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.