Despite the use of increasingly potent
antibiotics and aggressive cardiovascular monitoring and support, Gram-negative
bacteremia and ensuing
sepsis and
septic shock remain a leading cause of morbidity and mortality after surgery and in
critically ill patients. In previous years several new agents and techniques have been developed to improve management and outcome of severe Gram-negative
infections. A recently introduced treatment is passive immunotherapy by administration of poly- or monoclonal
anti-endotoxin antibodies. The current view--sustained by experimental and human studies--on the mechanism of protection afforded by
immunotherapy is that the harmful effects of
endotoxin are neutralized by cross-reactive
antibodies to the core
glycolipid structure of rough mutant Gram-negative bacilli. Two recent large clinical trials reported impressive results achieved through the use of monoclonal
anti-endotoxin antibodies in certain subgroups of patients with Gram-negative
sepsis. However, this treatment is empirical, expensive and it does not affect overall
sepsis mortality.
Cytokines such as
tumor necrosis factor alpha and
interleukin-1 play a pivotal role in
sepsis. Experimental studies suggest that specific antagonism of these mediators might offer great perspectives for the treatment of Gram-negative
sepsis. An early multi-pharmacological approach aimed at interruption of multiple steps underlying the inflammatory septic cascade will probably constitute the most promising future treatment of severe Gram-negative
infectious disease.