OBJECTIVES: To define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization. DESIGN: Pharmacokinetic sampling was undertaken in 19 subjects receiving standard meropenem dosing (20 mg/kg/dose, 8 hr) recruited from March 2019 to March 2022. Sampling occurred once each day following meropenem given 24 hours apart, during the first 3 PICU days. Data analysis was completed in 2023 and noncompartmental analysis was performed to assess pharmacodynamic exposure targets for sepsis. Clearance and volume of distribution at 20 mg/kg/dose were used to simulate mean exposures at 40 and 60 mg/kg/dose. SETTING: PICU in a tertiary care center. SUBJECTS: Patients 4 weeks old or older with hypotension requiring fluid resuscitation and vasopressor therapy, receiving meropenem as empiric therapy for sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Augmented renal clearance (ARC) was documented in eight of 19 subjects, previously associated with subtherapeutic plasma concentrations, while three of 19 had acute kidney injury and decreased renal clearance. When assessed by pharmacodynamic exposure targets for sepsis (plasma meropenem concentrations above the minimum inhibitory concentration [MIC] of Pseudomonas aeruginosa for 70% or 100% of the dosing interval), ten of 19 and nine of 19 children, respectively, had subtherapeutic plasma meropenem exposures during PICU day 1, even for pathogens with an MIC considered "susceptible" by U.S. Food and Drug Administration criteria. Therapeutic meropenem pharmacodynamic exposures were associated with a positive 24-hour fluid balance on PICU day 1 and a negative 24-hour fluid balance by day 3, although profound variability was noted in fluid administered and renal output. CONCLUSIONS: Given the variability in meropenem systemic exposure in pediatric septic shock, therapeutic drug monitoring, or monitoring for ARC, is suggested during the first days of hospitalization to allow daily assessments of dosing needs to achieve pharmacodynamic exposure targets for sepsis.