Skip Navigation


JAC Advance Access originally published online on March 27, 2008
Journal of Antimicrobial Chemotherapy 2008 61(6):1288-1294; doi:10.1093/jac/dkn120
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrowOA All Versions of this Article:
61/6/1288    most recent
dkn120v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Barcia-Macay, M.
Right arrow Articles by Van Bambeke, F.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Barcia-Macay, M.
Right arrow Articles by Van Bambeke, F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Original research

Cellular pharmacokinetics of telavancin, a novel lipoglycopeptide antibiotic, and analysis of lysosomal changes in cultured eukaryotic cells (J774 mouse macrophages and rat embryonic fibroblasts)

Maritza Barcia-Macay, Fatima Mouaden, Marie-Paule Mingeot-Leclercq, Paul M. Tulkens and Françoise Van Bambeke*

Université catholique de Louvain, Faculté de Médecine, Unité de Pharmacologie cellulaire et moléculaire, B-1200 Brussels, Belgium

Received 17 December 2007; returned 13 January 2008; revised 12 February 2008; accepted 22 February 2008

* Corresponding author. Tel: +32-2-764-7378; Fax: +32-2-764-7373; E-mail: vanbambeke{at}facm.ucl.ac.be

Background: Telavancin is a lipoglycopeptide with multiple mechanisms of action that include membrane-destabilizing effects towards bacterial cells. It shows bactericidal activity against forms of Staphylococcus aureus (phagolysosomal infection) with different resistance phenotypes [methicillin-resistant S. aureus, vancomycin-intermediate S. aureus or vancomycin-resistant S. aureus]. We examine here the uptake, efflux and intracellular distribution of telavancin in eukaryotic cells as well as its potential to induce lysosomal changes (in comparison with vancomycin and oritavancin).

Methods: J774 macrophages and rat embryo fibroblasts were exposed for up to 24 and 72 h to telavancin (5–90 mg/L). The following studies were performed: measurement of 14C-labelled telavancin cellular uptake and subcellular distribution (cell fractionation), determination of pericellular membrane integrity (lactate dehydrogenase release), electron microscopy with morphometric analysis of changes in lysosome size and determination of total phospholipid and cholesterol content.

Results: The uptake of telavancin proceeded linearly as a function of time and concentration in both cell types (clearance rate of ~10 mL/g of protein/h). Efflux (macrophages) was ~5.7-fold slower. Telavancin subcellular distribution was superimposable on that of a lysosomal marker (N-acetyl-β-hexosaminidase). It did not cause an increase in the release of lactate dehydrogenase and did not induce significant increases in total phospholipid or cholesterol content. It caused only mild morphological lysosomal alterations (similar to vancomycin and much less than oritavancin by morphometric analysis).

Conclusions: Telavancin is taken up by eukaryotic cells and localizes in lysosomes, causing mild morphological alterations without evidence of lipid metabolism alterations. These data support our observations that telavancin is active against intracellular S. aureus.

Keywords: glycopeptides , cellular pharmacokinetics , lipids , membrane , oritavancin , vancomycin


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.