CSF pharmacokinetics-pharmacodynamics of linezolid in critically brain injured patients, with or without central nervous system healthcare-associated infection. The PK-Pop-LCR Study: A Multicenter Pharmacokinetics and Pharmacodynamics Population Study.

Linezolid is an alternative to vancomycin for treating Gram-positive central nervous system (CNS) healthcare-associated infections. The recommended dosing regimen remains debated. PK-Pop-LCR is a prospective population pharmacokinetic-pharmacodynamic multicenter study which included brain injured patients with an external ventricular drainage receiving linezolid at different dosing regimens. The cerebrospinal fluid (CSF) penetration of linezolid was investigated and a population pharmacokinetic model developed using plasma and CSF data. Monte Carlo simulations were conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) in CSF against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), for different dosing regimens. The plasma pharmacodynamic target, AUC/MIC > 100, was used in CSF. Over 25 patients included, blind adjudication confirmed 14 cases of CNS infections. The mean AUCCSF/fAUCplasma ratio was close to 80% with no difference between patients with and without CNS infection, despite higher CSF cytokines levels in CNS-infected patients. The recommended dose of 1200 mg/24h allowed to reach PTAs [≥] 90% only for MICs [≤] 0.5 mg/L, and CFR of 3.2% and 40% for MRSA and MRSE, respectively. 2 700 mg/24h would allow to achieve PTA > 90% for MIC up to 1 mg/L and CFR of 90% for MRSE but none of dosing regimens tested was appropriate for MRSA infections. We confirmed the extensive CSF distribution of linezolid. Higher doses than those recommended should be considered to treat CNS infection in critically brain injured patients. However, pharmacodynamic target for CNS infections should be further investigated to confirm these findings. FundingsFrench Ministry of Health.