Identifying optimal dosing strategies for meropenem in the paediatric intensive care unit through modelling and simulation.

BACKGROUND: Meropenem, a ß-lactam antibiotic commonly prescribed for severe infections, poses dosing challenges in critically ill patients due to highly variable pharmacokinetics. OBJECTIVES: We sought to develop a population pharmacokinetic model of meropenem for critically ill paediatric and young adult patients. PATIENTS AND METHODS: Paediatric intensive care unit patients receiving meropenem 20-40 mg/kg every 8 h as a 30 min infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling. Nonlinear mixed effects modelling was conducted using Monolix®. Monte Carlo simulations were performed to provide dosing recommendations against susceptible pathogens (MIC ≤ 2 mg/L). RESULTS: Data from 48 patients, aged 1 month to 30 years, with 296 samples, were described using a two-compartment model with first-order elimination. Allometric body weight scaling accounted for body size differences. Creatinine clearance and percentage of fluid balance were identified as covariates on clearance and central volume of distribution, respectively. A maturation function for renal clearance was included. Monte Carlo simulations suggested that for a target of 40% fT > MIC, the most effective dosing regimen is 20 mg/kg every 8 h with a 3 h infusion. If higher PD targets are considered, only continuous infusion regimens ensure target attainment against susceptible pathogens, ranging from 60 mg/kg/day to 120 mg/kg/day. CONCLUSIONS: We successfully developed a population pharmacokinetic model of meropenem using real-world data from critically ill paediatric and young adult patients with an opportunistic sampling strategy and provided dosing recommendations based on the patients' renal function and fluid status.

Pharmacokinetic Factors Associated With Early Meropenem Target Attainment in Pediatric Severe Sepsis.

OBJECTIVES: To determine the frequency of early meropenem concentration target attainment (TA) in critically ill children with severe sepsis; to explore clinical, therapeutic, and pharmacokinetic factors associated with TA; and to assess how fluid resuscitation and volume status relate to early TA. DESIGN: Retrospective analysis of prospective observational cohort study. SETTING: PICU in a single academic quaternary care children's hospital. PATIENTS: Twenty-nine patients starting meropenem for severe sepsis (characterized as need for positive pressure ventilation, vasopressors, or ≥ 40 mL/kg bolused fluid), of which 17 were newly escalated to PICU level care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Concentration-time profiles were analyzed using modeling software employing opportunistic sampling, Bayesian estimation, and a population pharmacokinetic model. Time above four times minimum inhibitory concentration (T > 4×MIC), using the susceptibility breakpoint of 1 µg/mL, was determined for each patient over the first 24 hours of meropenem therapy, as well as individual clearance and volume of distribution (Vd) estimates. Twenty-one of 29 patients met a target of 40%T > MIC 4 µg/mL. Reaching TA, vs. not, was associated with lower meropenem clearance. We failed to identify a difference in Vd or an association between the TA group and age, weight, creatinine-based estimated glomerular filtration rate (eGFR), or the amount of fluid administered. eGFR was, however, negatively correlated with overall T > MIC. CONCLUSIONS: Eight of 29 pediatric patients with early severe sepsis did not meet the selected TA threshold within the first 24 hours of meropenem therapy. Higher clearance was associated with failure to meet targets. Identifying patients likely to have higher meropenem clearance could help with dosing regimens.