Background Linezolid is an alternative to vancomycin for treating Gram-positive central nervous system (CNS) healthcare-associated infections. The recommended dosing regimen remains debated.

Methods PK-Pop-LCR, a prospective population pharmacokinetic-pharmacodynamic multicenter study, 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 Staph-ylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), for different dosing regimens. The plasma pharmacodynamic target, AUC/MIC > 100, was used in CSF.

Findings Over 25 patients included, blind adjudication confirmed 14 cases of CNS infections. Mean AUCCSF/fAUCplasma ratio was close to 80% and not different 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% 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. None of dosing regimens tested was appropriate for MRSA infections.

Interpretation 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.

Fundings French Ministry of Health.

CDF received honoraria for lectures from Pulsion and support for attending meetings and/or travel from Codman, SOPHYSA and Pfizer. JP received honoraria for lectures from Masimo, Edwards Lifesciences, support for attending meetings and/or travel from Masimo and consulting fees from AOP Orphan, Takeda, Masimo and Acticor Biotech. All other authors report no potential conflicts.

NCT03481569

This study was funded by the French Ministry of Health.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Committee for the Protection of Persons of Sud-Ouest and Outre-Mer IV (CPP17-016a/2017-002993-37) and the Agence Nationale de Securite du Medicament et des Produits de Sante gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.