Rapid In Vitro Assessment of Antimicrobial Drug Effect Bridging Clinically Relevant Pharmacokinetics: A Comprehensive Methodology.

Abstract

Rapid in vitro assessment of antimicrobial drug efficacy under clinically relevant pharmacokinetic conditions is an essential element of both drug development and clinical use. Here, we present a comprehensive overview of a recently developed novel integrated methodology for rapid assessment of such efficacy, particularly against the emergence of resistant bacterial strains, as jointly researched by the authors in recent years. This methodology enables rapid in vitro assessment of the antimicrobial efficacy of single or multiple drugs in combination, following clinically relevant pharmacokinetics. The proposed methodology entails (a) the automated collection of longitudinal time-kill data in an optical-density instrument; (b) the processing of collected time-kill data with the aid of a mathematical model to determine optimal dosing regimens under clinically relevant pharmacokinetics for single or multiple drugs; and (c) in vitro validation of promising dosing regimens in a hollow fiber system. Proof-of-concept of this methodology through a number of in vitro studies is discussed. Future directions for the refinement of optimal data collection and processing are discussed.