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:

• Antimicrobials
• β-lactamases
• multi-drug resistance
• pharmacodynamics
• pharmacokinetics

Article highlights

• Understanding of the pharmacokinetics/pharmacodynamics (PK/PD) of antimicrobials, including β-lactamase inhibitors, is needed to construct a dosing regimen that maximizes clinical benefit.

• Historically, the PK/PD of β-lactamase inhibitors have not been a substantial component of β-lactam-β-lactamase inhibitor compound development, resulting in dosages without validation of target exposures.

• Traditional PK/PD indices are normalized by the minimum inhibitory concentration (MIC); however, MIC does not always predict efficacy of β-lactamase inhibitors.

• New thresholds must be explored to advance the correlation of β-lactamase inhibitor exposure and efficacy.

• The PK/PD driver of efficacy and target exposures varies among β-lactamase inhibitors and can depend on the infecting organism, type and amount of β-lactamase production.

• Further research is needed to improve the understanding of the β-lactamase inhibitor exposure-response relationship to enhance clinical efficacy and avoid resistance development.

Declaration of interest

DP Nicolau has provided consultative services, participated in the speaker’s bureau or has received grant funding from the following companies: Melinta, Pfizer, Venatorx, Wockhardt. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.