Contribution of soluble endotoxin released from Gram-negative bacteria by antibiotics to the pathogenesis of experimental sepsis in mice

The results from our laboratory summarized in this review support the importance of endotoxin release from the Gram-negative microbe as a requirement for the full manifestation of the biological activity of the lipopolysaccharide (LPS) macromolecule. They further suggest that LPS is the most important bacterial component released from Gramnegative microbes treated in vitro with cell-wall active antibiotics in terms of biological activity. The use of several experimental mouse models of infection confirm that mice treated with the reversible hepatotoxin, D-galactosamine, are sensitive to both endotoxin lethality and to infection with Gram-negative microbes. Infected LPS-sensitive animals can be protected if they are treated with antibiotics, but the degree of protection (e.g. 5-10-fold) is significantly less than that observed when infection-sensitive but LPS-insensitive mice are similarly treated (500-fold protection). Additional levels of protection in infected, antibiotic-treated mice can be observed with antiendotoxin agents (e.g. polymyxin B-dextran, monoclonal antibody). Finally, antibiotics with equivalent minimal inhibitory concentrations for Escherichia coli, but differing in their mode of action and endotoxin releasing potential in vitro, also differ in their protective efficacy in vivo to reduce mortality in infected animals. Collectively, these data provide evidence to support a role for microbe-derived endotoxin, released from the microbial surface following treatment with cell-wall active antibiotics, in the pathogenesis of experimental Gram-negative sepsis.