A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent on the risk of death: A meta-analytic/meta-regression study

Combination antimicrobial therapy is commonly used for the treatment of sepsis and septic shock. The most accepted rationale for this approach is an increased spectrum of coverage, even though current antimicrobials possess extremely broad activity. Assuming the pathogenic organism is susceptible to one antibiotic, the incremental benefit of combination therapy is uncertain. Although some animal models (1–3) and clinical studies of infection, including endocarditis, Gram-negative bacteremia, and neutropenic infections (4–6), support such combination therapy, the potential clinical benefit in other severe infections associated with sepsis and septic shock has been questioned. Two separate meta-analyses have failed to demonstrate evidence of improvement of outcome with combination therapy in immunocompetent patients with sepsis and/or Gramnegative bacteremia (7, 8). Meta-regression studies have found that efficacy of some medical therapies, including immunomodulatory therapy of sepsis, can be contingent on the underlying severity of illness and risk of death (9–12). A potential survival benefit with combination antimicrobial therapy may be similarly restricted to high-risk groups. A benefit in the most severely ill patients may be diluted or offset by less severely ill patients in whom no benefit exists or adverse effects of combination therapy dominate. We report a meta-analysis/metaregression study undertaken to determine whether combination antimicrobial therapy reduces mortality compared to monotherapy in patients with serious bacterial infections that can cause sepsis/ septic shock. The specific hypothesis was that any beneficial effect of combination antimicrobial therapy on mortality of lifethreatening infection is restricted to patients with septic shock or otherwise high-risk of death.