The rate of penicillin-resistant Streptococcus pneumoniae isolates in Spain is high. At present, penicillin and ceftriaxone are two drugs chosen for treating serious infections. In this study the bactericidal activity of four antimicrobial regimens against ten clinical isolates of S. pneumoniae (five with an intermediate resistance to penicillin and five highly resistant ones), was determined by means of kill kinetics studies using either penicillin, or ceftriaxone, in combination with vancomycin, or fosfomycin. The concentrations of the antimicrobial regimens (MICs 4x, 1x and 1/4x) were within possible physiological levels. While the combinations of penicillin, or ceftriaxone, plus vancomycin showed a significant increase in bactericidal activity, the bacterial reductions obtained in combination with fosfomycin were greater, achieving synergistic effects. These results suggest that in vivo trials with a regimen composed of ceftriaxone and fosfomycin would be worthwhile.