DEVELOPMENT AND APPLICATION OF AN IN VITRO PHARMACODYNAMIC MODEL FOR USE IN EXAMINING NOVEL DOSING STRATEGIES FOR AMOXICILLIN VS. BETA-LACTAMASE NEGATIVE AMPICILL1N RESISTANT HAEMOPIHLUS INFLUENZAE

Abstract

An in vitro pharmacodynamic model was designed to investigate the pharmacokinetic/pharmacodynamic (PK/PD) relationships of pulsatile, continuous infusion and traditional divided dose regimens of amoxicillin versus two strains of beta- lactamase-negative ampicillin-resistant (BLNAR) Haemophilus influenzae. Initial PK/PD model validation studies were conducted using the well characterized beta-lactam drug/organism combination of cephalexin and Staphylococcus aureus. This model generally reports a direct relationship between bactericidal activity and percent time above the minimum inhibitory concentration (%T>MIC) during a 24 h dosing interval which is independent of drug concentration, as expected for a beta-lactam. However, the relationship between bactericidal activity and %T>MIC is dependent on flow rate in this PD model. Continuous infusion regimens of amoxicillin demonstrated significantly greater bactericidal effects, measured by the area between the antibiotic time-kill curve and untreated growth control curve (ABBC integral), as compared to traditional divided dosing or pulsatile regimens achieving equivalent or greater %T>MIC. Thus, continuous infusion dosing regimens of amoxicillin represent effective and novel dosing strategies for infections caused by BLNAR H. influenzae.