic model

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 AUC₂₄ given once daily, twice daily, and by continuous infusion (CI). Drug effect, characterized by computing the log₁₀ 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: AUC₂₄/MIC, C_max/MIC, and %T > MIC. Once daily regimens provided much less activity than twice daily or CI regimens. AUC₂₄/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-log₁₀ reduction in log₁₀ ratio would require free drug %T > MIC of 58% or AUC₂₄/MIC of 86. Bacteriostasis was achieved at a %T > MIC and an AUC₂₄/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.