Garenoxacin, a novel des-F(6)-quinolone, was tested against 40423 pathogenic isolates associated with community-acquired respiratory tract infections (CA-RTIs). The strains included Streptococcus pneumoniae (18887), Haemophilus influenzae (15555), and Moraxella catarrhalis (5981), each isolated from a significant infection monitored by the SENTRY Antimicrobial Surveillance Program (1999-2005; North America, Latin America, and Europe). All tests were performed by reference broth microdilution methods for garenoxacin and 19 comparison agents. The garenoxacin MIC(90) and percentage (%) of strains inhibited at < or =1 microg/mL (proposed susceptible breakpoint) were S. pneumoniae (0.06 microg/mL, >99.9% susceptible), H. influenzae (< or =0.03 microg/mL, >99.9%), and M. catarrhalis (< or =0.03 microg/mL, 100.0%). The garenoxacin potency versus the pneumococci was 16- to 32-fold greater than levofloxacin or ciprofloxacin and 2-fold superior to moxifloxacin (MIC(90), 0.12 microg/mL). Resistances to other classes of antimicrobials did not adversely influence garenoxacin MIC results. Ciprofloxacin- or levofloxacin-resistant (MIC, > or =4 microg/mL) S. pneumoniae had higher garenoxacin MIC(90) values (1 microg/mL), but 90.6% to 97.5% of strains remained susceptible. Strains of all 3 monitored pathogens with mutations in the quinolone resistance determining region (QRDR) had higher garenoxacin MIC results, with > or =3 to 4 QRDR mutations required to elevate garenoxacin MIC values to > or =2 microg/mL. In conclusion, garenoxacin possesses a potent activity against pneumococci, H. influenzae, and M. catarrhalis strains worldwide, at a level significantly greater than the available tested agents in the fluoroquinolone class (ciprofloxacin, levofloxacin, and moxifloxacin). Only 13 and 4 isolates (0.07% and 0.03%) of S. pneumoniae and H. influenzae, respectively, had a garenoxacin MIC at > or =2 microg/mL, thus, making this new "respiratory antipneumococcal" quinolone an attractive candidate for the therapy of contemporary CA-RTI (bronchitis, pneumonia, and sinusitis).