THERAPEUTIC EFFICACY OF A POLYMYXIN-B DEXTRAN-70 CONJUGATE IN EXPERIMENTAL-MODEL OF ENDOTOXEMIA

Numerous studies have suggested that Lipopolysaccharide (LPS), a major component of the cell wall of gram-negative bacteria, is responsible for the initiation of gram-negative septic shock. Previously, others h ave designed therapeutic regimens to target the biologically active li pid A region of LPS by either neutralization of the biological propert ies of LPS or enhancement of clearance of this molecule. One such comp ound capable of neutralizing lipid A is the antibiotic polymyxin B. Ho wever, the clinical utility of polymyxin B is limited by its toxicity. We therefore covalently conjugated this antibiotic to the high-molecu lar-weight polysaccharide dextran 70, resulting in reduced toxicity of polymyxin B but retention of its endotoxin-neutralizing ability. The studies described in this report were designed to test the in vivo eff icacy of this compound in an experimental animal model of gram-negativ e septic shock. Mice were administered graded doses of Escherichia col i or Pseudomonas aeruginosa along with D-galactosamine and the antibio tic imipenem. We had previously determined that antibiotic chemotherap y provides significant protection against E. coli-mediated lethality w ith smaller doses of bacteria; however, the antibiotic does not provid e protection against larger doses of bacteria, but it is effective at killing the bacterial inoculum in vivo. Administration of the polymyxi n B-dextran 70 conjugate provided significant protection when given wi th an antibiotic but was not effective by itself. A requirement for a pretreatment period prior to E. coli challenge was shown to depend upo n the bacterial challenge dose. In other studies using this D-galactos amine sensitization model, we demonstrated that the lipid A-specific c onjugate had no effect on lethality caused by Staphylococcus aureus or tumor necrosis factor alpha. The results of these studies indicate th at this compound is effective in preventing lethal gram-negative septi c shock in mice and may be useful as a potential therapeutic agent in humans as well.