(923) Population Pharmacokinetics of Meropenem in Pediatric Patients With Sepsis

Introduction: Augmented renal clearance (ARC) is a metabolic phenomenon in critically ill patients resulting in enhanced renal elimination of drugs. The impact of ARC due to sepsis on therapeutic concentrations of beta-lactam antibiotics over the first days of hospitalization has not been prospectively characterized. Guidelines for optimized dosing have yet to be determined. Limited data have been published on the impact of ARC on meropenem concentrations in pediatric sepsis. Our study used pharmacokinetic (PK) data and renal biomarkers to prospectively assess meropenem therapy in this vulnerable population.

Methods: This prospective study was conducted from 2019-2023, enrolling children who met diagnostic criteria for sepsis and were receiving meropenem 20 mg/kg IV every 8 hours. Serial plasma collections were performed over 8 hours following a dose of meropenem every 24 hours over three days. Clinical data, including fluid balance, ventilation, and vasoactive medication requirement, were collected as well at 8-hour intervals. Estimated glomerular filtration rate (e-GFR) was calculated by the modified Schwartz formula. Data were analyzed using non-linear mixed effects modeling (NONMEM, version 7.3).

Results: A total of 26 pediatric patients were enrolled with a median age 12.6 years (range 1.2- 19.6), serum creatinine (SCr) 0.36 mg/dL (0.09-2.57), cystatin C (CYS) 448.9 mg/d (178.3-1824.1), and neutrophil gelatinase-associated lipocalin (NGAL) 176.05 ng/mL (29.3-1000). A two-compartment model with allometrically scaled weight on clearance (0.75) initially best described the data. Using the final PK model, median meropenem clearance was 0.15 L/hr/kg (range 0.05-0.51, interquartile range (IQR) 0.06-0.25). Median meropenem concentration was 12.5 mcg/mL(range 0.03-217, IQR 2.67-43.75). The median GFR was 139 (23-364, IQR 93-204) mL/min/1.73 m2. Statistically significant covariates for meropenem clearance were age, weight, and diagnosis of appendicitis, along with e-GFR, CYS, NGAL, and albumin.

Conclusions: Children with sepsis show significant variability in meropenem clearance and concentrations over a broad range of eGFR documented within the first 3 days of sepsis. Future work will include dose optimization and individualization strategies based on the factors identified for these complex patients.