Infections & Intoxications involving Gastro-intestinal Tract College of Nursing Syeda S. Fatima

Lecture Objectives- Upon completion of the lecture, the students will be able to: Discuss the causes and mode of transmission of Intoxications of the gastro-intestinal tract. Explain the pathogenesis of the different infections. Evaluate the laboratory diagnosis for the identification of the etiologic agent. Determine the antibiotic of choice for treatment.

Focused Terminologies- Intoxication- an abnormal state that is essentially a poisoning. CAMP (Cyclic adenosine monophosphate )- it is used for intracellular signal transduction, for transferring the effects of hormones like glucagon and adrenaline, which cannot pass through the plasma membrane. Edema-is an abnormal accumulation of fluid in the interstitium, located beneath the skin and in the cavities of the body. Papule- is a solid, rounded growth that is elevated from the skin. It is usually less than 1 cm (0.5 in.) across. Pustules- are small bumps on the skin that fill with fluid or pus, most common on the back, neck, chest, and face.

Infection associated with consumption of contaminated food is often termed “Food Poisoning”, but “food associated infection” is a better term. True food poisoning occurs after consumption of food containing toxins which may be bacterial in origin. Bacteria multiply and produce toxins within contaminated food. Organisms may be destroyed while cooking but the toxins remain unaffected. When toxin is consumed, it acts within hours.

Gram Positive Rods

Bacillus

Bacillus species- They are gram positive, forms endospores and are either strictly or facultatively aerobic. Usually encountered in the laboratory as airborne contaminants. Bacillus anthracis is the cause of the disease anthrax.

Bacillus anthracis- Anthrax is a rare disease. In 2001, 20 cases occurred in USA which included cutaneous and inhalation anthrax. Infections result from exposure to B. anthracis powder sent through mail.

Epidemiology- Anthrax is an enzootic disease (i.e., the disease occurrence changes little over time). Anthrax effects sheep, goats and horses and is transmitted to human by contact with infected animal products or contaminated dust. Infection is initiated by the subcutaneous inoculation of spores through incidental skin abrasions.

Inhalation of spore-laden dust causes pulmonary form of anthrax (this form of pneumonia is known as “Woolsorter’s disease”). Organism’s spores remain viable for many years in contaminated pastures, or in bones, wool, hair, hides or other animal materials. Spores are highly resistant to physical and chemical agents.

Pathogenesis- Bacillus anthracis possess a capsule that is anti-phagocytic and is essential for full virulence. Organism also produces exotoxins (edema factor) which causes elevation of intracellular cAMP. Exotoxin is also responsible for severe edema usually seen in B. anthracis infections. Lethal toxin is responsible for tissue necrosis. Organism’s protective antigen mediates cell entry of edema factor and lethal toxin. In addition to capsule, exotoxin, lethal toxin and protective antigen plays a role in pathogenesis.

Clinical Significance- a.Cutaneous Anthrax b. Pulmonary Anthrax (Woolsorter’s Disease) c. Gastro-intestinal Anthrax

A. Cutaneous Anthrax- About 95% of the human cases are cutaneous. Upon introduction of organisms or spores that germinate, a papule develops. It rapidly evolves into a painless, black, severely swollen “malignant pustule”, which eventually crusts over. Organisms invade regional lymph nodes and then general circulation leading to fatal septicemia.

B.Pulmonary Anthrax (Woolsorter’s Disease)- It is caused by inhalation of spores. Characterized by progressive hemorrhagic lymphadenitis (inflammation of the lymph nodes).

C. Gastrointestinal Anthrax- When a person eats raw or undercooked meat from an animal infected with anthrax, they can develop gastrointestinal anthrax. Once ingested, anthrax spores can affect the upper gastrointestinal tract (throat and esophagus), stomach, and intestines. Infection usually develops from 1 to 7 days after exposure. Without treatment, more than half of patients with gastrointestinal anthrax die. With proper treatment, 60% of patients survive.

Laboratory Diagnosis- Organism is easily recovered from clinical materials and is present in massive numbers. Microscopically the organism appears as blunt-ended bacilli that occur singly, in pairs or frequently in chains. On blood agar the colonies are large, grayish and non- hemolytic with an irregular border. A direct immuno-florescence assay aids in identification of the organism.

Treatment- Cutaneous Anthrax: Doxycycline, Ciprofloxacin or Erythromycin. Inhalation Anthrax: multidrug therapy (Ciprofloxacin+ Rifampin+ Vancomycin). Prevention- A cell-free vaccine is available for high risk workers. Post exposure prophylaxis can be done by Ciprofloxacin or Doxycycline. Other Species of Bacillus: Bacillus cereus also causes food poisoning by enterotoxins with either emetic or diarrheal effects.

Clostridium

Clostridia- They are the anaerobic, gram positive blunt ended rods. They form endospores. Most species are motile. They grow on enriched media in presence of a reducing agent such as Cysteine or Thioglycollate. Clinically significant species of Clostridium include-  C. perfringens- causes histotoxic infections, myonecrosis and food poisoning.  C. difficle- causes pseudomembranous colitis  C. tetani- causes tetanus (“lock-jaw”)  C. botulinum- causes botulism

Epidemiology- Clostridia are part of the intestinal flora in humans and other mammals. Clostridial species produce destructive and invasive infections when introduced into the tissues. Their presence in infectious processes is opportunistic and often derived from patients normal flora. Endospore formation facilitates their persistent survival in the environment.

C. perfringens

Clostridium perfringens- Large, rod-shaped, non-motile, gram positive, encapsulated bacillus. They are ubiquitous in nature i.e., their vegetative form as part of the normal flora of vagina and GI tract. When introduced into tissues, organism causes anaerobic cellulitis and myonecrosis (gas gangrene). Some strains of C. perfringens also cause food poisoning.

Pathogenesis- C. perfringens secretes a variety of exotoxins, enterotoxins and hydrolytic enzymes that facilitates the disease process.  Exotoxins: 12 exotoxins are elaborated, Alpha toxin is the most important which cause lysis of mammalian endothelial cells as well as erythrocytes, leukocytes and platelets.  Enterotoxin: heat labile protein that acts on the small intestine.  Degradative enzymes: C. perfringens produce hydrolytic enzymes such as proteases, Dnases, hyaluronidase and collagenases, which liquefy the tissue and promotes spread of infection.

Clinical Significance- a.Food Poisoning- C. perfringens is the common cause of food poisoning. Onset of nausea, abdominal cramps and diarrhea occurs 8- 18hrs after eating contaminated food. Fever is absent, vomiting is rare. Recovery can be seen within 1-2 days. Higher inoculum is required for the symptoms to occur. Clostridial enterotoxin food poisoning involves cooking that fails to inactivate the spores, followed by holding the food for several hours which favors bacterial growth.

b. Gas Gangrene (Myonecrosis)- Clostridial spores are introduced into the tissues. Severe open wounds or car accident injuries are the pre- disposing condition. Alpha toxin and other exotoxins are secreted leading to excessive cell killing. Production of enzymes that break down the ground substances facilitates the spread of infection.

Fermentation of tissue carbohydrates results in gas, accumulation of gas bubble in subcutaneous spaces produces a crinkling sensation. The exudates are copious and foul smelling. Systemic effects such as shock, renal failure and intravascular hemolysis can also be seen. Untreated myonecrosis is fatal within days of initiation of gangrene.

Laboratory Identification- When cultured anaerobically on blood agar C. perfringens produces colonies that are a unique double zone of hemolysis. In food poisoning, the organism can be sought in suspected food and patients feces.

Treatment & Prevention- Immediate and thorough removal of foreign material and devitalized tissue and exposure of the tissue to oxygen is the prevention and treatment for Gas gangrene. C. perfringens is sensitive to penicillin.

C. botulinum

Focused Terminologies- Flaccid paralysis- it is an abnormal condition characterized by the weakening or the loss of muscle tone. Floppy baby syndrome- it is an abnormal condition of newborns and infants manifested by inadequate tone of the muscles (Hypotonia). Antitoxin- it is an antibody with the ability to neutralize a specific toxin, they are produced by certain animals, plants, and bacteria.

Clostridium botulinum- Causes botulism, due to neurotoxin. Leads to flaccid paralysis. Contact with the organism is not required, pure intoxication can lead to the disease. Epidemiology- Spores of C. botulinum frequently contaminate vegetables and meat or fish. Under favorable conditions including strict anaerobic conditions, organisms germinate and toxin is produced.

Pathogenesis- Human disease is always caused by types A, B or E toxins. Toxins affect the peripheral cholinergic synapses by blocking the neurotransmitter junction and inhibiting the release of neurotransmitter Acetylcholine. This prevents contraction and causes Flaccid paralysis.

Clinical Significance- a.Classic botulism: It is a food poisoning. After12-36hrs of ingesting toxin containing food (not necessarily viable organisms), patient begins to experience the following-  difficulties in focusing vision  swallowing and other cranial nerve functions. No fever or sign of sepsis. Progressive paralysis of striated muscle groups develops. Patient usually succumbs to respiratory paralysis also. Recovery is protracted, lasting several weeks.

b. Infant botulism- It is a cause of floppy baby syndrome. Organism colonizes the large bowel of infants, toxin produced is slowly absorbed. Constipation, feeding problems and lethargy are common early signs. Formula supplements contaminated with C. botulinum spores may transmit the organism. The condition is the cause of sudden infant death syndrome.

Laboratory Identification- Organisms can be cultures and identified by standard anaerobic methods. Toxin is also identifiable in serum, stool and blood. Treatment & Prevention- Antitoxin which neutralizes unbound botulinum toxin should be administered as soon as possible.

C. tetani

Focused Terminologies- Spastic paralysis- it is a form of paralysis where the nervous system that controls coordinated movement of the voluntary muscles is disabled, leads to tightness or stiffness.

C. tetani- C. Tetani spores are common in garden and other soils. It produces a powerful neurotoxin that is transported to the central nervous system where it causes Spastic paralysis. Pathogenesis- Tetanus toxin called Tetanospasmin is extremely potent toxin. It is transported from infected locus by retrograde neuronal flow or blood. A toxin is produced which contains a heavy fragment (B) and light fragment (A). Heavy fragment: helps binding to neurons and cell penetration of light fragment. Light fragment: blocks neurotransmitter release at inhibitory synapses. This causes severe muscle spasms.

Clinical Significance- Tetanus incubation period varies from 4 days to several weeks. Tetanus presents as a spastic paralysis, in which muscles spasms first involve the site of infection. In early stages, the jaw muscles are affected so that the mouth cannot open (trismus or “lockjaw”). Gradually other voluntary muscles will be involved. Death is usually the result of paralysis of chest muscle leading to respiratory failure.

Laboratory Identification- C. tetani has a characteristic morphology with long, slender rod and round, terminal spores bacillus. It is shows characteristic swarming growth on anaerobic blood agar.

Treatment- Prompt administration of antitoxin to neutralize any toxin not yet bound to neurons is the first order treatment. Organism is sensitive to penicillin. Prevention- Active immunization with Tetanus toxoid (formalin inactivated toxin) prevents toxin. It is administered as a triple vaccine with diphtheria toxoid and pertussis antigens (DPT). Boosters doses should be given every ten years.

C. difficle

Clostridium difficle- Diarrhea, a common complication of antimicrobial treatment. It can range from loose stools to life-threatening pseudomembranous colitis. After the organisms introduction to a site, the environment- dust, bedding, toilets become contaminated with spores and a new residents are easily colonized. They are then at higher risk for developing the adverse intestinal effect of antibiotic treatments.

Pathogenesis- C. difficle is a minor component of the normal flora of large intestine. When antimicrobial treatment suppresses predominant species, C. difficle proliferates. Pathogenic strains produce two toxins i.e., A and B. Toxin A is an enterotoxin that causes excessive fluid secretion and also stimulates inflammatory response. Toxin B is a cyto-toxin, in tissue culture it disrupts protein synthesis and causes disorganization of cytoskeleton.

Clinical Significance- All antimicrobial drugs have been reported as predisposing to clostridial antibiotic associated diarrhea (AAD)and colitis. Three drugs most commonly implicated are Clindamycin, Ampicillin and Cephalosporins. Severity of the disease varies from mild diarrhea through varying degree of inflammation of the large intestine to a fulminant Pseudomembranous Colitis (PMC). The pseudomembranous exudate composed of mucus, fibrin, inflammatory cells and cell debris overlying an ulcerated epithelium. It is demonstrated by endoscopy.

Laboratory Identification- C. difficle can be cultured from stools and identified by routine anaerobic procedures. Useful tests are demonstrating toxin production in stool extracts. ELISA for exotoxins A and B or Tissue culture cytotoxicity assays. Treatment- Discontinuance of the predisposing drugs and fluid replacement. Oral administration of vancomycin.

Model Multiple Choice Question- A 67 year old man had surgery for ruptured sigmoid colon diverticulum with an abscess, repair was done and abscess was drained. He was treated with gentamicin and ampicillin, 10 days later and 4 days after discharged from the hospital he developed malaise, fever and cramping abdominal pain. He had multiple episodes of diarrhea, his stool showed the presence of polymorphonuclear cells. Sigmoidoscopy showed mucosa inflamed. Which one of the following is the etiologic agent? a.Bacillus cereus toxin b.Clostridium difficle toxin c.Enterohemorrhagic E. coli d.Staphylococcus aureus enterotoxin

Reference- Sherris Medical Microbiology fifth edition. Microbiology by Lippincott Williams & Wilkins 2 nd edition.

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