Propensity to release endotoxin after two repeated doses of cefuroxime in an in vitro kinetic model: higher release after the second dose.

OBJECTIVES: To study endotoxin release from two strains of Escherichia coli after exposure to two repeated doses of cefuroxime in an in vitro kinetic model.
METHODS: Cefuroxime in concentrations simulating human pharmacokinetics was added to the bacterial solution with a repeated dose after 12 h. In another experiment, tobramycin was given concomitantly with the second dose of cefuroxime. Samples for viable counts and endotoxin analyses were drawn before the addition of antibiotics and at 2 and 4 h after each dose.
RESULTS: The propensity to release endotoxin, expressed as log10 endotoxin release (EU)/log10 killed bacteria, was higher after the second than after the first dose, 0.80+/-0.04 and 0.65+/-0.01, respectively, in the ATCC strain and 0.80+/-0.04 and 0.65+/-0.02, respectively, in the clinical strain (P<0.001). Endotoxin was released earlier after the second dose (P<0.001). Addition of tobramycin at the second dose reduced the endotoxin release in comparison with that of cefuroxime alone (P<0.001).
CONCLUSIONS: The propensity to liberate endotoxin is higher after the second dose of cefuroxime than after the first, resulting in a higher release of endotoxin than expected from bacterial count. The release after the second dose can be reduced by the addition of tobramycin.