Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis

Abstract

Data of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for meropenem. Population PK data were analyzed using NONMEM software. Fifty-seven patients (mean age, 2.96 years [range, 0.101 to 14.4]; mean body weight, 15.8 kg [range, 5.0 to 65.0]) were included. A total of 135 meropenem concentrations were obtainable for population PK modeling. The median number of samples per patients was 2 (range, 1 to 4). A two-compartment model with first-order elimination was optimal for PK modeling. Weight and creatinine clearance (estimated by the Schwartz formula) were significantly correlated with the PK parameters of meropenem. The probabilities of target attainment for pathogens with low MICs of 1 and 2 μg/ml were 87.5% and 68.6% following administration of 40 mg/kg/dose (every 8 h [q8h]) as a 4-h infusion and 98.0% and 73.3% with high MICs of 4 and 8 μg/ml following administration of 110 mg/kg/day as a continuous infusion in critically ill infants and children under 70% fT>MIC (the free time during which the plasma concentration of meropenem exceeds the MIC), respectively. The standard dosage regimens for meropenem did not meet an appropriate PD target, and an optimal dosing regimen was established in critically ill infants and children. (This study has been registered at ClinicalTrials.gov under identifier NCT03643497.)

Key Challenges in Providing Effective Antibiotic Therapy for Critically Ill Patients with Bacterial Sepsis and Septic Shock

“…Another very recent study included 57 patients in the PICU, 35 with sepsis, with a median age of 1.44 years (range 0.101-14.4 years) and CL CR estimated by the Schwartz formula of 155 mL/min/1.73 m 2 (57.9-279 mL/min/1.73 m 2 ). 82 Most patients (43 of 57) had an eCL CR ≥ 130 mL/min/1.73 m 2 . The eCL CR was included as a covariate on total meropenem clearance using an empirical power function.…”

“…Simulations suggested 80% of patients in the PICU with ARC did not achieve therapeutic meropenem exposure for susceptible pathogens. Another very recent study included 57 patients in the PICU, 35 with sepsis, with a median age of 1.44 years (range 0.101–14.4 years) and CL CR estimated by the Schwartz formula of 155 mL/min/1.73 m 2 (57.9–279 mL/min/1.73 m 2 ) 82 . Most patients (43 of 57) had an eCL CR ≥ 130 mL/min/1.73 m 2 .…”

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

“…But Shekar et al found that variability in meropenem clearance was correlated with creatinine clearance or the presence of CRRT ( Shekar et al, 2014 ). Wang et al demonstrated that standard dosage regimens for meropenem did not meet an appropriate PD target but they did not do research on children undergoing extracorporeal life support (ECLS) ( Wang et al, 2020 ).…”

Extended or Continuous Infusion of Carbapenems in Children with Severe Infections: A Systematic Review and Narrative Synthesis

“…At a MIC of 8 mg/L, the CI of MER (90 mg/kg/d) might achieve an optimal PTA in children with creatinine clearances of 40–120 mL/min/1.73 m 2 . In addition, Wang et al [ 25 ] found that the PTA values for pathogens with high MICs (4 and 8 mg/L), such as Enterobacteriaceae and Pseudomonas aeruginosa , could still reach 98.0% and 73.3%, respectively, in severely infected infants and children after CI of MER (110 mg/kg/d). Germovsek et al [ 26 ] performed simulations based on a PPK model in neonates and infants with severe infections and stated that the EI/CI modes could increase the plasma PTA but might decrease the PTA in cerebrospinal fluid.…”