title: In vitro pharmacodynamics of the new ketolides HMR 3004 and HMR 3647 (Telithromycin) against Chlamydia pneumoniae.
abstract: The ketolides HMR 3004 and HMR 3647 (telithromycin) are a new class of macrolides that have a potential clinical efficacy against intracellular pathogens. The objectives of this study were to investigate the MIC, minimum bactericidal concentration, and time-dependent killing of two Chlamydia pneumoniae strains of the two ketolides. The killing effect was also studied with a newly developed intracellular in vitro kinetic model. Furthermore, HMR 3647 was studied for the effect of a subinhibitory concentration of 0.5 times the MIC after a preexposure of 10 times the MIC during 12 h. The MICs for both strains were 0.0039 and 0.0156 mg/liter for HMR 3004 and HMR 3647, respectively. Killing with 10 times the MIC was time dependent, increasing from a 1-log-unit decrease in the number of inclusions per well at 48 h to a maximal effect of 2.8-log-unit decrease after 96 h. A preexposure of 10 times the MIC of HMR 3647 for 12 h followed by a subinhibitory concentration of 0.5 times the MIC increased the killing effect to a 1.2-log-unit reduction in inclusions per well. An exposure for 12 h gave poor reduction of inclusions, while a static dose of 10 times the MIC for 72 h showed a 2.2-log-unit reduction in inclusions per well. In the kinetic model, a small number of inclusions were detected after 72 h by one exposure of 10 times the MIC. Regrowth could not be detected after 120 h. The ketolides HMR 3004 and HMR 3647 have bactericidal activity and show a significant sub-MIC effect on the intracellular pathogen C. pneumoniae.
authors.affiliation: Departments of Infectious Diseases, University Hospital, Uppsala, Sweden. ingegerd.gustafsson@medsci.uu.se
authors.forename: I
authors.initials: I
authors.lastname: Gustafsson
authors.forename: E
authors.initials: E
authors.lastname: Hjelm
authors.forename: O
authors.initials: O
authors.lastname: Cars
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016993:Chlamydophila pneumoniae / Q000187:drug effects*; D006801:Humans; D048628:Ketolides; D007700:Kinetics; D018942:Macrolides; D008826:Microbial Sensitivity Tests; D008954:Models, Biological
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D018942:Macrolides; C105420:RU 64004; C106791:telithromycin