There has been little improvement in
septic shock mortality in the past 70 years, despite ever more broad-spectrum and potent antimicrobials. In the past, resuscitative elements have been the primary area of clinical
septic shock management and research. The question of the optimal use of antimicrobial
therapy was relatively ignored in recent decades. This review explores the pathophysiology of
sepsis in an attempt to produce a better understanding and define key determinants of antimicrobial
therapy response in
septic shock. Optimizing existing antimicrobials delivery can drive significant improvements in the outcome of
sepsis and
septic shock. Inappropriate antimicrobial selection and dosing or delays in the administration substantially increase mortality and morbidity in life-threatening
infections. Definitive combination
therapy (where a pathogen known to be susceptible to a given agent is additionally covered by another agent) remains controversial. Although some in vitro studies, animal models, and clinical studies of
infection including
endocarditis, gram-negative
bacteremia, and neutropenic
infections have supported combination
therapy, the potential clinical benefit in other severe
infections has been questioned. Several meta-analyses have failed to demonstrate improvement of outcome with combination
therapy in immunocompetent patients with
sepsis and/or gram-negative
bacteremia. These meta-analyses did not undertake subgroup analyses of the
septic shock population. This article reviews the existing evidence supporting combination
therapy for severe
infections,
sepsis, and
septic shock.