Microbiology: Enterotoxins vs Endotoxins

Enterotoxins

Enterotoxins are exotoxins that primarily target the intestinal mucosa, disrupting fluid and electrolyte balance.
Enterotoxigenic E. coli releases an enterotoxin causing hypersecretory diarrhea in neonatal farm animals.

Endotoxins

Endotoxins, found in the outer walls of Gram-negative bacteria, are a leading cause of morbidity and mortality in livestock.
Endotoxins are lipopolysaccharides released into the surroundings during rapid bacterial proliferation, cell wall breakage, or both.
Endotoxins are present in the intestinal tract as part of the normal microbiota and are not typically absorbed unless the intestinal mucosa is compromised.
Small amounts of endotoxin absorbed into the bloodstream are detoxified in the liver, but excessive amounts or compromised liver function can lead to endotoxemia.
Common causes of endotoxemia in horses include gastrointestinal diseases like colitis, intestinal strangulation, obstruction, and ileus.
Endotoxin can enter the bloodstream through severe localized infections like coliform mastitis in dairy cattle, disseminated infections like coliform septicemia in calves, and other sites like the mammary gland, peritoneum, abscesses, injured tissue, or traumatized tissue.

Metabolic Toxins

Metabolic toxins can accumulate due to incomplete elimination of toxic materials normally produced by the body or abnormal metabolism.
Normally, these toxic products are excreted in urine and feces or detoxified in the plasma and liver.
Hepatic dysfunction can lead to toxin accumulation and toxemia due to disruptions in detoxification processes.
Obstruction of the lower alimentary tract can increase the absorption of toxic phenols, cresols, and amines, resulting in autointoxication.
In monogastric animals, these products of protein putrefaction are typically not absorbed in the large intestine; however, regurgitation into the small intestine can lead to rapid absorption.
Abnormal metabolism can produce histamine and histamine-like substances in damaged tissues.
Ketonemia due to fat metabolism imbalance and lactic acidemia from acute ruminal acidosis (grain overload) are examples of toxemia caused by abnormal metabolism.

Pathogenesis of Toxemia

Carbohydrate Metabolism:
- Endotoxemia leads to a decrease in plasma glucose concentration, with severity dependent on endotoxemia intensity.
- Liver glycogen depletion occurs, and tissue glucose tolerance decreases.
- Blood pyruvate and lactate levels rise due to poor tissue perfusion and anaerobic metabolism.
Protein Metabolism:
- Tissue breakdown (catabolism) increases, leading to a rise in serum urea nitrogen concentration.
- Changes in plasma amino acid levels occur, including increased urinary nitrogen excretion and whole-body protein turnover.
- Total serum protein increases due to antibody production.
- Globulins increase while albumin decreases as part of the acute phase reaction.
Cardiovascular and Circulatory Effects:
- Capillary dilation and potential damage reduce effective circulating blood volume.
- Decreased cardiac output, combined with reduced blood volume, leads to low blood pressure and circulatory failure.
Organ Function:
- Liver function is impaired.
- Renal tubules and glomeruli damage cause elevated blood non-protein nitrogen and albuminuria.
- Alimentary tract function and motility are reduced, leading to appetite loss, impaired digestion, and constipation.
- Skeletal muscle weakness occurs, resulting in general weakness and eventually prostration.
- General depression of function, manifested by dullness, depression, and coma.
Hematopoietic System:
- Hemopoiesis is suppressed, and leukocyte count increases, with the specific cell type affected varying by toxemia type and severity.
- Leukopenia can occur but is often associated with aplasia of leukopoietic tissue related to viruses or exogenous substances like radioactive materials.
- Some toxins can cause hypersensitivity, leading to anaphylaxis or allergic reactions upon subsequent exposure.

Clinical Presentation

Acute Toxemia:
- Depression, anorexia, and muscular weakness are common in acute endotoxemia.
- Calves may not suck voluntarily and lack a suck reflex.
- Feces may be scarce or a low-volume diarrhea present.
- Heart rate increases, pulse is weak, rapid, but regular.
- Fever is common early on, but temperature may normalize or become subnormal later.
- Terminal stages involve significant muscular weakness leading to collapse and death from coma or convulsions.
Endotoxemia:
- Primarily associated with bacteremia or septicemia caused by Gram-negative organisms, especially E. coli.
- Clinical signs include:
  - Depression
  - Hyperthermia followed by hypothermia
  - Tachycardia followed by decreased cardiac output
  - Decreased systemic blood pressure
  - Cool skin and extremities
  - Diarrhea
  - Congested mucosae with prolonged capillary refill time
  - Muscular weakness leading to recumbency
  - Renal failure, often featuring anuria
  - Disseminated intravascular coagulation (DIC) characterized by petechial and ecchymotic hemorrhages on mucous membranes, sclera, and bleeding from vein puncture sites.

Clinical Presentation of Toxemia

Toxic or Septic Shock:
- Rapid toxin formation or release into the circulation with high toxicity.
- Severe peripheral vasodilation causing a drop in blood pressure.
- Pale mucosal membranes
- Hypothermia
- Tachycardia
- Weak pulse
- Muscle weakness
Chronic Toxemia:
- Lethargy
- Isolation from the group
- Lack of appetite
- Growth or production failure
- Emaciation

Laboratory Findings

Mild Endotoxemia:
- Leukocytosis and neutrophilia
Severe Endotoxemia:
- Leukopenia, neutropenia, and lymphopenia, increasing in severity and duration with endotoxemia progression.
- Low plasma glucose concentration
- High serum urea concentration (non-protein nitrogen)
- Low serum albumin and total protein concentration (acute endotoxemia), reflecting increased capillary permeability.
- Azotemia due to decreased glomerular filtration rate.
- Mild hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia, potentially related to inappetence and reduced gastrointestinal motility.
Chronic Toxemic States:
- High serum total protein concentration with elevated globulins

Treatment of Endotoxemia

Primary Principles:
- Removal of infection foci
- Administration of broad-spectrum antimicrobial agents effective against Gram-negative bacteria (avoidance of β-lactam antibiotics alone due to potential endotoxin release, but acceptable with co-administration of aminoglycosides).
- Aggressive fluid and electrolyte therapy to address hypovolemia, hypoglycemia, electrolyte imbalances, and acid-base disruptions
- Correction of peripheral vasoconstriction
- Restore acceptable pulse quality
- Restore urine output
- Increase central venous pressure
- Achieve a mean arterial blood pressure greater than 65 mm Hg
- Restore cardiac output
- Restore oxygen delivery to acceptable levels
Specific Treatments:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids to inhibit cyclooxygenase pathway products.
- NSAIDs like flunixin meglumine (1.1-2.2 mg/kg BW/day intravenously for 5 days) and phenylbutazone (5 mg/kg BW/day intravenously for 5 days in calves) have analgesic, anti-inflammatory, and antipyretic properties.
- Glucocorticoids can improve capillary endothelial integrity, tissue perfusion, decrease complement and clotting cascade activation, reduce neutrophil aggregation, stabilize lysosomal membranes, protect against hepatic injury, and improve survival. However, potential immunosuppression is a concern.
- Inotropic agents (like dobutamine 0.5-1.0 µg/kg BW/min in adults and 1-3 µg/kg BW/min in neonates) enhance cardiac contractility, boosting cardiac output and oxygen delivery
- Vasopressor agents (like norepinephrine 0.01-1 µg/kg BW/min) increase systemic arterial blood pressure in hypotensive animals not responding to intravenous fluid or dobutamine.
- Antiserum (hyper-immune serum) available commercially for treating endotoxemia in horses.