Abstract
Objectives: To develop a population pharmacokinetic model of meropenem in children with sepsis receiving extracorporeal life support (ECLS) and optimize the dosage regimen based on investigating the probability of target attainment (PTA).Methods: The children with sepsis were prospectively enrolled in a pediatric intensive care unit from January 2018 to December 2019. The concentration-time data were fitted using nonlinear mixed effect model approach by NONMEM program. The stochastic simulation considering various scenarios based on proposed population pharmacokinetics model were conducted, and the PTAs were calculated to optimize the dosage regimens.Results: A total of 25 children with sepsis were enrolled, of whom13 received ECMO, 9 received CRRT, and 4 received ECMO combined with CRRT. 12 children received a two-step 3-h infusion and 13 children received 1-h infusion. Bodyweight and creatinine clearance had significant impacts on the PK parameters. ECMO intervention was not related to the PK properties. If 100%T > MIC was chosen as target, children receiving 40 mg/kg q8h over a 3 h-infusion only reached the PTA up to 77.4%. If bacteria with MIC 2 mg/L were to be treated with meropenem and the PTA target was 50%T > MIC, a dose of 40 mg/kg q8h for 1 h infusion would be necessary.Conclusions: The PK properties of meropenem in septic children receiving extracorporeal life support were best described. We recommended the opitimized dosing regimens for septic children receiving ECLS depending on the PTA of PK target 50%T > MIC and 100%T > MIC, for children with sepsis during ECLS with different body weight, estimated creatinine clearance (eCRCL) and MIC of bacteria.
Highlights
For Severe infection is a leading cause of hospital admission and a common cause of mortality in the Intensive Care Unit (ICU) and Pediatric Intensive Care Unit (PICU) (Kempker and Martin 2016). β-lactam antibiotics are the most commonly prescribed drugs for septic children with numerous clinical indications
To develop a population pharmacokinetic model of meropenem in children with sepsis receiving extracorporeal life support (ECLS) and optimize the dosage regimen based on investigating the probability of target attainment (PTA)
A total of 25 children with sepsis were enrolled, of whom13 received extracorporeal membrane oxygenation (ECMO), 9 received continuous renal replacement therapy (CRRT), and 4 received ECMO combined with CRRT. children received a twostep 3-h infusion and children received 1-h infusion
Summary
For Severe infection is a leading cause of hospital admission and a common cause of mortality in the Intensive Care Unit (ICU) and Pediatric Intensive Care Unit (PICU) (Kempker and Martin 2016). β-lactam antibiotics are the most commonly prescribed drugs for septic children with numerous clinical indications. Β-lactam antibiotics are the most commonly prescribed drugs for septic children with numerous clinical indications. Septic children receive broad-spectrum antibiotics, blood purification therapy and even extracorporeal membrane oxygenation (ECMO) (Rhodes et al, 2017), their mortality rate can reach approximately 25% worldwide (Menon and Wong 2015; Mathias et al, 2016), while the antimicrobial effect is not often ideal and individual differences exist. The probability of target attainment (PTA) of the dosing interval during which the free drug concentration exceeds the minimal inhibitory concentration (%T > MIC) has been proven to be correlated with clinical improvement in patients treated with meropenem (Ariano et al, 2005; Li et al, 2007; Crandon et al, 2016). The high inter- and intra-patient variability in meropenem concentrations suggested that individual therapy was needed for meropenem treatment in order to achieve target concentration
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