Cellular accumulation and pharmacodynamic evaluation of the intracellular activity of CEM-101, a novel fluoroketolide, towards Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in human THP-1 macrophages.

Lemaire, Sandrine;Van Bambeke, Françoise;Tulkens, Paul M.
(2009) Antimicrobial Agents and Chemotherapy — Vol. 53, n° 9, p. 3734-3743 (2009)

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Abstract
CEM-101 is a novel fluoroketolide with lower MICs compared to 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 S. aureus (ATCC 25923 [methicillin-sensitive]), L. monocytogenes (strain EGD), and L. pneumophila (ATCC 33153). CEM 101 reached cellular to extracellular concentration ratios of about 350 within 24 h (vs. approximately 20, 30 and 160 for telithromycin, clarithromycin, and azithromycin). This intracellular accumulation was suppressed by incubation at pH </= 6 and by monensin (proton ionophore), and was unaffected by verapamil (P-gp inhibitor; 2-fold accumulation increase for azithromycin) or gemfibrozil. While keeping with the general properties of the macrolide antibiotics in terms of maximal efficacy (approximate Emax of 1 log10 CFU decrease compared to the post-phagocytosis inoculum after 24 h incubation), CEM-101 showed significantly greater potency against phagocytized S. aureus when compared to telithromycin, clarithromycin and azithromycin (EC50 and static concentrations about 3, 6 and 15-fold lower). CEM-101 was also about 50-fold and 100-fold more potent than azithromycin against phagocytized L. monocytogenes and L. pneumophila. These differences in EC50 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.
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Lemaire, S., Van Bambeke, F., & Tulkens, P. M. (2009). Cellular accumulation and pharmacodynamic evaluation of the intracellular activity of CEM-101, a novel fluoroketolide, towards Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in human THP-1 macrophages. Antimicrobial Agents and Chemotherapy, 53(9), 3734-3743. https://doi.org/10.1128/AAC.00203-09 (Original work published 2009)