Antimicrobial resistance observed among common respiratory tract pathogens--Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis--may complicate empiric therapeutic selection to treat community-acquired respiratory tract infections. The Tracking Resistance in the United States Today (TRUST) study determined the in vitro activities of frequently prescribed antimicrobial agents against isolates collected from all 50 states from 2001 to 2005. For S pneumoniae (N = 27,781), susceptibility of selected agents in ascending order were penicillin (oral) (65.4%), trimethoprim-sulfamethoxazole (TMP-SMX) (69.5%), erythromycin (72.0%), cefuroxime (oral) (75.9%), tetracycline (85.3%), amoxicillinclavulanate (92.6%), ceftriaxone (nonmeningitis) (96.6%), and levofloxacin (99.0%). Susceptibility to levofloxacin, which was used as a representative of the respiratory fluoroquinolones, was near 99% from 2001 to 2005, and the minimum inhibitory concentration (90%) (MIC(90)) remained unchanged at 1 microg/mL. Levofloxacin and the other respiratory fluoroquinolones remained highly effective against penicillin-resistant S pneumoniae(PRSP) (98%-99% susceptible). However, susceptibility of PRSP to amoxicillin-clavulanate decreased from 62%S in 2003 to 48%S in 2005. Haemophilus influenzae susceptibility to ampicillin averaged near 70%, and near 75% to TMP-SMX. Susceptibility rates to levofloxacin and the other respiratory fluoroquinolones for H influenzae and M catarrhalis remained at or near 100%. Although resistance rates among S pneumoniae have stabilized for penicillin (oral) at elevated levels and increased for macrolides, susceptibility to the respiratory fluoroquinolones has consistently remained high, as they have for H influenzae and M catarrhalis.