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Influence of extracorporeal membrane oxygenation on the pharmacokinetics of ceftolozane/tazobactam: an ex vivo and in vivo study.

ABSTRACT: BACKGROUND:Extracorporeal membrane oxygenation (ECMO) is increasingly used in intensive care units and can modify drug pharmacokinetics and lead to under-exposure associated with treatment failure. Ceftolozane/tazobactam is an antibiotic combination used for complicated infections in critically ill patients. Launched in 2015, sparse data are available on the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam. The aim of the present study was to determine the influence of ECMO on the pharmacokinetics of ceftolozane-tazobactam. METHODS:An ex vivo model (closed-loop ECMO circuits primed with human whole blood) was used to study adsorption during 8-h inter-dose intervals over a 24-h period (for all three ceftolozane/tazobactam injections) with eight samples per inter-dose interval. Two different dosages of ceftolozane/tazobactam injection were studied and a control (whole blood spiked with ceftolozane/tazobactam in a glass tube) was performed. An in vivo porcine model was developed with a 1-h infusion of ceftolozane-tazobactam and concentration monitoring for 11 h. Pigs undergoing ECMO were compared with a control group. Pharmacokinetic analysis of in vivo data (non-compartmental analysis and non-linear mixed effects modelling) was performed to determine the influence of ECMO. RESULTS:With the ex vivo model, variations in concentration ranged from -?5.73 to 1.26% and from -?12.95 to -?2.89% respectively for ceftolozane (concentrations ranging from 20 to 180 mg/l) and tazobactam (concentrations ranging from 10 to 75 mg/l) after 8 h. In vivo pharmacokinetic exploration showed that ECMO induces a significant decrease of 37% for tazobactam clearance without significant modification in the pharmacokinetics of ceftolozane, probably due to a small cohort size. CONCLUSIONS:Considering that the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam is not clinically significant, normal ceftolozane and tazobactam dosing in critically ill patients should be effective for patients undergoing ECMO.

SUBMITTER: Mane C

PROVIDER: S-EPMC7251674 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Influence of extracorporeal membrane oxygenation on the pharmacokinetics of ceftolozane/tazobactam: an ex vivo and in vivo study.

Mané Camille C Delmas Clément C Porterie Jean J Jourdan Géraldine G Verwaerde Patrick P Marcheix Bertrand B Concordet Didier D Georges Bernard B Ruiz Stéphanie S Gandia Peggy P

Journal of translational medicine 20200527 1

<h4>Background</h4>Extracorporeal membrane oxygenation (ECMO) is increasingly used in intensive care units and can modify drug pharmacokinetics and lead to under-exposure associated with treatment failure. Ceftolozane/tazobactam is an antibiotic combination used for complicated infections in critically ill patients. Launched in 2015, sparse data are available on the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam. The aim of the present study was to determine the influence of ...[more]

PMID: 32460856

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Project description:Critical illness and extracorporeal circulation, such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), may alter the pharmacokinetics of piperacillin-tazobactam. We aimed to develop a population pharmacokinetic model of piperacillin-tazobactam in critically ill patients during ECMO or CRRT and investigate the optimal dosage regimen needed to achieve ≥90% of patients attaining the piperacillin pharmacodynamic target of 100% of dosage time above MIC of 16 mg/L. This prospective observational study included 26 ECMO patients, of which 13 patients received continuous venovenous hemodiafiltration (CVVHDF). A population pharmacokinetic model was developed using nonlinear mixed-effects models, and Monte Carlo simulations were performed to evaluate creatinine clearance (CrCL) and infusion method in relation to the probability of target attainment (PTA) in four patient groups according to combination of ECMO and CVVHDF. A total of 244 plasma samples were collected. In a two-compartment model, clearance decreased during ECMO and CVVHDF contributed to an increase in the volume of distribution. The range of PTA reduction as CrCL increased was greater in the order of intermittent bolus, extended infusion, and continuous infusion method. Continuous infusion should be considered in critically ill patients with CrCL of ≥60 mL/min, and at least 12, 16, and 20 g/day was required for CrCL of <40, 40 to 60, and 60 to 90 mL/min, respectively, regardless of ECMO or CVVHDF. In patients with CrCL of ≥90 mL/min, even a continuous infusion of 24 g/day was insufficient to achieve adequate PTA. Therefore, further research on permissible high continuous infusion dose focused on the risk of toxicity is required. (This trial has been registered at ClinicalTrials.gov under registration no. NCT02581280, December 1, 2014.) IMPORTANCE To the best of our knowledge, this is the first large prospective pharmacokinetic/pharmacodynamic (PK/PD) study of piperacillin-tazobactam in ECMO patients. We used piperacillin-tazobactam plasma concentration data from four different cases (concomitant use of ECMO and CVVHDF, receiving ECMO only, weaned from ECMO and receiving CVVHDF, and weaned from ECMO and not receiving CVVHDF) to provide preliminary insights into the incremental effects of critical illness, ECMO, and CVVHDF on PK. Our analysis revealed that volume of distribution increased in patients on CVVHDF and clearance decreased during ECMO and as creatinine clearance was reduced. When targeting 100% fT>MIC (16 mg/L, clinical breakpoint for Pseudomonas aeruginosa), continuous infusions would have achieved the highest percentage of target attainment compared to intermittent bolus or extended infusion if the total daily dose was the same. Continuous infusion should be considered in critically ill patients with creatinine clearance of ≥60 mL/min, regardless of ECMO or CVVHDF.

Dataset Information

Influence of extracorporeal membrane oxygenation on the pharmacokinetics of ceftolozane/tazobactam: an ex vivo and in vivo study.

Publications

Influence of extracorporeal membrane oxygenation on the pharmacokinetics of ceftolozane/tazobactam: an ex vivo and in vivo study.

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