Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with haemophilus influenzae middle ear infection

Background The pharmacodynamic differences among 3 AZM regimens(R): single dose simulated sustained release (SSR);3DR & 5DR in gerbils with middle ear infections were evaluated. Method The middle ears of gerbils were inoculated with 1 of 2 strains of Hemophilus Influenzae (HI)(MIC=0.5 & 2.0 mg/L). An AZM SSR regimen was developed to mimic human SR profiles, & to find an ED50 dose. The same total dose was also administered as 3DR & 5DR. Bacterial counts (CFU) and serum concentrations were obtained serially over 72-hr with 1 group of drug-free controls for each strain. The PK data were fit to a 3-cmpt model using IT2S2. Time course of CFU were fit to a PD model with capacity-limited bacterial growth, 1st-order rate constant for death (Kd) & a Hill-type function in which AZM either inhibits replication or enhances Kd. Each experiment was fit individually using ADAPT II. Results The goodness of fit for the PK model was excellent with an overall r2 of 0.883. The effect of AZM was best modeled as enhancing bacteria death (Kd); the maximum effect of drug was an ~4.7 fold increase in Kd. The AZM SSR had more activity than the 3DR and 5DR (CFU AUC0-72, for the 3D and 5D were 7- 47-fold > AZMSSR). Goodness of fit for the PD model was excellent with an overall r2 of 0.713 Conclusions Compared to AZM 3D or 5DR, front-loading the AUC with AZM SSR results in a more rapid and complete bacterial eradication of HI optimizing the probability of positive clinical outcomes & reducing the likelihood of resistance development through mutation or selection. Clinical Pharmacology & Therapeutics (2005) 77, P89–P89; doi: 10.1016/j.clpt.2004.12.234