Optimized Dosing Regimens of Meropenem in Septic Children Receiving Extracorporeal Life Support

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.

Antimicrobial Dosing Recommendations in Pediatric Continuous Renal Replacement Therapy: A Critical Appraisal of Current Evidence

“…The most frequently studied drug in children receiving CRRT was meropenem, accounting for nine of the included studies ( 4 , 5 , 26 – 32 ). Vancomycin followed with three included studies ( 33 – 35 ).…”

Population pharmacokinetics in critically ill neonates and infants undergoing extracorporeal membrane oxygenation: a literature review

“…This is mostly due to meropenem’s chemical characteristics. According to Wang et al ’s study 23 about a popPK model of meropenem in children with sepsis receiving extracorporeal life support, the PK characteristics of meropenem were not affected by ECMO intervention. Furthermore, ECMO and CRRT can raise Vd due to the extracorporeal circuits, although this study indicated that the impact on meropenem concentration was smaller than previously documented haemofilters.…”

“… 40 The differences in Vd and Cl of some of the studied drugs, such as vancomycin, between ECMO and non-ECMO controls demonstrated significant intrastudy variability, with some studies showing increased values for the PK parameters, 31 32 36 while others showed decreased values or no change. 23 24 41 …”

“…40 The differences in Vd and Cl of some of the studied drugs, such as vancomycin, between ECMO and non-ECMO controls demonstrated significant intrastudy variability, with some studies showing increased values for the PK parameters, 31 32 36 while others showed decreased values or no change. 23 24 41 In this literature review, most studies evaluated both VV and VA modalities of ECMO together. According to Bhatt-Mehta et al's study, 42 there was no statistically significant difference between VA and VV bypass type in terms of Vd (0.61±0.15 vs 0.74±0.23 L/kg), Cl (0.157±0.046 vs 0.199±0.085 L/hour) and t 1/2 (10.04±2.45 vs 10.75±3.43 hours) (p>0.05).…”

“…However, the bulk of the studies did not include non-ECMO comparator groups, and the comparisons were based on PK data provided in other published data 40. The differences in Vd and Cl of some of the studied drugs, such as vancomycin, between ECMO and non-ECMO controls demonstrated significant intrastudy variability, with some studies showing increased values for the PK parameters,31 32 36 while others showed decreased values or no change 23 24 41…”