title: Cellular pharmacokinetics and intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines.
abstract: OBJECTIVE
  Optimal treatment of infections caused by Staphylococcus aureus, Listeria monocytogenes and Legionella pneumophila requires antibiotics with intracellular activity. Linezolid accumulates poorly within cells. Torezolid (TR-700) is a novel methyltetrazolyl oxazolidinone with potentially different cellular pharmacokinetic properties. Our aim was to examine the accumulation and intracellular activities of torezolid in this context.
  
  
  METHODS
  Measurement of torezolid cell content and antibacterial activity in comparison with linezolid using human macrophages (THP-1) and human endothelial cells [human umbilical vein endothelial cells (HUVECs)], applying models allowing for the quantitative evaluation of the pharmacodynamics of antibiotics towards intracellular bacteria.
  
  
  RESULTS
  Torezolid accumulated rapidly in THP-1 macrophages, reaching a stable intracellular to extracellular ratio of approximately 10 (compared with approximately 1-2 for linezolid) within 15 min. On a weight concentration basis (mg/L), torezolid was approximately 5- to 10-fold more potent intracellularly (lower concentration needed to achieve a bacteriostatic effect) than linezolid against phagocytosed S. aureus, L. monocytogenes and L. pneumophila, with no change in maximal efficacy (approximately 1 log(10) reduction of the original, post-phagocytosis inoculum). When drugs were compared at equipotent concentrations (multiples of the MIC), no difference was seen between linezolid and torezolid, but the higher potency of torezolid allowed control of intracellular infections caused by linezolid-resistant S. aureus.
  
  
  CONCLUSIONS
  Torezolid exerts intracellular activity at lower extracellular concentrations than linezolid because of its greater potency independent of its greater intracellular accumulation. This may confer an advantage to torezolid in vivo if the drug can be used at dosages creating serum concentrations similar to those achieved with linezolid.
authors.affiliation: Unité de Pharmacologie cellulaire et moléculaire & Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier 73, Brussels, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lemaire
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
authors.forename: Peter C
authors.initials: PC
authors.lastname: Appelbaum
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tulkens
mesh_terms: D000900:Anti-Bacterial Agents / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002460:Cell Line; D015169:Colony Count, Microbial; D003600:Cytosol / Q000737:chemistry; D042783:Endothelial Cells / Q000737:chemistry / Q000382:microbiology; D006801:Humans; D016952:Legionella pneumophila / Q000187:drug effects*; D008089:Listeria monocytogenes / Q000187:drug effects*; D008264:Macrophages / Q000737:chemistry / Q000382:microbiology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D023303:Oxazolidinones / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013777:Tetrazoles / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D013777:Tetrazoles; C546016:tedizolid