JAC Advance Access originally published online on September 16, 2009
Journal of Antimicrobial Chemotherapy 2009 64(5):1035-1043; doi:10.1093/jac/dkp267
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Original research |
Cellular pharmacokinetics and intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines
1 Unité de Pharmacologie cellulaire et moléculaire & Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium 2 Hershey Medical Center, Hershey, PA 17033, USA
Received 18 May 2009; returned 18 June 2009; revised 1 July 2009; accepted 2 July 2009
* Corresponding author. Unité de Pharmacologie cellulaire et moléculaire, Université catholique de Louvain, UCL 73.70, Avenue E. Mounier 73, B-1200 Brussels, Belgium. Tel: +13227647371; Fax: +13227647373; E-mail: tulkens{at}facm.ucl.ac.be
Background and aims: 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 
10 (compared with 1–2 for linezolid) within 15 min. On a weight concentration basis (mg/L), torezolid was 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 (1 log10 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.
Keywords: linezolid , Staphylococcus aureus , Legionella pneumophila , Listeria monocytogenes , pharmacodynamics