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An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients

BACKGROUND AND OBJECTIVES: Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be p...

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Autores principales: Wallenburg, Eveline, ter Heine, Rob, Schouten, Jeroen A., Raaijmakers, Jelmer, ten Oever, Jaap, Kolwijck, Eva, Burger, David M., Pickkers, Peter, Frenzel, Tim, Brüggemann, Roger J. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249689/
https://www.ncbi.nlm.nih.gov/pubmed/35377133
http://dx.doi.org/10.1007/s40262-022-01113-6
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author Wallenburg, Eveline
ter Heine, Rob
Schouten, Jeroen A.
Raaijmakers, Jelmer
ten Oever, Jaap
Kolwijck, Eva
Burger, David M.
Pickkers, Peter
Frenzel, Tim
Brüggemann, Roger J. M.
author_facet Wallenburg, Eveline
ter Heine, Rob
Schouten, Jeroen A.
Raaijmakers, Jelmer
ten Oever, Jaap
Kolwijck, Eva
Burger, David M.
Pickkers, Peter
Frenzel, Tim
Brüggemann, Roger J. M.
author_sort Wallenburg, Eveline
collection PubMed
description BACKGROUND AND OBJECTIVES: Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine. METHODS: In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin–tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function. RESULTS: A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T(>1×MIC) (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T(>5×MIC) with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively. CONCLUSIONS: A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases. CLINICALTRIALS.GOV IDENTIFIER: NCT03738683. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-022-01113-6.
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spelling pubmed-92496892022-07-03 An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients Wallenburg, Eveline ter Heine, Rob Schouten, Jeroen A. Raaijmakers, Jelmer ten Oever, Jaap Kolwijck, Eva Burger, David M. Pickkers, Peter Frenzel, Tim Brüggemann, Roger J. M. Clin Pharmacokinet Original Research Article BACKGROUND AND OBJECTIVES: Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine. METHODS: In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin–tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function. RESULTS: A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T(>1×MIC) (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T(>5×MIC) with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively. CONCLUSIONS: A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases. CLINICALTRIALS.GOV IDENTIFIER: NCT03738683. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-022-01113-6. Springer International Publishing 2022-04-04 2022 /pmc/articles/PMC9249689/ /pubmed/35377133 http://dx.doi.org/10.1007/s40262-022-01113-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research Article
Wallenburg, Eveline
ter Heine, Rob
Schouten, Jeroen A.
Raaijmakers, Jelmer
ten Oever, Jaap
Kolwijck, Eva
Burger, David M.
Pickkers, Peter
Frenzel, Tim
Brüggemann, Roger J. M.
An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients
title An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients
title_full An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients
title_fullStr An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients
title_full_unstemmed An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients
title_short An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients
title_sort integral pharmacokinetic analysis of piperacillin and tazobactam in plasma and urine in critically ill patients
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249689/
https://www.ncbi.nlm.nih.gov/pubmed/35377133
http://dx.doi.org/10.1007/s40262-022-01113-6
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