Antiendotoxin strategies for the prevention and treatment of septic shock. New approaches and future directions.
Therapy for Gram-negative sepsis remains unsatisfactory despite a concerted effort to develop new treatments for this common, life-threatening syndrome. Current research continues on several fronts to improve the treatment options available to clinicians in the management of these critically ill patients. Recently, a greater understanding of the complex molecular basis of endotoxin-mediated pathophysiological effects in humans has generated a number of novel therapeutic agents for sepsis. Several of these treatment strategies have already entered clinical trials and it is hoped that some of these therapies will become widely available in the near future. In this review, the current status of the most promising new antiendotoxin agents is summarised, and the major obstacles to the successful clinical development of these therapies are described. New antiendotoxin therapies include those which interrupt the synthesis of endotoxin, bind and neutralise its activity, prevent endotoxin interactions with host effector cells and interfere with endotoxin-mediated signal transduction pathways. Potential therapeutic strategies involving these agents consist of endotoxin analogues, antibodies, subunit vaccines, binding columns, recombinant human proteins and small molecule inhibitors of endotoxin synthesis and intracellular signalling. The pitfalls of previous antiendotoxin clinical investigations and the perils of future clinical trial designs are discussed in the context of unmet needs and realistic expectations for success. While considerable progress has been made, effective and new treatments for Gram-negative bacterial sepsis continues to elude us at the present time. This has been to the detriment of patients, investigators and pharmaceutical companies alike. It will require focused efforts by basic scientists, continued support by industry and enlightened study designs by clinical investigators to successfully develop antiendotoxin in therapies for use in septic patients in the future.
Opal
S M
SM
Infectious Disease Division, Brown University School of Medicine, Providence, Rhode Island, USA. Steven_Opal@brown.edu
Yu
R L
RL
D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000906:Antibodies / Q000627:therapeutic use; D000936:Antigen-Antibody Complex; D023181:Antimicrobial Cationic Peptides; D001428:Bacterial Vaccines / Q000008:administration & dosage; D001798:Blood Proteins / Q000627:therapeutic use; D019446:Endotoxemia / Q000517:prevention & control*; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000276:immunology; D006090:Gram-Negative Bacteria; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008565:Membrane Proteins; D011994:Recombinant Proteins / Q000008:administration & dosage; D012772:Shock, Septic / Q000517:prevention & control*
D000900:Anti-Bacterial Agents; D000906:Antibodies; D000936:Antigen-Antibody Complex; D023181:Antimicrobial Cationic Peptides; D001428:Bacterial Vaccines; D001798:Blood Proteins; D004731:Endotoxins; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011994:Recombinant Proteins; C021623:bactericidal permeability increasing protein; C092845:E 5531