Bactericidal titers of loracarbef (LY 163892) in serum and killing rates in volunteers receiving 400 versus 200 milligrams

Abstract

In a randomized crossover trial, six volunteers received 200- and 400-mg doses of loracarbef (LY 163892), a new oral cephalosporin. Mean +/- standard error of the mean concentrations in serum obtained after 1.5 and 3 h were 13.2 +/- 2.8 and 4.3 +/- 0.7 mg/liter, respectively, after the 400-mg dose and 6.9 +/- 1.0 and 1.7 +/- 0.2 mg/liter, respectively, after the 200-mg dose. Bactericidal reciprocal titers measured against respiratory pathogens in serum suggested that loracarbef would be highly effective against Streptococcus pneumoniae and Streptococcus pyogenes (median titers, 8 to 128 at 1.5 h and less than 2 to 32 at 3 h) and beta-lactamase-negative Haemophilus influenzae (median titers, 4 at 1.5 h and 2 to 4 at 3 h). Other species (Branhamella catarrhalis, Streptococcus anginosus, Staphylococcus aureus) were associated with lower bactericidal titers. Killing curves performed against 12 strains demonstrated that the bioactivity of loracarbef (measured by the reduction in the area under the control growth curve) was significantly correlated with the concentration/MIC ratio, whereas the initial rate of killing was not, once the concentration was greater than the MIC. Our results suggest that administration of 400 mg of loracarbef every 8 h might be associated with more favorable pharmacodynamic parameters against target bacteria.