The Ins and Outs of Susceptibility Testing for New β-Lactam/β-Lactamase Inhibitor Combinations for Gram-Negative Organisms

Dingle, Tanis C.; Pitout, Johann

doi:10.1128/jcm.00807-21

Cited by 6 publications

(1 citation statement)

References 32 publications

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“…The traditional MIC of the BL/BLI combination is determined at a fixed exposure of BLI that disregards the impact of dynamic inhibitor concentrations on susceptibility. 72–74 To address this concern, a modified PK/PD index, fT >MICi has been proposed for BL/BLI combinations, which reflects the effect of different BLI concentrations on the susceptibility of the bacteria and on how each β-lactamase-producing isolate interacts with the inhibitor. 39 , 41 , 74 However, this target measure remains to be validated against multiple species of bacteria.…”

Section: Discussionmentioning

confidence: 99%

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

Assefa,

Roberts,

Mohammed

et al. 2024

Journal of Antimicrobial Chemotherapy

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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.

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Section: Discussionmentioning

confidence: 99%

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

Assefa,

Roberts,

Mohammed

et al. 2024

Journal of Antimicrobial Chemotherapy

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Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors

Wimmer

Hoff

Martin

et al. 2023

Bioorganic Chemistry

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Aztreonam and avibactam combination therapy for metallo-β-lactamase-producing gram-negative bacteria: a comprehensive review

Sangiorgio,

Calvo,

Stefani

2024

Clinical Microbiology and Infection

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The Ins and Outs of Susceptibility Testing for New β-Lactam/β-Lactamase Inhibitor Combinations for Gram-Negative Organisms

Abstract: Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam are among the newest β-lactam/β-lactamase inhibitors (BL/BLIs) introduced to the North American antibiotic market. All have broad Gram-negative activity, including against certain carbapenemases.

Cited by 6 publications

References 32 publications

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

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

Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors

Aztreonam and avibactam combination therapy for metallo-β-lactamase-producing gram-negative bacteria: a comprehensive review

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