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.