The aim of the present investigation was to study and compare the killing activity of two new fluoroquinolone compounds, moxifloxacin and grepafloxacin, and a new generation macrolide, clarithromycin, against three clinical isolates of Streptococcus pneumoniae (penicillin-susceptible, -intermediate and -resistant) and two Streptococcus pyogenes (erythromycin-susceptible and -resistant) strains by simulating their human pharmacokinetics in a pharmacodynamic model. Results were achieved by measuring the reduction in viable bacterial count during the 24-h experimental period. All three antimicrobials led to a continuous reduction in the bacterial counts of penicillin-susceptible S. pneumoniae and erythromycin-susceptible S. pyogenes strains, the maximal reduction observed after 8-10 hours being 5-6 logs for moxifloxacin and 3 logs for grepafloxacin; clarithromycin exhibited a similar reduction of 5 logs only after 24 h. No regrowth was observed for any strain after 24 h with any of the antibiotics. The bactericidal activity of both the fluoroquinolones was not affected by penicillin resistance of S. pneumoniae and erythromycin resistance of S. pyogenes. In contrast, clarithromycin was not able to reduce the bacterial count of penicillin-resistant S. pneumoniae and erythromycin-resistant S. pyogenes strains. Moxifloxacin exhibited, within 24 h, higher and faster bactericidal activity than grepafloxacin and clarithromycin against S. pneumoniae, and was not affected by penicillin resistance. These results suggest that moxifloxacin is a promising new agent for treatment of streptococcal infections.