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Review
. 2014 Jan 1;5(1):80-97.
doi: 10.4161/viru.26913. Epub 2013 Nov 1.

An alternate pathophysiologic paradigm of sepsis and septic shock: implications for optimizing antimicrobial therapy

Anand Kumar  1
Affiliations
Free PMC article
Review

An alternate pathophysiologic paradigm of sepsis and septic shock: implications for optimizing antimicrobial therapy

Anand Kumar. Virulence. .
Free PMC article

Abstract

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.

Keywords: antibiotic; antimicrobial; combination therapy; infection; life-threatening infection; pharmacokinetics; sepsis; septic shock; survival.

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Figures

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Figure 1. SIRS, sepsis, severe sepsis, and septic shock. SIRS, systemic inflammatory response. Adapted from reference . See text for explanation.
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Figure 2. Immunologic view of sepsis and septic shock. SIRS, systemic inflammatory response. Adapted from reference . See text for explanation.
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Figure 3. Microbiologic view of sepsis and septic shock. See text for explanation.
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Figure 4. Composite view of sepsis and septic shock. See text for explanation.
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Figure 5. Impact of appropriate antimicrobial therapy in sepsis and septic shock. See text for explanation.
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Figure 6. Impact of earlier antimicrobial therapy in sepsis and septic shock. See text for explanation.
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Figure 7. Impact of more potent antimicrobial therapy in sepsis and septic shock. See text for explanation.
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