Biological Agents Targeting Sepsis Mediators Are NOT Part of Current Clinical Management
Biological agents that target various mediators of sepsis, including activated protein C (drotrecogin alfa), are explicitly NOT recommended in the current clinical management of severe sepsis or septic shock. The most recent Surviving Sepsis Campaign guidelines (2016/2017) provide clear directives against using these agents based on their failure to demonstrate mortality benefit and associated risks.
Current Guideline Recommendations Against Biological Agents
Antithrombin
- The Surviving Sepsis Campaign strongly recommends AGAINST using antithrombin for treatment of sepsis and septic shock (strong recommendation, moderate quality of evidence) 1.
- Earlier guidelines from 2012/2013 similarly recommended against antithrombin use (grade 1B) 1.
- Antithrombin was associated with increased bleeding risk when administered with heparin, without demonstrating mortality benefit 1.
Intravenous Immunoglobulins
- The guidelines recommend AGAINST using IV immunoglobulins in adult patients with severe sepsis or septic shock (grade 2B) 1.
Activated Protein C (Drotrecogin Alfa)
- Drotrecogin alfa (Xigris) was withdrawn from the market in 2011 and is no longer available 1.
- The 2012/2013 Surviving Sepsis Campaign guidelines include a historical note documenting the evolution of recommendations regarding this agent, acknowledging its removal from clinical practice 1.
- While the initial PROWESS trial in 2001 showed a 6.1% absolute reduction in 28-day mortality 2, 3, 4, subsequent trials failed to replicate these findings 2, 5.
- The drug was associated with increased bleeding complications (3.5% vs 2.0% with placebo) 3, 4.
Cytokine Modulators
- Studies on IL-1 receptor antagonist, TNF inhibitors, and interferon gamma did NOT show clinical benefit (EI recommendation) 1.
Other Biological Agents
- Intravenous selenium is NOT recommended for treatment of severe sepsis (grade 2C) 1.
- Erythropoietin is NOT recommended as specific treatment of anemia associated with severe sepsis (grade 1B) 1.
Why These Agents Failed
The failure of biological agents in sepsis reflects several critical issues:
- Contemporary early resuscitation strategies (early antibiotics within 1 hour, aggressive fluid resuscitation) may have mitigated the inflammatory processes and microvascular thrombosis that these agents were designed to target 2.
- Clinical phenotype versus mechanistic phenotype mismatch: Later trials focused on refractory shock as a clinical phenotype, but this may not correlate with the dysregulated coagulation that biological agents target 2.
- Heterogeneity of sepsis: The sepsis syndrome is too complex and variable for single-mediator targeted therapies to be universally effective 2, 6.
What IS Recommended Instead
The cornerstone of sepsis management focuses on:
- Empiric broad-spectrum antimicrobials within 1 hour for patients with sepsis or septic shock (strong recommendation, moderate quality evidence) 1.
- Aggressive fluid resuscitation and hemodynamic support 1.
- Source control and appropriate supportive care 1.
- Vasopressor therapy when fluid resuscitation fails to restore hemodynamic stability 1.
Special Populations
Even in neutropenic patients with sepsis, where immune dysfunction is prominent:
- High-dose corticosteroids should NOT be used (EI recommendation) 1.
- Substitutive doses of hydrocortisone are NOT recommended in neutropenic patients with sepsis (DI recommendation) 1.
- G-CSF and GM-CSF showed marginal benefit in reducing infection-related mortality but did NOT influence overall mortality 1.
Critical Caveat
The only biological agent with any current consideration is low-dose hydrocortisone (200 mg/day) in adult septic shock patients when adequate fluid resuscitation and vasopressor therapy CANNOT restore hemodynamic stability (grade 2C) 1. However, this is NOT recommended for sepsis without shock (grade 1D) 1.