In vitro activity of four newer fluoroquinolones (clinafloxacin, gemifloxacin, moxifloxacin, sitafloxacin) and an equal number control drugs in the same class (ciprofloxacin, grepafloxacin, levofloxacin, trovafloxacin) was determined by reference dilution tests against 2156 recent United States clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. All the fluoroquinolones demonstrated excellent in vitro activity against these pathogens. Streptococcus pneumoniae isolates were fully susceptible to clinafloxacin, sitafloxacin, and gemifloxacin at 0.5 microg/ml, and over 98% of sampled strains had MICs of </=1 microg/ml for grepafloxacin, moxifloxacin and trovafloxacin. Penicillin resistance did not influence the potency of the tested fluoroquinolones. All the isolates of H. influenzae and M. catarrhalis were inhibited by the investigational, as well as comparator fluoroquinolones at </=0.5 microg/ml, irrespective of their beta-lactamase producing abilities. In conclusion, the investigational fluoroquinolones demonstrated excellent activity against these major respiratory tract pathogens isolated in 1999, and some remain safe candidates for empiric therapy of community-acquired respiratory tract infections and selected infections in hospitalized patients.