Cerebrospinal fluid penetration of linezolid in neurosurgical patients

Introduction

Linezolid is a new antimicrobial agent effective against drug-resistant Gram-positive pathogens commonly responsible for central nervous system (CNS) infections in neurosurgical patients hospitalized in ICUs.

Materials and methods

We studied the penetration of linezolid into the cerebrospinal fluid (CSF) in 14 neurosurgical patients. Drug disposition in serum and CSF was studied by administering linezolid 600 mg twice daily (1 hour i.v. infusion) for the treatment of Gram-positive CNS infections or as chemoprohylaxis. Serum and CSF linezolid steady-state concentrations were analyzed by HPLC and the concentration-time profiles obtained were analyzed to estimate pharmacokinetic parameters.

Results

Mean ± SD linezolid peak and trough concentrations were 19.7 ± 9.9 μg/ml and 5.8 ± 5.2 μg/ml in serum and 9.8 ± 5.6 μg/ml and 5.8 ± 4.2 μg/ml in CSF, respectively. The mean ± SD areas under the concentration-time curves during the 12-hour dosing interval (AUC0-Ts) were 195.6 ± 159.6 hour* μg/ml for serum and 88± 55 hour* μg/ml for CSF, with a mean penetration ratioAUC0-T CSF:AUC0-T serum of 0.50. The mean elimination half-life oflinezolid in CSF was longer than that in serum (18.3 ± 19.2 compared with 5.9 ± 3.3 hours). Serum and CSF linezolid concentrations exceeded the breakpoint of 4 μg/ml for susceptible target pathogens for the entire dosing interval in the majority of patients. Two patients with documented Staphylococcus aureus CNS infection and one with primary MRSE bacteremia were successfully treated.

Conclusion

These findings suggest that linezolid may achieve adequate CSF concentrations in patients requiring antibiotics for the management/prophylaxis of Gram-positive CNS infections. More studies are needed regarding clinical efficacy of linezolid regarding the management of CNS infections.