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Antimicrobial Agents and Chemotherapy, September 2009, p. 3734-3743, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.00203-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in Human THP-1 Macrophages 
,
Sandrine Lemaire,
Françoise Van Bambeke, and
Paul M. Tulkens*
Unité de Pharmacologie Cellulaire et Moléculaire and Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
Received 14 February 2009/ Accepted 22 June 2009
CEM-101 is a novel fluoroketolide with lower MICs than those of telithromycin and macrolides. Our aim was to assess the cellular accumulation and intracellular activity of CEM-101 using models developed for analyzing the pharmacokinetics and pharmacological properties of antibiotics against phagocytized bacteria. We used THP-1 macrophages and Staphylococcus aureus (ATCC 25923 [methicillin (meticillin) sensitive]), Listeria monocytogenes (strain EGD), and Legionella pneumophila (ATCC 33153). CEM-101 reached cellular-to-extracellular-concentration ratios of about 350 within 24 h (versus approximately 20, 30, and 160 for telithromycin, clarithromycin, and azithromycin, respectively). This intracellular accumulation was suppressed by incubation at a pH of 
6 and by monensin (proton ionophore) and was unaffected by verapamil (P-glycoprotein inhibitor; twofold accumulation increase for azithromycin) or gemfibrozil. While keeping with the general properties of the macrolide antibiotics in terms of maximal efficacy (Emax; approximately 1-log10-CFU decrease compared to the postphagocytosis inoculum after a 24-h incubation), CEM-101 showed significantly greater potency against phagocytized S. aureus than telithromycin, clarithromycin, and azithromycin (for which the 50% effective concentration [EC50] and static concentrations were about 3-, 6-, and 15-fold lower, respectively). CEM-101 was also about 50-fold and 100-fold more potent than azithromycin against phagocytized L. monocytogenes and L. pneumophila, respectively. These differences in EC50s and static concentrations between drugs were minimized when data were expressed as multiples of the MIC, demonstrating the critical role of intrinsic drug activity (MIC) in eliciting the antibacterial intracellular effects, whereas accumulation per se was unimportant. CEM-101 should show enhanced in vivo potency if used at doses similar to those of the comparators tested here.
* Corresponding author. Mailing address: Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL 73.70, Avenue E. Mounier 73, B-1200 Brussels, Belgium. Phone: 3227647371. Fax: 3227647373. E-mail: tulkens{at}facm.ucl.ac.be
Published ahead of print on 29 June 2009.
Supplemental material for this article may be found at http://aac.asm.org/.
Antimicrobial Agents and Chemotherapy, September 2009, p. 3734-3743, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.00203-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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