Use of simulation strategies to predict subtherapeutic meropenem exposure caused by augmented renal clearance in critically ill pediatric patients with sepsis

OBJECTIVES The objectives of this study were to 1) define extent and potential clinical impact of increased or decreased renal elimination of meropenem in children with sepsis, based on analysis of renal function during the first 2 days of PICU stay; and 2) estimate the risk of subtherapeutic meropenem exposure attributable to increased renal clearance. METHODS This retrospective study evaluated patients with a diagnosis of sepsis, receiving meropenem from the PICU at Rady Children’s Hospital San Diego from 2015–2017. Meropenem exposure was estimated by using FDA-approved doses (20 and 40 mg/kg/dose) on day 1 and day 2 of PICU stay, based on a population pharmacokinetic (PK) model. For this population with sepsis, we assessed time-above-minimum inhibitory concentration (T>MIC) for pathogen MICs. RESULTS Meropenem treatment was documented in 105 episodes of sepsis with a 48% rate of pathogen detection. By day 2, increased eGFR (>120 mL/min/1.73 m²) was documented in 49% of patients, with 17% meeting criteria for augmented renal clearance ([ARC] >160 mL/min/1.73 m²) and 10%, for decreased function. Simulations documented that 80% of PICU patients with ARC did not achieve therapeutic meropenem exposure for Pseudomonas aeruginosa with a MIC of 2, using standard doses to achieve a pharmacodynamic goal of 80% T>MIC. CONCLUSIONS Approximately 3 of every 20 children with sepsis exhibited ARC during the first 48 hours of PICU stay. Simulations documented an increased risk for subtherapeutic meropenem exposure, suggesting that higher meropenem doses may be required to achieve adequate antibiotic exposure early in the PICU course. ABBREVIATIONS ARC, augmented renal clearance; CNS, central nervous system; CrCL, creatinine clearance; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; GFR, glomerular filtration rate; ICU, intensive care unit; MIC, minimum inhibitory concentration; PICU, pediatric intensive care unit; PK, pharmacokinetic; pRIFLE, pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (renal injury assessment score); PTA, probability of target attainment; SCr, serum creatinine; SIRS, systemic inflammatory response syndrome; TDM, therapeutic drug monitoring; T>MIC, time-above– minimum inhibitory concentration.