Pkpop-LCR study: Pharmacokinetic and Pharmacodynamic of linezolid in neurointensive care patients with external ventricular drainage
Résumé
Background
Nosocomial central nervous system (CNS) infections require rapid effective antimicrobial therapy. Reaching appropriate concentrations in CNS remains challenging because of bloodbrain barrier and cerebrospinal fluid (CSF) turnover. The main goal of this multicenter prospective study was to explore PK/PD of Linezolid (LNZ) in CSF and efficacy of current dosing regimens in CNS infections.
Methods
Twenty five patients with external ventricular drainage (EVD) treated with LNZ by 600 mg every 12h (two doses (2D), n=17) or 8h (three doses (3D), n=8), for a CNS or other site infection. Blood and CSF samples were collected after steady-state (3-5 days), at predetermined sampling times. LNZ plasma data were first modelled by a population pharmacokinetic analysis. Thereafter, plasma parameters estimated and corrected for protein
binding of 31% were fixed to fit unbound CSF concentrations. In the final model, parameters for both plasma and CSF data were simultaneously estimated. Then, Monte Carlo simulations were conducted to determine the probability of target attainment (PTA) and the cumulative
fraction of response (CFR) in CSF of current dosing regimens against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE)[1].
Results
A two-compartment (one for plasma and one for CSF) linear model was found to be the most appropriate. LNZ was widely distributed into the CSF with a mean ratio of AUCCSF/AUCplasma of 90% for unbound concentrations. No difference in the penetration of LNZ into the CSF was observed between patients with and without meningitis. PTAs (AUC/MIC > 100) were greater than 90% only for MICs ≤ 0.5 mg/L after administration of the standard dosing regimens, suggesting no efficacy against MRSA and MRSE infections (CFR ≤ 13% and 70%, respectively).
Conclusions
Our results confirmed that 100% of unbound form of LNZ diffuse in CSF at steady-state [2-4], which could allow a plasma therapeutic drug monitoring to estimate the free concentration of LNZ in CSF to adapt treatments. However, according to our results, none of the studied dosing regimens reached widely the PKPD target. For the usual dosing regimen, linezolid CSF concentrations seem insufficient to treat MRSA and MRSE with MICs upper than 0,25 mg/L in ICU patients with CNS infections.
Domaines
Pharmacologie
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