Correspondence: P. Malacarne, U.O. Anestesia e Rianimazione, Azienda Ospedaliera Universitaria Pisana, Via Roma 57, 56126 Pisa, Italy. Tel: +39 050 992327. Fax: +39 050 992867. E-mail: pmalacarne@hotmail.com (Received 8 November 2010; accepted 13 April 2011) Introduction Linezolid, a recent oxazolidinone derivative antimi- crobial agent, is an established treatment option with demonstrated activity against multi-resistant Gram- positive microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococcus (CoNS) and vancomycin-resistant Enterococcus (VRE), with min- imum inhibitory concentration (MIC) values ranging from 0.5 up to 4 mg/l [1]. The pharmacokinetic/pharmacodynamic (PK/ PD) parameter used to define linezolid efficacy has been the time above the MIC (T  MIC) [2]. In vitro and in vivo studies have shown that T  MIC values of at least 40% are predictive of bacteriostatic activ- ity, while a T  MIC higher than 75% is associated with bactericidal activity [3,4]. However, more recent studies have demonstrated that the area under the time–concentration curve (AUC) over the MIC (AUC/MIC) is also able to predict linezolid effec- tiveness, especially for values higher than 50 [5] or 100 [2]. Linezolid is characterized by good central nervous system (CNS) penetration, as confirmed by a cere- brospinal fluid (CFS) to serum concentration ratio greater than 0.8 [6]. Recent findings have focused attention on the possible role of linezolid as an agent for CNS infections [7,8]. However, to date, limited data are available on CSF concentrations of linezolid [6–11] and only 4 studies have evaluated CSF line- zolid amounts over time [7–10]. Therefore, the pres- ent study was aimed at evaluating plasma and CSF ORIGINAL ARTICLE Linezolid in the central nervous system: Comparison between cerebrospinal fluid and plasma pharmacokinetics BRUNO VIAGGI 1 , ANTONELLO DI PAOLO 2 , ROMANO DANESI 2 , MARIALUISA POLILLO 2 , LAURA CIOFI 2 , MARIO DEL TACCA 2 & PAOLO MALACARNE 1 From the 1 U.O. Anestesia e Rianimazione, Azienda Ospedaliera Universitaria Pisana, and 2 Divisione di Farmacologia, Dipartimento di Medicina Interna, Università di Pisa, Pisa, Italy Abstract Background: Linezolid is effective against methicillin-resistant Staphylococcus aureus, which may cause central nervous system (CNS) infections, but drug concentrations in plasma are characterized by a large inter-patient variability. Therefore, the present study was aimed at evaluating linezolid pharmacokinetics in plasma and cerebrospinal fluid (CSF) in 7 patients with external ventricular drainage, who received linezolid 600 mg twice daily as 1-h intravenous infusion to prevent CNS infections. Methods: Plasma and CSF linezolid concentrations were measured by high-performance liquid chromatography (HPLC) after the 1 st and 5 th dose, and pharmacokinetics were evaluated by non-compartmental analysis. Results: Values of the CSF area under the time/concentration curve (AUC) (range 18.2–85.5 and 19.6–160.5 h  mg/l at the 1 st and 5 th dose, respectively) were lower than those calculated in plasma (range 27.6–224.0 and 27.5–166.1 h  mg/l, respectively). For minimum inhibitory concentration (MIC) = 1 mg/l, CSF AUC/MIC values were nearly equal to or greater than 100 only in 2 subjects after the 1 st and 5 th dose, whereas mean time above the MIC (T  MIC) values were higher than 75% in only 3 patients. Similar results were obtained when pharmacokinetic/pharmacodynamic parameters were evaluated in plasma. Conclusion: The present results suggest that changes in linezolid doses and measurement of drug concentrations should be considered as useful strategies to optimize treatment in some patients. Keywords: Linezolid, pharmacokinetics, central nervous system, cerebrospinal fluid, PK/PD Scandinavian Journal of Infectious Diseases, 2011; 43: 721–727 ISSN 0036-5548 print/ISSN 1651-1980 online © 2011 Informa Healthcare DOI: 10.3109/00365548.2011.582140 Scand J Infect Dis Downloaded from informahealthcare.com by Library of Health Sci-Univ of Il on 10/28/14 For personal use only.