Optimizing Tedizolid Dosing in Cerebral Nocardiosis: Clinical Impact of Direct Unbound Concentration Measurement and Population PK Modelling in Two Cases.

INTRODUCTION

Tedizolid, a second-generation oxazolidinone, exhibits potent in vitro activity against Gram-positive bacteria, including Nocardia species, and has a more favourable safety profile than linezolid during prolonged use. However, data on itsCSF penetration and efficacy remain scarce. We describe two cases of Nocardia farcinica brain abscess treated with tedizolid and report measured serum and cerebrospinal fluid (CSF) exposures.

CASE REPORTS: Two patients with N. farcinica brain abscesses (MIC for tedizolid 0.75 mg/L) treated with tedizolid as part of combination therapy. Total and unbound concentrations in serum and CSF were quantified using LC-MS/MS, and PK/PD modelling was performed. In case 1, a 60-year-old man with idiopathic CD4 lymphocytopenia initially improved but relapsed while receiving tedizolid 200 mg once daily. The unbound plasma fraction was 15.7%, and CSF exposure remained low, with a predicted fAUC0-24/MIC <3: below the PK/PD threshold used for staphylococcal skin infections. Tedizolid was discontinued, and the patient subsequently died. In case 2, a 72-year-old diabetic patient received 200 mg twice daily. The unbound plasma fraction was higher (30.1%). PK/PD modelling predicted a CSF fAUC0-24/MIC of 7.5, exceeding the proposed efficacy threshold. The patient completed therapy successfully and remained relapse-free after 2 years.

DISCUSSION: These cases highlight moderate CSF penetration of tedizolid and substantial interpatient variability in protein binding. Direct measurement of unbound concentrations was critical for accurate PK/PD assessment. Although higher dosing may improve central nervous system (CNS) exposure and outcomes, tedizolid should not be considered interchangeable with linezolid for CNS nocardiosis. Individualized monitoring of free plasma levels may help optimize dosing strategies.