1. Antimicrob Agents Chemother. 2010 Jun;54(6):2549-59. Epub 2010 Apr 12.

Cellular pharmacodynamics of the novel biaryloxazolidinone radezolid: studies
with infected phagocytic and nonphagocytic cells, using Staphylococcus aureus,
Staphylococcus epidermidis, Listeria monocytogenes, and Legionella pneumophila.

Lemaire S, Kosowska-Shick K, Appelbaum PC, Verween G, Tulkens PM, Van Bambeke F.

SIGA Technologies, Corvallis, Oregon, USA.

Radezolid is a novel biaryloxazolidinone in clinical development which shows
improved activity, including against linezolid-resistant strains. In a companion 
paper (29), we showed that radezolid accumulates about 11-fold in phagocytic
cells, with approximately 60% of the drug localized in the cytosol and
approximately 40% in the lysosomes of the cells. The present study examines its
activity against (i) bacteria infecting human THP-1 macrophages and located in
different subcellular compartments (Listeria monocytogenes, cytosol; Legionella
pneumophila, vacuoles; Staphylococcus aureus and Staphylococcus epidermidis,
mainly phagolysosomal), (ii) strains of S. aureus with clinically relevant
mechanisms of resistance, and (iii) isogenic linezolid-susceptible and -resistant
S. aureus strains infecting a series of phagocytic and nonphagocytic cells.
Radezolid accumulated to similar levels ( approximately 10-fold) in all cell
types (human keratinocytes, endothelial cells, bronchial epithelial cells,
osteoblasts, macrophages, and rat embryo fibroblasts). At equivalent weight
concentrations, radezolid proved consistently 10-fold more potent than linezolid 
in all these models, irrespective of the bacterial species and resistance
phenotype or of the cell type infected. This results from its higher intrinsic
activity and higher cellular accumulation. Time kill curves showed that
radezolid's activity was more rapid than that of linezolid both in broth and in
infected macrophages. These data suggest the potential interest of radezolid for 
recurrent or persistent infections where intracellular foci play a determinant

PMID: 20385852 [PubMed - in process]