A Critical Evaluation of New Agents for the Treatment of Sepsis

Abstract

OBJECTIVE - To evaluate new treatments directed against endotoxin, tumor necrosis factor alpha, and interleukin 1 for use in sepsis and related disorders (sepsis syndrome and septic shock). DATA SOURCES - Investigations of these treatments in animal models, healthy human volunteers, and patients with sepsis and related disorders. STUDY SELECTION - Particular attention was paid to studies of patients with sepsis and related disorders, especially randomized, double-blind, controlled trials. DATA EXTRACTION - Animal studies and investigations with human volunteers were judged by how closely the experimental model replicated the clinical disorder (sepsis). Patient trials were assessed by sample size and design. Results of all studies were used to evaluate the likelihood that a given treatment would reduce mortality. DATA SYNTHESIS - Direct comparison of E5 and HA-1A antibody studies is difficult because of differences in their design, definitions of shock, and methods of subgroup analysis. However, both antibodies improve outcome in some subgroups: E5 benefits patients with gram-negative infection (bacteremic or focal) who do not have refractory shock, and HA-1A benefits those with gram-negative bacteremia (regardless of whether shock is present) but not those with focal gram-negative infection. Two agents that may be beneficial in gram-positive and gram-negative infection are monoclonal antibodies to tumor necrosis factor alpha and receptor antagonists to interleukin 1. Preliminary results with both are reviewed. CONCLUSIONS - All three types of treatment may improve outcome in sepsis. The best results will probably be obtained with combination therapy that interrupts multiple points of the inflammatory cascade underlying sepsis.

Tolerance to endotoxin-induced expression of the interleukin-1 beta gene in blood neutrophils of humans with the sepsis syndrome.

“…Although there has been little improvement in the mortality of sepsis syndrome since it was defined as a clinical entity, knowledge of the pathogenesis of this frequently lethal process has been rapidly increasing (1). From this new information, new and promising therapies derived from studies of the pathogenic mechanisms responsible for the sepsis syndrome are emerging (3)(4)(5)(6).…”

Detection of Bacteria in Phagocyte‐Smears from Septicemia‐Suspected Blood by In Situ Hybridization Using Biotinylated Probes

“…Because Bacteremia is associated with high mortality, septicemia has always been an emergency condition treated by the blind administration of broad-spectrum antibiotics (1,2). As a result, the percentage of bacteria detected is low in blood cultures and blood smears submitted to the clinical microbiology laboratory using conventional processing and histology (16,18,21,29).…”

Viridans streptococcal septicaemia in neutropenic patients: role of proinflammatory cytokines

“…This is in agreement with previous studies reporting that the susceptibility of viridans streptococci against empirical antibiotic therapy does not correlate with better prognosis in this patient category. 1,4,18,20,21 We chose to test the isolates for induction of IL1b and TNFa since these cytokines' relation to severe sepsis and septic shock is well described: [22][23][24] IL8 due to its association with ARDS; 11,12,25 and TNFb and IFNg as markers for superantigen triggered T-cell activation. 26 In order to examine both cell wall components and potential exotoxin activity, we analysed the proinflammatory response induced by heat-killed bacteria as well as supernatants from overnight cultures containing extracellular proteins.…”