Recognition of a worldwide increase of penicillin-resistant Streptococcus pneumoniae and cross-resistance to other classes of antimicrobials have placed a great urgency on the need for new antimicrobial agents. Sparfloxacin, a novel pyridone carboxylic acid fluoroquinolone derivative was evaluated and compared to six other compounds for antimicrobial activity against erythromycin-resistant pneumococci (50 strains). The Etest susceptibility testing method was used to inoculate Mueller-Hinton agar supplemented with 5% sheep blood. There was extensive cross-resistance between erythromycin, clarithromycin (94%), and azithromycin (100%), but no cross-resistance was detected between macrolides/azalides and sparfloxacin (all strains susceptible at < or = 1.0 mu g/ml). Sparfloxacin (MIC90, 1 mu g/ml) was four-fold more active than ciprofloxacin and ofloxacin (MIC90, 4 mu g/ml). Sparfloxacin appears to possess excellent in vitro activity against erythromycin-resistant S. pneumoniae that were often highly resistant to beta-lactams, and further studies are recommended to investigate its in vivo efficacy against these multi-resistant organisms.