Sepsis

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Case Discussion

57 yo M with history of EtOH is seen for Pneumonia. 
Labs is as follow over the treatment course. 








Gm -ve infection causes one of the worst sepsis you can ever see. 
Clinical question why does sepsis occur? 

Some of the most frequently isolated bacteria in sepsis are Staphylococcus aureus (S. aureus), Streptococcus pyogenes (S. pyogenes), Klebsiella spp., Escherichia coli (E. coli), and Pseudomonas aeruginosa (P. aureginosa)

Bacterial Toxins

Bacterial toxins are mainly divided into three types based on their mode of action. 

  • Type I toxins disrupt host cells without the need to enter the cells. These include superantigens (SAgs) produced by S. aureus and S. progenies.
  •  Type II toxins, such as hemolysins and phospholipases destroy host cell membranes to invade and interrupt host defense processes within the cell.
  •  Type III toxins, also known as A/B toxins due to their binary structure; disrupt host cell defenses to allow dissemination to remote organs.  The B component of these toxins binds to the host cell surface, while the A component possess the enzymatic activity to damage the cell. 
  • Ref
  • Gram-positive and gram-negative bacterial toxins in sepsis  

 Endotoxins in Sepsis

  • LPS macromolecules that make up about 75% of the outer membrane of gram-negative bacte- ria that are capable of causing lethal shock
  • The structure of LPS generally consists of a hydrophobic lipid A domain, an oligo- saccharide core, and the outermost O-antigen polysaccharide
  • Lipid A is the single region of LPS that is recognized by the innate immune system. Picomolar concentrations of lipid A are sufficient to trigger a macrophage to produce proinflamma- tory cytokines like TNF-α and IL1β
  • To trigger an innate immune response, the lipid A portion of LPS alone is sufficient, yet the adaptive immune response during infection is usually directed toward the O-antigen
  • The key pattern recognition receptor for LPS recognition is Toll-like receptor 4 (TLR4)
  • LPS induces inflammatory cells to express a number of proin- flammatory cytokines including IL-8, IL-6, IL-1β, IL-1, IL-12, and IFNγ;  however, TNFα seems to be of critical importance during endotoxic shock  and causes tissue damage 
  • Despite the compelling evidence that LPS is a major factor in the pathophysiology of septic shock, recent trial targeting lipid-A portion of LPS with a drug called eritoran was unable to improve outcome in a large phase 3 clinical trial 
  • Ref
  • Gram-positive and gram-negative bacterial toxins in sepsis  

 

 

Hospital-Acquired Infections Due to Gram-Negative Bacteria NEJM 2010

Superantigen

  • Superantigens (SAg) are one of the most potent toxins pro- duced by bacteria, namely, S. aureus and S. progenies 
  • Unlike conventional antigens that are processed by antigen presenting cells and presented to T cells through the MHC-II molecules, SAgs bind directly to the outer leaflet of MHC-II molecules71-73 specific domains of the variable portion of β-chain (Vβ) of the T-cell receptor.
  • Unlike conventional antigens that normally activate <0.01% of T cells, SAgs activate >20% of T cells by binding to the MHC-II and T-cell receptor directly
  • This leads to a massive induction of proinflammatory T-helper 1 (Th1) cyto- kines including tumor necrosis factor (TNF), interferon γ (IFN γ), and interleukin-2 (IL-2)
  • Ref
  • Gram-positive and gram-negative bacterial toxins in sepsis  
Pseudomonas and Exotoxin
  • On the basis of weight, exotoxin A of this organism is the most toxic compound it produces.91 Exotoxin A is part of an enzyme family called mono-ADP-ribosyltransferase. The toxin affects the protein synthesis in host cells by catalyzing the ADP ribosylation of eukaryotic elongation factor 2, much like the mechanism of diphtheria toxin. 
  • Ref
  • Gram-positive and gram-negative bacterial toxins in sepsis  

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