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JAC Advance Access published online on October 24, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl424
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received July 26, 2006
Revised September 15, 2006
Accepted September 25, 2006

Original article

Evaluation of the extracellular and intracellular activities (human THP-1 macrophages) of telavancin versus vancomycin against methicillin-susceptible, methicillin-resistant, vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus

Maritza Barcia-Macay 1, Sandrine Lemaire 1, Marie-Paule Mingeot-Leclercq 1, Paul M. Tulkens 1, and Françoise Van Bambeke 1 *

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

* To whom correspondence should be addressed.
Françoise Van Bambeke, E-mail: vanbambeke{at}facm.ucl.ac.be


  Abstract

Objectives: To compare extracellular and intracellular activities of telavancin (versus vancomycin) against Staphylococcus aureus (MSSA, MRSA, VISA and VRSA).

Methods: Determination of cfu changes (3-24 h) in culture medium and in macrophages at concentrations ranging from 0.01 to 1000x MIC.

Results: Extracellularly, telavancin displayed a fast, concentration-dependent bactericidal activity against all strains. The concentration-effect relationship was bimodal for MSSA and MRSA [two successive sharp drops in bacterial counts (0.3-1x MIC and 100-1000x MIC) separated by a zone of low concentration dependency]. When compared at human total drug Cmax (vancomycin, 50 mg/L; telavancin, 90 mg/L) towards MSSA, MRSA and VISA, telavancin caused both a faster and more marked decrease of cfu, with the limit of detection (>5 log decrease) reached already at 6 versus 24 h for vancomycin. Intracellularly, the bactericidal activity of telavancin was less intense [-3 log (MSSA) to -1.5 log (VRSA) at Cmax and at 24 h]. A bimodal relationship with respect to concentration (at 24 h) was observed for both MSSA and MRSA. In contrast, vancomycin exhibited only marginal intracellular activity towards intraphagocytic MSSA, MRSA and VISA (max. -0.5 log decrease at 24 h and at Cmax).

Conclusions: Telavancin showed time- and concentration-dependent bactericidal activity against both extracellular and intracellular S. aureus with various resistance phenotypes. The data support the use of telavancin in infections where intracellular and extracellular S. aureus are present. Bimodality of dose responses (MSSA and MRSA) could indicate multiple mechanisms of action for telavancin.

Keywords: lipoglycopeptide; Gram-positive; bactericidal; phagolysosomes; concentration dependence.
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