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Purpose <p>Optimal dosing of meropenem and piperacillin/tazobactam in critically ill patients receiving renal replacement therapy (RRT) is uncertain due to variable pharmacokinetics. We aimed to develop generalisable optimised dosing recommendations for these antibiotics.</p> Methods <p>Prospective, multinational pharmacokinetic study including patients requiring various forms of RRT. Independent population PK models were developed, externally validated and applied to perform Monte Carlo dosing simulations using Monolix and Simulx. We calculated the probability that these dosing regimens achieved standard and high therapeutic unbound antibiotic concentrations over 100% of the dosing interval for the treatment of Enterobacterales and <i>Pseudomonas aeruginosa</i>.</p> Results <p>We enrolled 300 patients from 22 intensive care units across 12 countries receiving continuous veno-venous haemodialysis (13.0%), haemofiltration (23.3%), haemodiafiltration (48.4%) or sustained low-efficiency dialysis (15.3%). Models were developed using data from 234 patients (8322 samples) and validated with 66 additional patients (560 samples). Predictive performance was high, with mean prediction errors of −&#xa0;5.2% for meropenem and −&#xa0;16.9% for piperacillin. Dosing simulations showed that meropenem and piperacillin/tazobactam dosing requirements were dependent on urine output and RRT intensity and duration (<i>p</i> &lt; 0.05). In all scenarios, extended/continuous infusions led to a better achievement of effective concentrations with lower daily doses compared to short infusion. Dosing nomograms were developed to inform dosing for different RRT settings, urine outputs, and target concentrations.</p> Conclusion <p>RRT intensity and duration and urine output determine meropenem and piperacillin/tazobactam dosing requirements in critically ill patients receiving RRT. Extended/continuous infusions facilitate the attainment of effective concentrations.</p>

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Meropenem and piperacillin/tazobactam optimised dosing regimens for critically ill patients receiving renal replacement therapy

  • 期刊论文

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  • 发表日期：

    2025年8月13日

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  • Jason A. Roberts,
  • Marta Ulldemolins,
  • Xin Liu,
  • João P. Baptista,
  • Irma Bilgrami,
  • Clement Boidin,
  • Alexander Brinkmann,
  • Pedro Castro,
  • Gordon Choi,
  • Louise Cole,
  • Jan J. De Waele,
  • Renae Deans,
  • Sine Donnellan,
  • Glenn M. Eastwood,
  • Otto R. Frey,
  • Sylvain Goutelle,
  • Rebecca Gresham,
  • Janattul Ain Jamal,
  • Gavin M. Joynt,
  • Salmaan Kanji,
  • Stefan Kluge,
  • Christina König,
  • Vasilios P. Koulouras,
  • Melissa Lassig-Smith,
  • Pierre-Francois Laterre,
  • Anna Lee,
  • Jean-Yves Lefrant,
  • Katie Lei,
  • Patricia Leung,
  • Mireia Llaurado-Serra,
  • Ignacio Martin-Loeches,
  • Mohd Basri Mat Nor,
  • Yugan Mudaliar,
  • Marlies Ostermann,
  • Sanjoy K. Paul,
  • Sandra L. Peake,
  • Jordi Rello,
  • Darren M. Roberts,
  • Michael S. Roberts,
  • Brent Richards,
  • Alejandro Rodríguez,
  • Anka C. Roehr,
  • Claire Roger,
  • Leonardo Seoane,
  • Mahipal Sinnollareddy,
  • Eduardo Sousa,
  • Dolors Soy,
  • Anna Spring,
  • Therese Starr,
  • Dianne Stephens,
  • Fabio Silvio Taccone,
  • Jane Thomas,
  • John Turnidge,
  • Miia Valkonen,
  • Julie M. Varghese,
  • Steven C. Wallis,
  • Robert J. Walker,
  • Tricia Williams,
  • Luke C. Wilson,
  • Xavier Wittebole,
  • Daniel F. B. Wright,
  • Xanthi T. Zikou,
  • Rinaldo Bellomo,
  • Jeffrey Lipman,
  • Max Andresen,
  • Sónia F. Baltazar,
  • Saber Barbar,
  • Eulália Costa,
  • Dominique Durand,
  • Ricardo Freitas,
  • Yarmarly Guerra Valero,
  • Margaret Haughton,
  • Andreas Koeberer,
  • Marin Kollef,
  • Kerenaftali Klein,
  • Ravindra Mehta,
  • Cathy McKenzie,
  • Laurent Muller,
  • Priya Nair,
  • Vineet Nayyar,
  • Jenny L. Ordóñez Mejia,
  • Georgia-Laura Panagou,
  • Jody Paxton,
  • Leah Peck,
  • Jean-Louise Vincent,
  • Ruth Wan,
  • Helen Young

摘要

Purpose

Optimal dosing of meropenem and piperacillin/tazobactam in critically ill patients receiving renal replacement therapy (RRT) is uncertain due to variable pharmacokinetics. We aimed to develop generalisable optimised dosing recommendations for these antibiotics.

Methods

Prospective, multinational pharmacokinetic study including patients requiring various forms of RRT. Independent population PK models were developed, externally validated and applied to perform Monte Carlo dosing simulations using Monolix and Simulx. We calculated the probability that these dosing regimens achieved standard and high therapeutic unbound antibiotic concentrations over 100% of the dosing interval for the treatment of Enterobacterales and Pseudomonas aeruginosa.

Results

We enrolled 300 patients from 22 intensive care units across 12 countries receiving continuous veno-venous haemodialysis (13.0%), haemofiltration (23.3%), haemodiafiltration (48.4%) or sustained low-efficiency dialysis (15.3%). Models were developed using data from 234 patients (8322 samples) and validated with 66 additional patients (560 samples). Predictive performance was high, with mean prediction errors of − 5.2% for meropenem and − 16.9% for piperacillin. Dosing simulations showed that meropenem and piperacillin/tazobactam dosing requirements were dependent on urine output and RRT intensity and duration (p < 0.05). In all scenarios, extended/continuous infusions led to a better achievement of effective concentrations with lower daily doses compared to short infusion. Dosing nomograms were developed to inform dosing for different RRT settings, urine outputs, and target concentrations.

Conclusion

RRT intensity and duration and urine output determine meropenem and piperacillin/tazobactam dosing requirements in critically ill patients receiving RRT. Extended/continuous infusions facilitate the attainment of effective concentrations.