Use of Simulation Strategies to Predict Subtherapeutic Meropenem Exposure Caused by Augmented Renal Clearance in Critically Ill Pediatric Patients With Sepsis

Abstract

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.

Scoping review of augmented renal clearance in critically ill pediatric patients

“…Review of titles and abstracts led to the retrieval of 215 potentially relevant full‐text citations. After full‐text review, 25 citations met the criteria for inclusion 16–41 . The most common reason for exclusion was non‐pediatric population studies (190 citations), followed by lack of ARC data (24 citations).…”

“…Table 1 summarizes the characteristics of the studies included based upon their primary objective 16–41 . The first articles related to ARC in pediatrics were published in 2015 and were pharmacokinetic objective studies 20,36 .…”

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

“…A recent retrospective study reviewed 105 episodes of sepsis treated with meropenem in patients of a pediatric ICU (PICU) with median age 10.1 years (interquartile range 4.4-15.2 years); median CL CR estimated by the Schwartz bedside equation was 119.9 mL/min/1.73 m 2 (79.29 to 148.3 mL/ min/1.73 m 2 ) on day 2 of PICU stay. 81 Meropenem exposures for patients in the study were estimated using a previously published covariate-adjusted population PK model for meropenem in children. Simulations suggested 80% of patients in the PICU with ARC did not achieve therapeutic meropenem exposure for susceptible pathogens.…”

“…Dosing simulations indicated that continuous infusion should be used in ARC regardless of the MIC of the infecting pathogen. A recent retrospective study reviewed 105 episodes of sepsis treated with meropenem in patients of a pediatric ICU (PICU) with median age 10.1 years (interquartile range 4.4–15.2 years); median CL CR estimated by the Schwartz bedside equation was 119.9 mL/min/1.73 m 2 (79.29 to 148.3 mL/min/1.73 m 2 ) on day 2 of PICU stay 81 . Meropenem exposures for patients in the study were estimated using a previously published covariate‐adjusted population PK model for meropenem in children.…”

Late augmented renal clearance in patients with COVID-19 in the intensive care unit. A prospective observational study

“…The mechanisms leading to ARC are not yet fully elucidated. However, in the better-organized ARC in bacterial sepsis patients, in which pro-inflammatory cytokines and increased renal blood flow in the hyperdynamic early phase of sepsis may be the driving force [ 2 , [5] , [6] , [7] , [8] ]. The occurrence of ARC in the later phases of ICU admission in critically ill COVID-19 patients may imply that the ARC may be of different origin.…”