What are the microbial components implicated in the pathogenesis of sepsis? Report on a symposium.

Despite considerable efforts in the past quarter century to improve therapy for sepsis, mortality rates remain unacceptably high. Microbe-derived constituents can induce the host to produce many mediators that can contribute to immune dysregulation, tissue damage, and death. Although endotoxin-mediated events are clearly important in gram-negative infections, gram-positive bacteria can also play a dominant role. Understanding the interplay of microbial constituents and host immune or inflammatory responses prompted a meeting at Rockefeller University in May 1998. Participants discussed the relative merits of a "2-hit" hypothesis to explain the course of lethal septic shock and a "multihit" synergistic threshold hypothesis. Recommendations include the following: (1) developing animal models that closely mimic human sepsis; (2) further investigating antibiotic effects on bacteria; (3) assessing the relationships between endotoxin, prokaryotic DNA, and peptidoglycan (i.e., independent, additive, or synergistic) in inducing host responses; and (4) developing new strategies to improve outcomes. Studies are needed to better define which and how different microbial constituents lead to sepsis and to provide critical leads for therapeutic intervention.