What are the optimal pharmacokinetic/pharmacodynamic targets for β-lactamase inhibitors? A systematic review

Abstract

Background Pharmacokinetic/pharmacodynamic (PK/PD) indices are widely used for the selection of optimum antibiotic doses. For β-lactam antibiotics, fT>MIC, best relates antibiotic exposure to efficacy and is widely used to guide the dosing of β-lactam/β-lactamase inhibitor (BLI) combinations, often without considering any PK/PD exposure requirements for BLIs. Objectives This systematic review aimed to describe the PK/PD exposure requirements of BLIs for optimal microbiological efficacy when used in combination with β-lactam antibiotics. Methods Literature was searched online through PubMed, Embase, Web of Science, Scopus and Cochrane Library databases up to 5 June 2023. Studies that report the PK/PD index and threshold concentration of BLIs approved for clinical use were included. Narrative data synthesis was carried out to assimilate the available evidence. Results Twenty-three studies were included. The PK/PD index that described the efficacy of BLIs was fT>CT for tazobactam, avibactam and clavulanic acid and fAUC0–24/MIC for relebactam and vaborbactam. The optimal magnitude of the PK/PD index is variable for each BLI based on the companion β-lactam antibiotics, type of bacteria and β-lactamase enzyme gene transcription levels. Conclusions The PK/PD index that describes the efficacy of BLIs and the exposure measure required for their efficacy is variable among inhibitors; as a result, it is difficult to make clear inference on what the optimum index is. Further PK/PD profiling of BLI, using preclinical infection models that simulate the anticipated mode(s) of clinical use, is warranted to streamline the exposure targets for use in the optimization of dosing regimens.

Revisiting the Checkerboard to Inform Development of β-Lactam/β-Lactamase Inhibitor Combinations

“…However, there is also the implication that the dose selection for approved β-lactam and β-lactamase inhibitor combinations currently in clinical use may have been suboptimal. Independent support for this premise can be found in the recently published systematic review by Assefa et al [51]. The authors surveyed the nonclinical evidence that has been used to identify PK/PD indices and target values for approved β-lactam and β-lactamase inhibitor combinations.…”