1: J Antimicrob Chemother. 2009 Nov;64(5):1035-43. Epub 2009 Sep 16. Cellular pharmacokinetics and intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines. Lemaire S, Van Bambeke F, Appelbaum PC, Tulkens PM. Unité de Pharmacologie cellulaire et moléculaire & Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier 73, Brussels, Belgium. 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 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. PMID: 19759040 [PubMed - in process] Related Links Cellular accumulation and pharmacodynamic evaluation of the intracellular activity of CEM-101, a novel fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in human THP-1 macrophages. [Antimicrob Agents Chemother. 2009] PMID:19564365 Comparative activity of quinolones (ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin) against extracellular and intracellular infection by Listeria monocytogenes and Staphylococcus aureus in J774 macrophages. [J Antimicrob Chemother. 2005] PMID:15731197 Contrasting effects of human THP-1 cell differentiation on levofloxacin and moxifloxacin intracellular accumulation and activity against Staphylococcus aureus and Listeria monocytogenes. [J Antimicrob Chemother. 2008] PMID:18544595 Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. [Antimicrob Agents Chemother. 2006] PMID:16495241 Effect of recombinant human gamma interferon on intracellular activities of antibiotics against Listeria monocytogenes in the human macrophage cell line THP-1. [Antimicrob Agents Chemother. 1996] PMID:8723471