Variation in the Propensity to Release Endotoxin after Cefuroxime Exposure in Different Gram-negative Bacteria: Uniform and Dose-dependent Reduction by the Addition of Tobramycin

Abstract

An aminoglycoside in combination with a β-lactam antibiotic is often recommended for the treatment of severe infections. The aim of the present study was to study whether cefuroxime-induced endotoxin release could be reduced by addition of tobramycin in different Gram-negative bacteria and how endotoxin release was affected by bacterial killing rate and number of killed bacteria. Three Escherichia coli strains, 1 Klebsiella, 1 Salmonella and 1 Neisseria strain were exposed in vitro to 2, 10 and 50× minimum inhibitory concentration of cefuroxime, tobramycin or a combination of both. The cefuroxime-induced endotoxin release in the 6 strains varied from 0.1 to 9.9×10<formula>^×−3</formula> EU/killed bacterium. By adding tobramycin, highly significant reductions of 96%, 93%, 97%, 86% and 85% were seen in the 3 E. coli strains and in the Klebsiella and the Salmonella strain, respectively. In the Neisseria strain, the reduction was less. Increasing doses of tobramycin or the combination led to significant endotoxin release reduction in 4/6 strains. In conclusion, addition of tobramycin reduced penicillin-binding protein-3-β-lactam binding-induced endotoxin release in all tested Gram-negative strains, despite a large interspecies variation in the propensity to release endotoxin. Besides broadening the spectrum and increasing the killing rate, this might be of benefit in the most severe forms of sepsis.