Pharmacokinetics-pharmacodynamics of β-lactamase inhibitors: are we missing the target?

Abstract

Introduction: β-lactamase production in Gram-negative bacteria is a leading cause of antimicrobial resistance. β-lactamase inhibitors are therapeutic agents used in combination with a partner antimicrobial to overcome the production of these enzymes and restore antimicrobial activity. To address the ongoing threat of multi-drug resistant bacteria, a recent wave of β-lactamase inhibitor development has occurred. Emphasis on the pharmacokinetics and pharmacodynamics of these agents is needed to optimize their clinical impact. Areas covered: This review will describe methods currently used to define the pharmacokinetics/pharmacodynamics of β-lactamase inhibitors. Minimal focus will be on the structure and mechanism of β-lactamase inhibitors. Emphasis will be placed on the use of specific thresholds to normalize β-lactamase inhibitor exposure. In vitro and in vivo pharmacokinetic/pharmacodynamic data specific to FDA approved and pipeline β-lactamase inhibitors will be explored. Expert opinion: Describing the exposure-response relationship of β-lactamase inhibitors is an ongoing challenge due to the dynamic relationship of the β-lactamase inhibitor with the active partner compound. Pharmacokinetic/pharmacodynamic indices and target exposures lack generalizability, as they are often specific to the infecting organism and/or β-lactamase, rather than β-lactamase inhibitor class. Selected dosage regimens of new agents should be validated via the use of population target attainment analyses.

Keywords: -lactamases; Antimicrobials; multi-drug resistance; pharmacodynamics; pharmacokinetics.