Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Meropenem in Neurocritical Care Patients: a Prospective Two-Center Study

Abstract

Morbidity and mortality related to ventriculitis in neurocritical care patients remain high. Antibiotic dose optimization may improve therapeutic outcomes. In this study, a population pharmacokinetic model of meropenem in infected critically ill patients was developed. We applied the final model to determine optimal meropenem dosing regimens required to achieve targeted cerebrospinal fluid exposures. Neurocritical care patients receiving meropenem and with a diagnosis of ventriculitis or extracranial infection were recruited from two centers to this study. Serial plasma and cerebrospinal fluid samples were collected and assayed. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. We sought to determine optimized dosing regimens that achieved meropenem cerebrospinal fluid concentrations above pathogen MICs for 40% of the dosing interval, or a higher target ratio of meropenem cerebrospinal fluid trough concentrations to pathogen MIC of ≥1. In total, 53 plasma and 34 cerebrospinal fluid samples were obtained from eight patients. Meropenem pharmacokinetics were appropriately described using a three-compartment model with linear plasma clearance scaled for creatinine clearance and cerebrospinal fluid penetration scaled for patient age. Considerable interindividual pharmacokinetic variability was apparent, particularly in the cerebrospinal fluid. Percent coefficients of variation for meropenem clearance from plasma and cerebrospinal fluid were 41.7% and 89.6%, respectively; for meropenem, the volume of distribution in plasma and cerebrospinal fluid values were 63.4% and 58.3%, respectively. High doses (up to 8 to 10 g/day) improved attainment of meropenem cerebrospinal fluid target exposures, particularly for less susceptible organisms (MICs, ≥0.25 mg/L). Standard meropenem doses of 2 g every 8 h may not achieve effective concentrations in cerebrospinal fluid in all critically ill patients. Higher doses, or alternative dosing methods (e.g., loading dose followed by continuous infusion) may be required to optimize cerebrospinal fluid exposures. Doses of up to 8 to 10 g/day either as intermittent boluses or continuous infusion would be suitable for patients with augmented renal clearance; lower doses may be considered for patients with impaired renal function as empirical suggestions. Ongoing dosing should be tailored to the individual patient circumstances. Notably, the study population was small and dosing recommendations may not be generalizable to all critically ill patients.

Keywords: CSF; carbapenem; dosing; pharmacodynamics; pharmacokinetics; sepsis.

FIG 1

Pharmacokinetic model. K₁₂, transfer rate constant from central to CSF compartment; K₂₁, transfer rate constant from CSF to central compartment; K_cp, transfer rate constant from central to peripheral compartment; K_pc, transfer rate constant from peripheral to central compartment; CL, clearance from central compartment; CL₂, clearance from CSF compartment.

FIG 2

Comparison between observed antibiotic concentrations versus concentrations predicted by pharmacokinetic model in plasma and cerebrospinal fluid. (A) Plasma model for population and individual; (B) cerebrospinal fluid model for population and individual.

FIG 3

Observed meropenem concentration-time data and visual predictive check of the final model. (A) Plasma model, dots represent observed meropenem concentrations in plasma; (B) cerebrospinal fluid model, dots represent observed meropenem concentrations in CSF.

FIG 4

Probabilities of target attainment in CSF for a 40% fT_>MIC with simulated patient age of 60 years for a creatinine clearance of 50 mL/min (A), 100 mL/min (B), or 150 mL/min (C). q8h, administered every 8 h; q6h, administered every 6 h; CI, continuous infusion; g/d, grams per day.

FIG 5

Probabilities of target attainment in CSF for a C_min/MIC of ≥1 with a simulated patient age of 60 years and a creatinine clearance of 50 mL/min (A), 100 mL/min (B), or 150 mL/min (C). q8h, administered every 8 h; q6h, administered every 6 h; CI, continuous infusion; g/d, grams per day.