Therapeutic efficacy of a polymyxin B-dextran 70 conjugate in experimental model of endotoxemia

Abstract

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 have designed therapeutic regimens to target the biologically active lipid A region of LPS by either neutralization of the biological properties of LPS or enhancement of clearance of this molecule. One such compound capable of neutralizing lipid A is the antibiotic polymyxin B. However, the clinical utility of polymyxin B is limited by its toxicity. We therefore covalently conjugated this antibiotic to the high-molecular-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 efficacy of this compound in an experimental animal model of gram-negative septic shock. Mice were administered graded doses of Escherichia coli or Pseudomonas aeruginosa along with D-galactosamine and the antibiotic imipenem. We had previously determined that antibiotic chemotherapy provides significant protection against E. coli-mediated lethality with smaller doses of bacteria; however, the antibiotic does not provide protection against larger doses of bacteria, but it is effective at killing the bacterial inoculum in vivo. Administration of the polymyxin B-dextran 70 conjugate provided significant protection when given with an antibiotic but was not effective by itself. A requirement for a pretreatment period prior to E. coli challenge was shown to depend upon the bacterial challenge dose. In other studies using this D-galactosamine sensitization model, we demonstrated that the lipid A-specific conjugate had no effect on lethality caused by Staphylococcus aureus or tumor necrosis factor alpha. The results of these studies indicate that this compound is effective in preventing lethal gram-negative septic shock in mice and may be useful as a potential therapeutic agent in humans as well.

Contemporary Assessment of Antimicrobial Susceptibility Testing Methods for Polymyxin B and Colistin: Review of Available Interpretative Criteria and Quality Control Guidelines

“…Due to its ability to bind strongly to the lipopolysaccharides of gram-negative bacteria and membranes, formulations such as polymyxin B-dextran 70 and covalent polymyxin B conjugated with human immunoglobulin G have been used as an adjuvant therapy of septic shock (3,5,8). These combination agents reduce the polymyxin toxicity profiles.…”

Polymyxin B-Conjugated α2-Macroglobulin as an Adjunctive Therapy to Sepsis: Modes of Action and Impact on Lethality

“…Because soluble PMB was found to be nephrotoxic and neurotoxic, attempts have been made to decrease the toxicity of PMB without compromising its anti-LPS effect. One approach to capitalize on the potential neutralizing properties of PMB is the conjugation of PMB to polymers such as dextran (Bucklin et al, 1995) or immunoglobulin G (Drabick et al, 1998).…”

Limitation of Polymyxin B on Suppression of Endotoxin Shock Induced by Salmonella Infection in Mice

“…2), and suppression of sCD14 expression was initiated at 12 h p.i. Taken together, our results suggest that in addition to the well-known LPS-binding activity of PLB, 22,23) a reduction of bacterial numbers in combination with downregulation of sCD14 as molecule participating in LPS-signaling is another mechanism by which PLB counters endotoxin shock. Our model also showed a time dependence of the therapeutic effect of PLB.…”