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,

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]

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