The activity of CEM-101, a fluoroketolide, was compared to those of 11 other antimicrobial agents using the reference broth microdilution method tested against 103 Neisseria meningitidis strains, including ciprofloxacin-nonsusceptible isolates with confirmed gyrA (T91I) mutations. Among the tested isolates, 79.6% were serogroup B or C and all isolates were susceptible to ceftriaxone, azithromycin, minocycline, and rifampin. However, penicillin-nonsusceptible strains were observed (15.5%) and susceptibility to trimethoprim-sulfamethoxazole was only 50.5%. CEM-101 was the most active macrolide-like compound (MIC(90), < or = 0.015 microg/ml) compared with MIC(90)s of telithromycin (MIC(90), 0.03 microg/ml), azithromycin and clarithromycin (MIC(90), 0.12 microg/ml), and erythromycin (MIC(90), 0.25 microg/ml). CEM-101 could provide a potent alternative for the prophylaxis of meningococcal disease.