The in vitro activity of lomefloxacin (SC-47111; NY-198), a new difluorinated quinolone, was compared with those of ofloxacin, ciprofloxacin, fleroxacin, amoxicillin, cefuroxime, and trimethoprim against 585 recent clinical isolates and other strains with known mechanisms of resistance. The MICs of lomefloxacin against 90% of the members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and staphylococci were between 0.25 and 4 micrograms/ml. Ninety percent of Neisseria sp. and Haemophilus influenzae were susceptible to less than or equal to 0.06 micrograms/ml, and streptococci (including Streptococcus pyogenes, Streptococcus pneumoniae, and enterococci) and Bacteroides fragilis were susceptible to 8 micrograms/ml. Lomefloxacin was comparable in activity to fleroxacin and ofloxacin, but it was less active than ciprofloxacin. There was cross-resistance between the quinolone group of antimicrobial agents. The protein binding of lomefloxacin was 15.4%, and serum had little effect on the activity of the compound. However, urine at pH 5.0 decreased the activity by two- to eightfold compared with that at pH 7.0