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, but its optimal dosing remains debated. The PK-Pop-LCR prospective population pharmacokinetic/pharmacodynamic (PK/PD) study included acute brain injured (ABI) patients with an external ventricular drainage (EVD) receiving linezolid. A population PK model developed using plasma and cerebrospinal fluid (CSF) data, and Monte Carlo simulations calculated the 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). PD targets for CSF were AUC/MIC > 70 and 100% T> MIC. Toxicity thresholds (plasma Cmin,ss > 7 mg/L and AUCss > 300mg.h/L) was also assessed. CNS infections were confirmed in 14 of 25 patients included. Median AUCCSF/unbound AUCplasma ratio was around 80% for all patients despite higher CSF cytokines levels in CNS-infected patients. EVD flow rate influenced linezolid CSF exposure. For AUCCSF/MIC, 1200 mg/24h allowed to reach PTAs ≥90% only for MICs<1 mg/L, and CFR of 11.2% (MRSA) and 67.0% (MRSE). For T>MIC, 1200mg by continuous infusion (CI) would achieve CFR>95% for MRSE, while 2400mg (CI) would be needed for MRSA (PTA>90% for MIC=4mg/L; CFR = 95%) but with around 40% toxicity risk. We confirmed the extensive CSF distribution of linezolid. Higher doses (2400mg CI) may be considered for probabilistic treatment of CNS infection in ABI patients, despite CSF PK/PD targets further investigated. Early individualized dose adjustment based on MIC and drug monitoring is essential to balance efficacy and safety.