Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections

Abstract

Background: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events.

Methods: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM.

Results: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23-40) weeks and 21 (1-92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 μg/mL for 50% of the dose interval and >2 μg/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5-148).

Conclusions: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.

FIGURE 1

Goodness-of-fit figures: A) and B), measured versus population predicted (PRED) and individual predicted (IPRED) concentrations in the final model; C) and D), weighted residuals plot for the final population PK model versus time after previous dose and IPRED, respectively. LN(DV/IPRED) indicates natural log of the ratio of the observed concentration (DV) divided by the predicted individual concentrations (IPRED); DV, dependent variable (observed meropenem concentrations).

FIGURE 2

Meropenem measured cerebrospinal fluid (CSF)/predicted plasma concentration ratio: A) measured CSF/predicted plasma concentration ratio versus time of CSF collection (9 CSF sample data points; duplicate CSF samples collected 0.5 hours after dose overlap); B) measured CSF/predicted plasma concentration ratio versus white blood cell count (WBC) in the CSF (8 CSF sample data points with documented CSF WBC; duplicate CSF samples collected 0.5 hours after dose overlap).