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Antimicrobial Agents and Chemotherapy, August 2004, p. 2853-2860, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2853-2860.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Cellular Pharmacokinetics and Pharmacodynamics of the Glycopeptide Antibiotic Oritavancin (LY333328) in a Model of J774 Mouse Macrophages

Françoise Van Bambeke,^* Stéphane Carryn, Cristina Seral, Hugues Chanteux, Donatienne Tyteca,^¶ Marie-Paule Mingeot-Leclercq, and Paul M. Tulkens

Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, Brussels, Belgium

Received 15 December 2003/ Returned for modification 29 March 2004/ Accepted 28 April 2004

The intracellular pharmacokinetics and pharmacodynamics of oritavancin (LY333328) were studied in cultured cells. Oritavancin was avidly accumulated by J774 and THP-1 macrophages and rat fibroblasts and to a lesser extent by LLC-PK1 and Caco-2 cells. In J774 macrophages, the level of accumulation reached a plateau (at 370-fold the extracellular concentration) within 24 h and was partly defeated by a rise in serum protein levels. Efflux was incomplete (with a plateau at two-thirds of the original level at 6 h). In short-term kinetic studies, oritavancin uptake was linear for up to 4 h (as was the case for horseradish peroxidase and small latex beads, used as markers of the fluid phase and adsorptive endocytosis, respectively), which was in contrast to azithromycin and chloroquine uptake (which accumulate in cells by diffusion and segregation). The rates of clearance of oritavancin and latex beads were comparable (150 and 120 µl x mg of protein^–1 x h^–1, respectively) and were approximately 200 times higher than that of horseradish peroxidase. Oritavancin accumulation was partially reduced by monensin but was unaffected by acidic pH (these conditions abolished chloroquine accumulation). Cell-associated oritavancin was found in lysosomal fractions after homogenization of J774 macrophages and fractionation by isopycnic centrifugation. Oritavancin was bactericidal against intracellular Staphylococcus aureus (phagolysosomal infection) but was unable to control the intracellular growth of Listeria monocytogenes (cytosolic infection), even though its cellular concentration largely exceeded the MIC (0.02 mg/liter) and minimal bactericidal concentration (2 mg/liter). We conclude that oritavancin enters cells by adsorptive endocytosis (favored by its lipophilic side chain and/or the presence of three protonatable amines), which drives it to lysosomes, where it exerts antibiotic activity.

Present address: Department of Veterinary Science and Microbiology, University of Arizona, Tucson.

Present address: Department of Clinical Microbiology, University Hospital "Lozano Blesa," Zaragoza, Spain.

Present address: Unité de Microbiologie, Université Catholique de Louvain, Brussels, Belgium.

^¶ Present address: Unité de Biologie Cellulaire, Université Catholique de Louvain, Brussels, Belgium.

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