Pharmacodynamics of telithromycin in vitro against respiratory tract pathogens

Telithromycin (HMR 3647) is a new ketolide that belongs to a new class of s emisynthetic 14-membered-ring macrolides which have expanded activity again st multidrug-resistant gram-positive bacteria. The aim of the present study was to investigate different basic pharmacodynamic properties of this new compound. The following studies of telithromycin were performed: (i) studie s of the rate and extent of killing of respiratory tract pathogens with dif ferent susceptibilities to erythromycin and penicillin exposed to a fixed c oncentration that corresponds to a dose of 800 mg in humans, (ii) studies o f the rate and extent of killing of telithromycin at five different concent rations, (iii) studies of the rate and extent of killing of the same pathog ens at three different inocula, (iv) studies of the postantibiotic effect a nd the postantibiotic sub-MIC effect of telithromycin, and (v) determinatio n of the rate and extent of killing of telithromycin in an in vitro kinetic model. In conclusion, telithromycin exerted an extremely fast killing of a ll strains of Streptococcus pneumoniae both with static concentrations and in the in vitro kinetic model. A slower killing of the strains of Streptoco ccus pyogenes was noted, with regrowth in the kinetic model of a macrolide- lincosamide-streptogramin B-inducible strain. The strains of Haemophilus in fluenzae were not killed at all at a concentration of 0.6 mg/liter due to h igh MICs. A time-dependent killing was seen for all strains. No inoculum ef fect was seen for the strains of S. pneumoniae, with a 99.9% reduction in t he numbers of CFU for all inocula at both 8 h and 24 h. The killing of the strains of S. pyogenes was reduced by 1 log(10) CFU at 8 h and 2 to 3 log(1 0) CFU at 24 h when the two lower inocula were used but not at all at 8 and 24 h when the highest inoculum was used. For both of the H. influenzae str ains there was an inoculum effect, with 1 to 2 log,, CFU less killing for t he inoculum of 10(8) CFU/ml in comparison to that for the inoculum of 10(6) CFU/ml. Overall, telithromycin exhibited long postantibiotic effects and p ostantibiotic sub-MIC effects for all strains investigated.