Pharmacokinetics and Pharmacodynamics of β-Lactamase Inhibitors.

Abstract

Novel β-lactamase inhibitors have extended the reach of new and existing β-lactams against multidrug-resistant bacteria expressing β-lactamases. The efficacy of these combination therapeutics relies on a complex two-component pharmacodynamic (PD) system where the β-lactamase inhibitor inactivates the bacterial β-lactamase enzyme and frees the companion β-lactam to act against its penicillin-binding protein target. Despite considerable investigation into the pharmacokinetics (PK) and pharmacodynamics of β-lactams, the pharmacology of their companion β-lactamase inhibitors has only recently been rigorously explored. This review describes the diversity of β-lactamase enzymes, mechanisms of enzyme inhibition, and factors impacting the efficacy of clinically available β-lactamase inhibitors. Relevant PK differences among available inhibitors and the PK/PD properties of these agents are described independently of their companion β-lactams. In the modern era of antibiotic resistance, a comprehensive understanding of the pharmacology, PK, and PD of β-lactamase inhibitors is paramount to maximizing the therapeutic efficacy of existing β-lactam/β-lactamase inhibitor combinations and protecting novel agents in the drug development pipeline.