This study explored the in vitro activity of ceftaroline, a parenteral anti-MRSA cephalosporin in phase 3 development, against Streptococcus pneumoniae isolates not susceptible to previous parenteral antimicrobials. Among the S. pneumoniae isolates received in the Spanish Pneumococcal Reference Laboratory (January 2005 to September 2007), 655 strains were selected (60 nonsusceptible to penicillin, 250 to amoxicillin, 170 to cefotaxime; 339 resistant to erythromycin, 152 resistant to levofloxacin) according to current CLSI breakpoints (parenteral drugs/nonmeningitis), with 337 (51.5%) being invasive (84.3% from bacteremia). Antimicrobial susceptibility was determined by agar dilution in Mueller-Hinton agar supplemented with 5% sheep blood, with 10⁵ CFU/ml final inocula and incubation under 5% CO₂; controls included S. pneumoniae ATCC 6303, ATCC 49619, and five clinical isolates. Ceftaroline demonstrated potent in vitro activity against these strains, with MIC₅₀/MIC₉₀ values ranging from 0.03/0.12 μg/ml (levofloxacin-resistant strains) to 0.25/0.25 μg/ml (cefotaxime-resistant strains).