Anti-lipopolysaccharide and anti-tumor necrosis factor/cachectin antibodies for the treatment of gram-negative bacteremia and septic shock

Abstract

Endotoxin is composed of lipid A, the toxic moiety, of the core region, a conserved structure among Gram-negative bacteria, and of the O-side chains, a highly variable part responsible for the antigenic specificity. The concept of cross-protection afforded by antiserum raised against the core region of endotoxin is supported by the following data: experimentally antiserum protected against infections caused by a wide range of Gram-negative bacteria or endotoxins; in patients with Gram-negative bacteremia, survival was associated with high levels of anti-core antibodies, and mortality was reduced by the prophylactic or therapeutic use of immune serum or plasma. However, the proof that protection is afforded by cross-protective anti-core antibodies is still lacking. Furthermore, many experimental studies and clinical studies trials have shown controversial results. Ongoing experimental studies and recently completed clinical trials, using either polyclonal or monoclonal anti-core antibodies should help clarify the issues both of the clinical efficacy and of the mechanism of protection. Tumor necrosis factor/cachectin has been unequivocally shown, both in experimental animal models and in humans to be a pivotal mediator of the clinical and humoral manifestations of shock induced by endotoxin or by whole Gram-negative bacteria. In humans, TNF was been transiently detected in the blood of volunteers challenged with endotoxin, in a small proportion of patients with Gram-negative sepsis, but in the vast majority of patients with established septic shock. However, in patients the magnitude and the evolution of the blood concentration of TNF differed from that observed in animal models or in human volunteers after an acute challenge with either Gram-negative bacteria or endotoxin, probably reflecting differences in infectious stimuli. In children with meningococemia and in adults with Gram-negative septic shock, TNF was associated with the patient's outcome. Anti-TNF monoclonal antibodies are presently undergoing clinical investigation in patients with septic shock. However, one should keep in mind that TNF serves both beneficial and detrimental functions depending upon its concentration in body fluids.