UPmémoires

English

Pharmacokinetic-Pharmocodynamic of Meropenem in Cerebrospinal fluid in neuro-intensive care patients

Introduction

Nosocomial central nervous system (CNS) infection is rare but of bad prognosis, leading to devastating neurological complications and increased rate of mortality. The difficulty in treating nosocomial CNS infection is due to the blood brain barrier (BBB) making it a challenge to attain effective concentration at target site and being effective against multi-drug resistant (MDR) bacteria common in nosocomial CNS infection. Meropenem is a broad-spectrum antibiotic recommended in the treatment of nosocomial CNS infection. The main objective of our study was to describe distribution of meropenem at target site in patient with acute brain injury.

Method

We included in a national prospective multicenter study (CPP17-016a/2017-002993-37), 25 brain injured patients with an EVD and treated with meropenem for CNS or other infections. Blood and CSF were collected at different time depending on the dosing regimen: intermittent infusion (2g/8h or 2g/6h), continuous infusion (6-8g/Day) with or without loading dose of 2g. Total plasma and CSF concentrations (C°) were obtained by a Liquid Chromatography coupled with Tandem Mass Spectrometer. Unbound plasma (Plu) C° was calculated from meropenem protein binding of 2%. From a non-compartmental analysis, C° time profiles of meropenem were obtained. CSF to plasma ratio, of area under the curve (AUC) of C° over time for intermittent dosing (AUCCSF/AUCPlu), of C° at steady state for continuous infusion (CCSF/CPlu), were calculated, representing the rate of meropenem penetration into CSF. We then performed a PK population modelling with a Monte Carlo Simulation (MCS) to obtain probability of target attainment (PTA) and Cumulative fraction response (CFR). PTA and CFR were perfomed for patients without CNS infection (type 0) and with CNS infection (type 1).

Result

We included 25 patients after informed consent, (mean age: 54±16,20 years old), and analyzed 114 blood and 135 CSF samples. For all patients (with and without CNS infection) mean AUCCSF/AUCPlu was 0.15 ± 0.12 and CCSF/CPlu was 0.07 ± 0.06. PTA:100%T>MIC was reached in plasma for continuous infusion. For a MIC=2µg/ml in patients with CNS infection, PTA in CSF was 40% for 2g every 8h, 60% for 2g every 6h, 50% for 6g/Day of continuous infusion after loading dose of 2g and 65% for 8g/Day of continuous infusion after loading dose of 2g. CFR were higher than 90% for all species studied except Pseudomonas aeruginosa in patients with and without CNS infection.

Conclusion

As described in literature, Meropenem poorly penetrates the CSF with a large interindividual variability. The appropriate strategy to achieve optimal therapeutic concentrations for an optimal pharmacodynamic efficacy in most of CNS infections with GNB except for Pseudomonas aeruginosa or GNB with high MIC seems to be 6g/day continuous infusion. For intermittent dosing regimen longer duration of infusion should be preferred. For Pseudomonas aeruginosa, higher daily dose of meropenem should be considered and further studies are needed. For a probabilistic treatment 8g/day should probably be preferred first and in case of identification of a difficult to treat bacteria, a therapeutic drug monitoring of meropenem in CSF could be proposed to avoid treatment failure. The practice of therapeutic drug monitoring should be further studied to be proposed in routine.