Ibrahim El-Haffaf1,2, Romain Guilhaumou3, Lionel Velly4, Amélie Marsot5,6,7. 1. Faculty of Pharmacy, Université de Montréal, Pavillon Jean-Coutu, 2940 Chemin de Polytechnique, Montréal, QC, H3T 1J4, Canada. ibrahim.el-haffaf@umontreal.ca. 2. Laboratoire de Suivi Thérapeutique Pharmacologique et Pharmacocinétique, Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada. ibrahim.el-haffaf@umontreal.ca. 3. Service de Pharmacologie Clinique et Pharmacovigilance, Assistance Publique des Hôpitaux de Marseille, Aix Marseille Université, Institut de Neurosciences des Systèmes, Inserm UMR 1106, Marseille, France. 4. Service d'Anesthésie-Réanimation, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille et Institut de Neurosciences de la Timone, CNRS, Aix Marseille Université, Marseille, France. 5. Faculty of Pharmacy, Université de Montréal, Pavillon Jean-Coutu, 2940 Chemin de Polytechnique, Montréal, QC, H3T 1J4, Canada. 6. Laboratoire de Suivi Thérapeutique Pharmacologique et Pharmacocinétique, Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada. 7. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada.
Abstract
BACKGROUND AND OBJECTIVE: Piperacillin is a broad-spectrum β-lactam antibiotic commonly prescribed in intensive care units. Many piperacillin population pharmacokinetic models have been published, but few underwent an external evaluation. External evaluation is an important process to determine a model's capability of being generalized to other hospitals. We aimed to assess the predictive performance of these models with an external validation dataset. METHODS: Six models were evaluated with a dataset consisting of 30 critically ill patients (35 samples) receiving piperacillin by continuous infusion. Models were subject to prediction-based (bias and imprecision) and simulation-based evaluations. When a model had an acceptable evaluation, it was used for dosing simulations to evaluate the probability of target attainment. RESULTS: Bias and imprecision ranged from - 35.7 to 295% and from 22.7 to 295%, respectively. The models of Klastrup et al. and of Udy et al. were acceptable according to our criteria and were used for dosing simulations. Simulations showed that a loading dose of 4 g followed by a maintenance dose of 16 g/24 h of piperacillin infused continuously was necessary to remain above a pharmacokinetic-pharmacodynamic target set as a minimal inhibitory concentration of 16 mg/L in 90% of patients, for a median patient with a creatinine clearance of 76 mL/min. CONCLUSIONS: Despite the considerable variation in the predictive performance of the models with the external validation dataset, this study was able to validate two of these models and led to the elaboration of a dosing nomogram for piperacillin by continuous infusion that can be used by clinicians in intensive care units.
BACKGROUND AND OBJECTIVE: Piperacillin is a broad-spectrum β-lactam antibiotic commonly prescribed in intensive care units. Many piperacillin population pharmacokinetic models have been published, but few underwent an external evaluation. External evaluation is an important process to determine a model's capability of being generalized to other hospitals. We aimed to assess the predictive performance of these models with an external validation dataset. METHODS: Six models were evaluated with a dataset consisting of 30 critically ill patients (35 samples) receiving piperacillin by continuous infusion. Models were subject to prediction-based (bias and imprecision) and simulation-based evaluations. When a model had an acceptable evaluation, it was used for dosing simulations to evaluate the probability of target attainment. RESULTS: Bias and imprecision ranged from - 35.7 to 295% and from 22.7 to 295%, respectively. The models of Klastrup et al. and of Udy et al. were acceptable according to our criteria and were used for dosing simulations. Simulations showed that a loading dose of 4 g followed by a maintenance dose of 16 g/24 h of piperacillin infused continuously was necessary to remain above a pharmacokinetic-pharmacodynamic target set as a minimal inhibitory concentration of 16 mg/L in 90% of patients, for a median patient with a creatinine clearance of 76 mL/min. CONCLUSIONS: Despite the considerable variation in the predictive performance of the models with the external validation dataset, this study was able to validate two of these models and led to the elaboration of a dosing nomogram for piperacillin by continuous infusion that can be used by clinicians in intensive care units.
Authors: Mohd H Abdul-Aziz; Helmi Sulaiman; Mohd-Basri Mat-Nor; Vineya Rai; Kang K Wong; Mohd S Hasan; Azrin N Abd Rahman; Janattul A Jamal; Steven C Wallis; Jeffrey Lipman; Christine E Staatz; Jason A Roberts Journal: Intensive Care Med Date: 2016-01-11 Impact factor: 17.440
Authors: Joel M Dulhunty; Jason A Roberts; Joshua S Davis; Steven A R Webb; Rinaldo Bellomo; Charles Gomersall; Charudatt Shirwadkar; Glenn M Eastwood; John Myburgh; David L Paterson; Therese Starr; Sanjoy K Paul; Jeffrey Lipman Journal: Am J Respir Crit Care Med Date: 2015-12-01 Impact factor: 21.405
Authors: Stefan Hagel; Friedhelm Bach; Thorsten Brenner; Hendrik Bracht; Alexander Brinkmann; Thorsten Annecke; Andreas Hohn; Markus Weigand; Guido Michels; Stefan Kluge; Axel Nierhaus; Dominik Jarczak; Christina König; Dirk Weismann; Otto Frey; Dominic Witzke; Carsten Müller; Michael Bauer; Michael Kiehntopf; Sophie Neugebauer; Thomas Lehmann; Jason A Roberts; Mathias W Pletz Journal: Intensive Care Med Date: 2022-02-01 Impact factor: 41.787