Sepsis occurs in 1-2% of hospital admissions and is secondary to the appearance of bacterial toxins including the gram-negative lipopolysaccaride (LPS) or the gram-positive lipoteichoic acid (LTA) in the circulation. The frequent progression of sepsis to septic shock results in hypotension and inadequate tissue perfusion. Septic shock carries a 45% risk of mortality making it the most common cause of death in intensive care units. Consequently over 30 pharmaceutical products are in development for this condition although none have reached the market yet. Many of these target specific inflammatory mediators and have thus been, in general, unsuccessful since the process of sepsis involves multiple mediators. More successful strategies include the targeting of the end stage of sepsis, altered coagulation or, as described in a recent DiscoveryDossier (click here for access), mediators such as LPS. In this edition of TherapeuticAdvances, we focus on opportunities surrounding the therapeutic targeting of the gram-positive counterpart of LPS, LTA. This toxin is released by gram-positive bacteria following exposure to antibiotics or leukocytic mediators and plays an important role both in the colonization of bacteria and the consequent release of cytotoxic mediators in colonized organs. LTA binds CD-14 and Toll-like receptors, thus initiating numerous events associated with sepsis including the respiratory burst and the release of leukocytic mediators, the production of growth factors, arachidonic acid metabolites, reactive oxygen species and NO, cytokines and stimulators of chemotaxis and phagocytosis. In addition, LPA inhibits platelet aggregation, which may contribute in part to bleeding diathesis, a characteristic of gram-positive septicemic patients. One important aspect of septicemia is that gram-positive and gram-negative infections often co-exist, a phenomenon which, due to synergistic interaction of LPS and LTA, produces a clinical situation of even greater severity than infection with a single pathogen. Thus LTA sits at the heart of septicemia and blockade of its binding could confer significant clinical activity. Phase I studies support this since chimeric anti-LTA antibodies were able to reduce bacterial levels by 96%. Development of further LTA blockers represents a novel approach to a serious and largely unmet market.

Link to journal abstract:

Adapted from Ginsberg, Lancet Infect Dis 2002 Mar;2(3):171-9

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