To determine the influence of in vitro activity, pharmacokinetic properties, and therapeutic regimen on the antibacterial effect in vivo, we compared three
cephalosporins,
cefotiam,
cefmenoxime, and
ceftriaxone, in a rabbit model of experimental Escherichia coli
endocarditis after 4 days of treatment. The MBCs of
cefotiam,
cefmenoxime, and
ceftriaxone for the E. coli strain were 0.5, 0.125, and 0.06 microgram/ml, respectively. Killing curves
at 10 times the MBC were similar for the three
cephalosporins. In serum, the elimination half-life of
ceftriaxone was twice as much as the elimination half-life of
cefotiam or
cefmenoxime (2.8 +/- 0.45 versus 1.4 +/- 0.25 or 1.3 +/- 0.4 h, respectively).
Ceftriaxone was much more effective than
cefotiam. The bacterial titer in the vegetations (log10 CFU per gram of vegetation) was 7.56 +/- 1 with
cefotiam and 2.41 +/- 2.6 with
ceftriaxone, as their concentrations were 18 and 466 times higher, respectively, than their MBCs. Although
ceftriaxone and
cefmenoxime exhibited a similar rate of killing and percentage of protein binding,
ceftriaxone was more effective than
cefmenoxime at the same regimen of 15 mg/kg twice a day (3.08 +/- 1.1 versus 4.82 +/- 3.2 log10 CFU/g of vegetation). When
antibiotic was given as a single daily injection of 30 mg/kg, the antibacterial effect persisted for
ceftriaxone, but not for
cefmenoxime. The longer elimination half-life and the higher local concentration/MBC ratio of
ceftriaxone explained these results. The bacterial titer measured 24 h after the fourth injection of 30 mg of
ceftriaxone per kg confirmed that this regimen prevented regrowth of bacteria. These results suggest that the local
antibiotic level/MBC ratio roughly correlated with the antibacterial effect and could represent an adequate basis to explain the differences observed between the drugs in vivo. They also demonstrate that, provided that the dose is sufficient, a long-acting broad-spectrum
cephalosporin may be effective in severe gram-negative
infections, even when given at relatively long dosing intervals, in contrast with a rapidly cleared
drug with the same intrinsic activity.