Pharmacokinetics and Pharmacodynamics of β-Lactamase Inhibitors

Pharmacotherapy. 2019 Feb;39(2):182-195. doi: 10.1002/phar.2210. Epub 2019 Jan 20.

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.

Keywords: avibactam; clavulanate; clavulanic acid; diazabicyclooctanone; relebactam; sulbactam; tazobactam; vaborbactam.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / pharmacology*
  • Drug Resistance, Multiple, Bacterial
  • Humans
  • Microbial Sensitivity Tests
  • beta-Lactamase Inhibitors / pharmacokinetics*
  • beta-Lactamase Inhibitors / pharmacology*

Substances

  • Anti-Bacterial Agents
  • beta-Lactamase Inhibitors