title: Plasma and cerebrospinal fluid concentrations of linezolid in neurosurgical critically ill patients with proven or suspected central nervous system infections.
abstract: Linezolid is a valuable treatment option for central nervous system (CNS) infections caused by multidrug-resistant Gram-positive micro-organisms. Data regarding its penetration into the CNS have shown wide variability. The aim of this study was to describe the population pharmacokinetics of linezolid in plasma and cerebrospinal fluid (CSF) in critically ill patients with external CSF drainage and proven or suspected CNS infections. This was an observational pharmacokinetic (PK) study in 11 critically ill patients with proven or suspected CNS infection receiving linezolid. Serial blood and CSF samples were taken and were subject to population PK analysis. The median (interquartile range) of AUC(0-12h) was 47.6 (17.9-58.6) mgh/L in plasma and 21.1 (18.8-30.4) mgh/L in CSF, with a median CSF/plasma ratio of 0.77. At pre-dose at steady state, a strong positive correlation was observed between linezolid concentrations in CSF and plasma (Spearman's rho=0.758; P=0.011). For a minimum inhibitory concentration (MIC) of 2 mg/L, the median AUC(0-24h)/MIC values in plasma and CSF were <80 in all patients. A three-compartment linear model was found to be most appropriate. The mean value for linezolid clearance was 16.6L/h and mean volume of distribution was 101.3 L. No covariate relationships could be supported on any of the parameters. Linezolid demonstrated good penetration into the CNS but high interindividual PK variability. Administration of higher than standard doses of linezolid and therapeutic drug monitoring should therefore be considered as options to optimise linezolid dosing in critically ill patients with CNS infections.
authors.affiliation: Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Luque
authors.affiliation: Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Grau
authors.affiliation: Intensive Care Department, Hospital del Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Alvarez-Lerma
authors.affiliation: Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Ferrández
authors.affiliation: Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Campillo
authors.affiliation: Infectious Diseases Department, Hospital del Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain.
authors.forename: J P
authors.initials: JP
authors.lastname: Horcajada
authors.affiliation: Intensive Care Department, Hospital del Mar, Parc de Salut Mar, Paseo Marítimo 25-29, 08003 Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Basas
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia; Royal Brisbane & Women's Hospital, Brisbane, QLD, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia; Royal Brisbane & Women's Hospital, Brisbane, QLD, Australia. Electronic address: j.roberts2@uq.edu.au.
authors.forename: J A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D002494:Central Nervous System Infections / Q000188:drug therapy; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D016638:Critical Illness; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D009493:Neurosurgery; D023303:Oxazolidinones / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry*; D011446:Prospective Studies
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid
keywords: Central nervous system; Cerebrospinal fluid; Critically ill patients; Infection; Linezolid; Pharmacokinetics