The killing activities of trovafloxacin alone and in combination with beta-lactam agents (extended-spectrum cephalosporins, meropenem), rifampin, or vancomycin were evaluated against 20 genotypically characterized Streptococcus pneumoniae isolates for which amoxicillin MICs were greater than or equal to 4 mu g/ml (cefotaxime MICs, greater than or equal to 4 mu g/ml for six strains) at concentrations clinically achievable in cerebrospinal fluid. At 6 h the mean killing activity of trovaflosacin alone (range, 2.6 to 2.9 log(10) CFU/ml) did not vary significantly according to the susceptibility of the strains to beta-lactam agents. The activities of trovafloxacin or vancomycin added to the beta-lactam agents and the combination trovafloxacin-vancomycin were additive or indifferent, Against the ceftriaxone-resistant isolates, the killing activity of the combination of a beta-lactam agent and trovafloxacin did not differ significantly from that of a p-lactam agent and vancomycin.