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

Smith PF, Tsuji B, Booker BM, Forrest A, Bajic S, Kelchlin P, Bhavnani SM, Jones RN, Ambrose PG.

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 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) curve to drug-free control, was fit to a Hill-type model for 3 PK-PD measures of activity: AUC/MIC, C (max)/MIC, and %T > MIC. Once daily regimens provided much less activity than twice daily or CI regimens. AUC/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/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.

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