tifacogin and Pneumonia--Bacterial

Despite potent antibiotics, community-acquired pneumonia (CAP) remains the most common cause of death from infection and the seventh overall leading cause of death in the United States. For this reason, interest has been redirected into non-antibiotic therapeutic measures. Despite theoretical benefits, the existing literature does not suggest a clear benefit for corticosteroid treatment, but large prospective randomized trials are needed. Nonsteroidal antiinflammatory drugs may benefit oxygenation but have no documented effect on mortality. Activation of the coagulation system appears to be a major pathophysiological event in severe pneumonia, possibly even more so than for sepsis in general. The CAP subgroup in phase III sepsis trials of both drotrecogin alfa (activated) and tifacogin (recombinant tissue factor pathway inhibitor) demonstrated the greatest benefit. The immunomodulatory effects of macrolide antibiotics may play a significant role in management of severe CAP. Exogenous surfactant replacement is being explored as adjunctive therapy for acute lung injury due to CAP. Statin use before CAP diagnosis is associated with improved outcome but requires further research to determine if initiation at the time of diagnosis will affect outcome. Other therapies have theoretical benefit but are not yet in the stage of clinical trials.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antiviral Agents; Clinical Trials as Topic; Community-Acquired Infections; Drug Therapy, Combination; Glucocorticoids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interferon-gamma; Macrolides; Pneumonia, Bacterial; Prostaglandin Antagonists; Protein C; Proteins; Recombinant Proteins; Treatment Outcome; United States

The purpose of this analysis was to determine the potential efficacy of recombinant human tissue factor pathway inhibitor (tifacogin) in a subpopulation of patients with community-acquired pneumonia (CAP) from a phase III study of severe sepsis.. A retrospective review of patients with suspected pneumonia was conducted by an independent clinical evaluation committee (CEC) blinded to treatment assignment. The CEC reanalyzed data from patients enrolled in an international multicenter clinical trial of sepsis who had a diagnosis of pneumonia as the probable source of sepsis. The primary efficacy measure was all-cause 28-day mortality.. Of 847 patients identified on case report forms with a clinical diagnosis of pneumonia, 780 (92%) were confirmed by the CEC to have pneumonia. Of confirmed pneumonia cases, 496 (63.6%) met the definition for CAP. In the CEC CAP population, the mortality rates of the tifacogin and placebo groups were 70/251 (27.9%) and 80/245 (32.7%), respectively. The strongest signals were seen in patients with CAP not receiving concomitant heparin, having microbiologically confirmed infection, or having the combination of documented infection and no heparin. The reduction in mortality in this narrowly defined subgroup when treated with tifacogin compared with placebo was statistically significant (17/58 [29.3%] with tifacogin and 28/54 [51.9%] with placebo; unadjusted P value of less than 0.02).. Tifacogin administration did not significantly reduce mortality in any severe CAP patient. Exploratory analyses showed an improved survival in patients who did not receive concomitant heparin with microbiologically confirmed infections. These data support the rationale of an ongoing phase III study exploring the potential benefit of tifacogin in severe CAP.. ClinicalTrials.gov identifier NCT00084071.

Topics: Aged; APACHE; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Female; Gram-Negative Aerobic Bacteria; Gram-Positive Bacteria; Humans; Male; Middle Aged; Pneumonia, Bacterial; Proteins; Retrospective Studies; Survival Analysis; Treatment Outcome