Despite the advent of aminoglycoside and beta-lactam antibiotics and early antimicrobial intervention, overall morbidity and mortality associated with gram-negative sepsis and bacteremia remain high. Complications of sepsis have been related to the release of endotoxin from the cell walls of gram-negative bacilli. Although antibiotics can effectively kill gram-negative bacteria, they have no effect on lipopolysaccharide (LPS) and may, in fact, enhance its release when cell lysis occurs. Lipid A, the lipid portion of LPS, is composed of glucosamines, polar phosphate groups, and fatty acids. It represents the endotoxic component of gram-negative bacteria and is responsible for host responses to LPS, including fever, hypotension, and shock. E5 is a murine monoclonal immunoglobulin M antibody directed against the lipid A portion of the cell-wall endotoxin that is common to clinically important gram-negative bacilli. A clinical evaluation program of E5 included patients who were moderately to severely ill with clinical evidence of an infection usually caused by gram-negative bacteria. In pharmacokinetic and safety studies, laboratory tests revealed no evidence of antibody-mediated toxicity and serum antibody concentrations in the desired therapeutic range (>5 μg/mL) were found as late as 72 hours after initial infusion of E5. In a Phase II study, mortality rates at seven days in patients with documented gram-negative infection were 22 percent in the placebo group compared with 7 percent in the E5-treated groups. In a large Phase III multicenter trial of patients who had not progressed to refractory shock, those treated with E5 were significantly more likely to survive; these patients also experienced significantly greater resolution of organ failures than those who were given placebo. E3 appears to be well tolerated; no antibody-mediated toxicity has been noted in any studies to date. Minor allergic reactions were the most common adverse effect observed in the 247 patients given at least part of one dose of E5 (less than two percent incidence). No drug interactions have been reported with E5. Overall, infusions of E5 administered in clinical trials as an adjunct to antibiotics and supportive therapy have enhanced resolution of organ failure associated with gram-negative sepsis and have reduced mortality in patients not in refractory shock.
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology (medical)