The advent of modern antimicrobial
therapy following the discovery of
penicillin during the 1940s yielded remarkable improvements in case fatality rate of serious
infections including
septic shock. Since then, pathogens have continuously evolved under selective antimicrobial pressure resulting in a lack of significant improvement in clinical effectiveness in the antimicrobial
therapy of
septic shock despite ever more broad-spectrum and potent drugs. In addition, although substantial effort and money has been expended on the development novel non-antimicrobial
therapies of
sepsis in the past 30 years, clinical progress in this regard has been limited. This review explores the possibility that the current pathophysiologic paradigm of
septic shock fails to appropriately consider the primacy of the microbial burden of
infection as the primary driver of septic organ dysfunction. An alternate paradigm is offered that suggests that has substantial implications for optimizing antimicrobial
therapy in
septic shock. This model of
disease progression suggests the key to significant improvement in the outcome of
septic shock may lie, in great part, with improvements in delivery of existing antimicrobials and other anti-infectious strategies. Recognition of the role of delays in administration of antimicrobial
therapy in the poor outcomes of
septic shock is central to this effort. However, therapeutic strategies that improve the degree of antimicrobial cidality likely also have a crucial role.