Sofie Dhaese1,2, Aaron Heffernan3,4, David Liu5, Mohd Hafiz Abdul-Aziz5, Veronique Stove6,7, Vincent H Tam8, Jeffrey Lipman5,9,10, Jason A Roberts4,5,9,10, Jan J De Waele11,6. 1. Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium. sofie.dhaese@ugent.be. 2. Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. sofie.dhaese@ugent.be. 3. School of Medicine, Griffith University, Southport, QLD, Australia. 4. Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia. 5. UQ Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. 6. Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. 7. Department of Diagnostic Sciences, Ghent University Hospital, Ghent, Belgium. 8. College of Pharmacy, University of Houston, Houston, TX, USA. 9. Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. 10. Division of Anesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nimes, France. 11. Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium.
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.
BACKGROUND: Administering β-lactam antibiotics via prolonged infusions for critically illpatients 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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