An alternate pathophysiologic paradigm of sepsis and septic shock

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.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

“…A loading dose of 1 g of vancomycin will fail to achieve early therapeutic levels for a significant subset of patients. In fact, loading doses of antimicrobials with low volumes of distribution (teicoplanin, vancomycin, colistin) are warranted in critically ill patients to more rapidly achieve therapeutic drug levels due to their expanded extracellular volume related to volume expansion following fluid resuscitation [148][149][150][151][152].…”

Fungicidal versus fungistatic therapy of invasive Candida infection in non-neutropenic adults: a meta-analysis

“…A rapidly evolving body of research literature suggests that optimisation of antimicrobial therapy can improve outcome in severe, life-threatening infections (Kumar 2014). Approaches such as extended or continuous infusion of β-lactams, once-daily dosing of aminoglycosides and use of synergistic combinations of antibiotics share a common effect of increased pathogen clearance, i.e.…”

“…The most plausible possibility for better therapeutic success frequency may be the more rapid clearance of pathogen that should be inherent with the use of a fungicidal drug (all other things being equal). The underlying hypothesis driving this analysis was that the microbial burden during severe infectious illness is based, in part, on an increasing microbial burden relative to less severe illness and that persistence of severe illness drives an increased risk of death (Kumar 2014). Accelerated pathogen clearance (as expected by definition with microbicidal therapy) in severe infections should presumably result in more rapid illness resolution and improved survival.…”

“…While clinical trials to directly test the presumption of the superiority of microbicidal activity for a broad range of infection severity are inconsistent, the case for microbicidal drug therapy in severe life-threatening infections appears stronger (Duke et al 2002; Reboli et al 2007; Prasad et al 2012; Kumar 2014). Animal studies have shown that fungicidal therapy does result in accelerated tissue pathogen clearance in animal models of invasive candidiasis (Krishnan-Natesan et al 2010).…”

“…For serious invasive Candida infections (particularly those associated with haemodynamic instability) where speed of clearance of the organism may potentially be a factor in outcome (Kumar 2014), the fungistatic activity of triazoles may represent a distinct disadvantage. Whether the use of triazoles for invasive Candida infections is associated with inferior clinical outcomes compared to fungicidal agents is uncertain.…”