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Prolonged Versus Intermittent Infusion of β-Lactam Antibiotics: A Systematic Review and Meta-Regression of Bacterial Killing in Preclinical Infection Models

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Abstract

Background

Administering β-lactam antibiotics via prolonged infusions for critically ill patients is mainly based on preclinical evidence. Preclinical data on this topic have not been systematically reviewed before.

Objectives

The aim of this study was to describe the pharmacokinetic/pharmacodynamic (PK/PD) indices and targets reported in preclinical models and to compare the bactericidal efficacy of intermittent and prolonged infusions of β-lactam antibiotics.

Methods

The MEDLINE and EMBASE databases were searched. To compare the bactericidal action of β-lactam antibiotics across different modes of infusion, the reported PK/PD outcomes, expressed as the percentage of time (T) that free (f) β-lactam antibiotic concentrations remain above the minimal inhibitory concentration (MIC) (%fT>MIC) or trough concentration (Cmin)/MIC of individual studies, were recomputed relative to the area under the curve of free drug to MIC ratio (fAUC24/MIC). A linear mixed-effects meta-regression was performed to evaluate the impact of the β-lactam class, initial inoculum, Gram stain, in vivo or in vitro experiment and mode of infusion on the reduction of bacterial cells (in colony-forming units/mL).

Results

Overall, 33 articles were included for review, 11 of which were eligible for meta-regression. For maximal bactericidal activity, intermittent experiments reported a PK/PD target of 40–70% fT>MIC, while continuous experiments reported a steady-state concentration to MIC ratio of 4–8. The adjusted effect of a prolonged as opposed to intermittent infusion on bacterial killing was small (coefficient 0.66, 95% confidence interval − 0.78 to 2.11).

Conclusions

Intermittent and prolonged infusions of β-lactam antibiotics require different PK/PD targets to obtain the same level of bacterial cell kill. The additional effect of a prolonged infusion for enhancing bacterial killing could not be demonstrated.

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Author information

Author notes

  1. Sofie Dhaese and Aaron Heffernan contributed equally to this work.

Authors and Affiliations

  1. Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium

    Sofie Dhaese & Jan J. De Waele

  2. Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

    Sofie Dhaese, Veronique Stove & Jan J. De Waele

  3. School of Medicine, Griffith University, Southport, QLD, Australia

    Aaron Heffernan

  4. Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia

    Aaron Heffernan & Jason A. Roberts

  5. UQ Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

    David Liu, Mohd Hafiz Abdul-Aziz, Jeffrey Lipman & Jason A. Roberts

  6. Department of Diagnostic Sciences, Ghent University Hospital, Ghent, Belgium

    Veronique Stove

  7. College of Pharmacy, University of Houston, Houston, TX, USA

    Vincent H. Tam

  8. Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    Jeffrey Lipman & Jason A. Roberts

  9. Division of Anesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nimes, France

    Jeffrey Lipman & Jason A. Roberts

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  1. Sofie Dhaese
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Contributions

SD, AH, DL, JR and JDW conceived and designed the study. SD designed the search strategy and wrote the first draft. SD and MHA-A performed the literature search. SD extracted the data for the review and AH extracted the data for the meta-analysis and meta-regression. SD performed the meta-regression. SD, AH, DL, MHA-A, VS, VT, JL, JR and JDW contributed to the final draft and revision of the manuscript.

Corresponding author

Correspondence to Sofie Dhaese.

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Funding

There was no funding source for this study.

Conflict of interest

DL has previously received conference travel funding from MSD. JL has been a consultant for MSD, Australia. JR has been a consultant for Accelerate Diagnostics, Astellas, Bayer, bioMerieux and MSD, and has received investigator-initiated grants from MSD, The Medicines Company and Cardeas Pharma. JDW is supported by a grant from the Research Foundation Flanders (Senior Clinical Investigator Grant FWO, Ref. 1881020N), and has consulted for Accelerate, Bayer Healthcare, Cubist, Grifols, MSD and Pfizer (honoraria paid to institution). Sofie Dhaese, Aaron Heffernan, Mohd Hafiz Abdul-Aziz, Veronique Stove and Vincent H. Tam declare no competing interests.

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Raw data available upon request.

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Code written in R. R packages used are described in the manuscript. Code available in ESM 2.

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Dhaese, S., Heffernan, A., Liu, D. et al. Prolonged Versus Intermittent Infusion of β-Lactam Antibiotics: A Systematic Review and Meta-Regression of Bacterial Killing in Preclinical Infection Models. Clin Pharmacokinet 59, 1237–1250 (2020). https://doi.org/10.1007/s40262-020-00919-6

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