1: Antimicrob Agents Chemother. 2009 Sep;53(9):3734-43. Epub 2009 Jun 29.

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.

Lemaire S, Van Bambeke F, Tulkens PM.

Unité de Pharmacologie Cellulaire et Moléculaire and Louvain Drug Research
Institute, Université Catholique de Louvain, Brussels, Belgium.

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 < or = 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.

PMCID: PMC2737860 [Available on 2010/03/01]
PMID: 19564365 [PubMed - in process]

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