In vitro pharmacodynamics of the new ketolides HMR 3004 and HMR 3647 (telithromycin) against Chlamydia pneumoniae

The ketolides HMR 3004 and HMR 3647 (telithromycin) are a new class of macr olides that have a potential clinical efficacy against intracellular pathog ens. The objectives of this study were to investigate the MIG, minimum bact ericidal concentration, and time-dependent killing of two Chlamydia pneumon iae strains of the two ketolides, The killing effect was also studied with a newly developed intracellular in vitro kinetic model. Furthermore, HMR 36 47 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, res pectively, Killing with 10 times the MIC was time dependent, increasing fro m a 1-log-unit decrease in the number of inclusions per well at 48 h to a m aximal effect of 2.8-log-unit decrease after 96 h. A preexposure of 10 time s 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 inclus ions, while a static dose of 10 times the MIC for 72 h showed a 2.2-log-uni t reduction in inclusions per wed, Ln the kinetic model, a small number of inclusions were detected after 72 h by one exposure of 10 times the MIC. Re growth could not be detected after 120 h. The ketolides HMR 3004 and HMR 36 47 have bactericidal activity and show a significant sub-MIC effect on the intracellular pathogen C, pneumoniae.