Prevention and treatment of multiple organ dysfunction syndrome: lessons learned and future prospects

Abstract

Gram-negative bacteria commonly cause serious infections in hospitalized patients, and those that lead to bacteremic episodes and sepsis syndrome are associated with the highest mortality rate. Sepsis syndrome frequently progresses to multisystem organ dysfunction and failure, with as many as 400,000 cases occurring annually. Unfortunately, the associated mortality rate remains about 40%. Lipopolysaccharide (LPS, endotoxin), an integral component of the gram-negative bacterial outer membrane, plays a critical role in the pathophysiology of this lethal disease process. It is capable of interacting with host macrophages, a process that leads to the secretion of an increasingly well-characterized array of macrophage cytokines. Several different classes of compounds that bind directly to LPS and thereby neutralize its effects are being examined. These consist of anti-LPS monoclonal antibodies (mAbs), naturally occurring proteins and their derivatives (e.g., bactericidal/permeability-increasing protein [BPI], Limulus anti-LPS factor [LALF]), and certain antibiotics (polymyxin B, taurolidine). The molecular biology of BPI, LALF, and LPS binding protein (LBP, which augments the host response to LPS) is of considerable interest, as each demonstrates considerable genetic sequence homology. Although two anti-LPS monoclonal antibodies (HA-1A, E5) did not demonstrate efficacy during sepsis syndrome, information obtained from these clinical trials provided investigators with the ability to better understand this disease process. However, a detailed understanding of the biology of endotoxin antagonism is beginning to emerge, and the application of this knowledge in the clinical setting provides hope that it may be possible to reduce the mortality of sepsis syndrome caused by these microorganisms to a statistic well below the current 40%.