20: exotoxin producing clostridia - jonathan Flashcards by Jonathan Burgess

What are the two major mechanisms that cause illness with Clostridia?
What are examples of each?

Exotoxin-mediated disease: Botulism-toxin

Invasion and inflammation: tissue invasion and damage due to host’s immune system

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As an exotoxin producing bacteria, do clostridia organisms need to be consumed to cause illness?

As an exotoxin, botulism can be secreted by clostridia into food.
Only the exotoxin needs to be consumed to cause illness.
No clostridia need to be consumed.

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Aside from Clostridia botulism, what other bacteria is a common exotoxin food-borne diarrheal bacterial disease?

Staphylococcus aureus

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What are 2 possible pathogenic steps in establishing bacterial infection by ingesting toxin?

1) Toxins are pre-formed in food and ingested. No organism necessary. (ex: Botulism and S. aureus)
2) Ingestion of microorganism with adherence, colonization, and toxin is then formed in the gut. (ex: Botulism and Vibrio cholerae aka cholera toxin)

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What are the general characteristics of Clostridium?
Aerobic or anaerobic?
Gram status and shape?
Spore status?
Catalase status?
Oxidase stauts?

Obligate anaerobe
Gram positive rods
Spore forming
Catalase negative
Oxidase negative

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What is unique about the spore formation of clostridium for Dx purposes?

Location of the spore in the bacterium may aid in species identification (e.g. terminal spores = Clostridium tetani)

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State invasive status and basic illness of the following:
Clostridium botulism
Clostridium tetani
Clostridium difficile
Clostridium perifringens
Costridium septicum (don't need to know)
Clostridium ramosum (don't need to know)

Clostridium botulism: noninvasive and causes botulism
Clostridium tetani: generally noninvasive and causes tetanus (small invasive potential)
Clostridium defficile: noninvasive and causes pseudomembranous enterocolitis
Clostridium perifringens: very invasive and causes gangrene
Costridium septicum: invasive in malignancy
Clostridium ramosum: implies invasive in notes. Does not say.

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What symptoms do the following toxins cause…

1) Botulism toxin?
2) Tetanus toxin?
3) Exotoxin A and B (Clostridium difficile)?
4) Alpha toxin (Clostridium perfringens)?

1) flaccid paralysis
2) tetanus (locked jaw)
3) diarrhea in pseudomembranous colitis
4) lecithinase which hosts cell membrane in combination with other degradative enzymes as the cause for “Gas Gangrene”

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How would you Dx Clostridium tetani due to its spore location?

C. tetani have only one “terminal spore” that looks like a tennis racket. See slide 6 and 9 on Clostridia I ppt.
All other species have subterminal spores.

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What is the general epidemiology of C. tetanus…
Where is its natural habitat?
How common is it in the U.S. vs other countries?
How does infection occur?

Natural habitat is in the soil
Rare in the U.S. due to immunization and common in developing nations (eg infected umbilical stump)
Cases occur due to puncture wounds (a random nail with that contains soil bacteria) where spores germinate in the deep and dirty wound under anaerobic conditions

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What is the general pathogenesis of C. tetanus…
Is C. tetanus an invasive and/or toxin-mediate disease?
How many serotypes?
What organ system does C. tetanus infect?

C. tetanus is a noninvasive, toxin-mediated disease with one serotype.
Tetanus toxin is a neurotoxin that affects the CNS and PNS

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What are the subunits of the tetanus toxin?

What do each do?

Subunits A and B
B subunit binds to neuronal ganglioside
A subunit has neurotoxin activity

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What neurotransmitters does tetanus toxin affect?

inhibits the release of glycine and GABA resulting in spastic paralysis and convulsive contractions aka locked jaw

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What are the clinical syndromes associated with C. tetani...
What is the incubation period?
What is are the major muscle symptoms?
Bonus question: which muscle groups?
Is fever involved?
Is sensory deficit involved?
Note: we'll mention respiration next…

Incubation period is 4 days to several weeks
Main clinical feature is violent muscle spasm, predominently the FLEXOR muscles, plus clenched teeth, and neck and back arched (these are extensors)
Symmetrical paralysis is unique to tetanus (along with strycnine)
No fever
No sensory deficit
Respiratory complications…

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What pharyngeal and respiratory complications can occur with C. tetani?

respiratory failure possible
aspiration, dysphagia, and oral pharyngeal involvement
complications may be pulmonary infections and respiratory problems

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What is the Dx for C. tetani…

Clinical vs lab or both?

mainly clinical Dx and Hx
the organism is rarely still in the wound
the exotoxin causes symptoms

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What is the Tx for C. tetani (list 5 treatments including 2 antibiotics)?

human tetanus Ig
penicillin plus wound debridement (penicillin is used for Gram +)
metronidazole is used if there is a penicillin allergy
respiratory support if necessary
immunization with tetanus toxiod to prevent recurrence

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What are the two drugs used for C. tetani and why?

Penicillin is used for Gram +. It is a cell wall inhibitor.

Metronidazole is used if there is a penicillin allergy. It is a DNA replication inhibitor used for anaerobes.

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What is the prognosis of C. tetani infection?

60% fatality rate due to pulmonary complications and secondary infections
This is why we get vaccinated

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What is the immunization for C. tetani?

What is the immunization and booster schedule and what the vaccine is called.

DPT vaccine (diphtheria, pertussis, tetanus)
Three doses in first 6 months. Booster at year 1, prior school entry, and every 10 years.

Inactivated toxiod vaccine

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Due to the severity of C. tetanus, there is a prophylaxis protocol if a person has a possibly infected wound.

Wounds are either…

1) less than 6 hours old, clean, non-penetrating with neglible tissue damage
2) other wounds

In each circumstance, what prophylactic Tx is required for…
A) Pt with vaccine within 5 years?
B) Pt with vaccine between 5 and 10 years?
C) Pt with vaccine more than 10 years?
D) Pt with unknown vaccine status?

A) 1 and 2: no Tx required
B) 1 and 2: give one vaccine of inactivated toxiod
C) 1: give one vaccine of inactivated toxiod. 2: one vaccine plus human tetanus Ig
D) 1: three course vaccine. 2: three course vaccine plus human tetanus Ig

Slide 30 has flow chart.

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What is the bacteria and spore shape of Clostridium botulism?

Gram + rod with subterminal oval spores

Spore location is not diagnostic

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What is the general epidemiology of C. botulism…
Incidence level?
Natural habitat vs clinically-relevant habitat?
What is wound botulism?
What is the source of infant botulism?
(we discuss these latter two questions later in the deck)

Very low incidence
Soil organism that is often found in canned foods and smoked fish.
Botulism spores can germinate, grow, and produce botulism toxin in 2-3 days
Wound botulism is rare. Spores germinate in a wound.
Infant botulism is from honey. C. botulism grows anaerobically in the GI tract.

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Are botulism spores heat labile?

Is botulism toxin heat labile?

Spores are resistant to heat
Toxin is heat labile
therefore cook all canned foods

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``` Let's chat about botulism toxin… Is it resistant to heat? Is it resistant to stomach acid? How many types of toxins #? Which are the most common? How many subunits? ```

Heat labile Resistant to stomach acid 7 types of toxin (A to G) with A, B, and E being the most common two subunits to each toxin

Pathogenesis... Is C. botulism invasive? What tissue is ultimately affected? How does the toxin travel to that tissue?

C. botulism is not invasive. Affects nerves: flaccid paralysis (flaccid descending paralysis. Starts with the head and goes down. If hits respiratory muscles, you're dead.) The botulism toxin is absorbed in the intestine, carried through blood to nerves. The toxin binds to a receptor on the nerve an is taken up by the nerve.

What does botulism toxin do to nerves?

blocks acetylcholine release from nerve at neuromuscular junction details: the toxin is a protease that degrades the Ach vessicle docking proteins

``` What are the clinical symptoms of botolulism toxin… Main symptom? Fever? Mental status? Sensory system? Affects on pharynx? Affects on eyes? Respiration? ```

Flaccid paralysis with bilateral symmetry in peripheral and cranial nerves No fever Normal mental status No sensory deficit Dysphagia and dry throat Diplopia (double vision) and diluted pupils May affect respiratory muscles

Botulism symptoms broken down by system... GI/Urinary Neurologic Muscular

GI/Urinary: abdominal pain, intestinal ileus, urinary retention Neurologic: dry mouth, diplopia, dilated pupils, dysphagia, decreased gag reflex. NO sensory deficiency. Muscular: symmetrical muscle weakness. Respiratory muscle paralysis.

Botulism Dx… | Clinical or lab or both?

Usually clinical Dx Culturing microorgansim is not suggested because the preformed toxin is the culprit. However, detecting the toxin is a useful lab Dx

What are laboratory tests for botulism toxin?

detect toxin in serum, vomit, feces, or suspected food

What is an EMG used for with botulism? | Are the results conclusive?

electromyography tests diminished action potential of the peripheral nerves results are suggestive, not conclusive

What other illnesses must be considered in the differential Dx of botulism?

``` Myasthenia gravis (assymetrical) Guillain-Barre syndrome (assymetrical) ```

How is differential Dx performed between botulism and Guilain-Barre syndrom?

Both are ascending paralysis illnesses that can be distinguished by patient history and laboratory toxin detection (serum, vomit, feces)

What is Tx for botulism?

Stomach lavage (irrigate stomach to remove toxin) Horse antitoxin Supportive care, possibly including respiratory support

How is botulism prevented?

Cook all canned foods at 100 Celsius for 10 minutes

What are the two clinical variants of botulism besides food? | we've mentioned these earlier

Infant botulism | Wound botulism

Infant botulism… What ages are affected (age in months)? What is the common food source?

1-8 months | Honey

How are the symptoms of infant botulism different than adult botulism? What are the symptoms?

Symptoms are more subtle | Constipation, weak head control (flaccid neck muscles), cranial nerve deficit

How is Dx of infant botulism determined?

toxin or organism found in stool

What is Tx for infant botulism?

Supportive treatment | New antitoxin antibodies are being used

Quick word on Wound-associated botulism... How is infection caused? What is Dx?

Spores in soil contaminate wound, germinate, and produce toxin Dx by wound culture or toxin in serum

What is the aerobic status, invasion status, gram stain, and shape of Clostridium difficile?

anaerocbic, non-invasive gram + rod

What is the common clinical symptom caused by C. difficile?

antibiotic-associated diarrhea

What explains why C. diff is so low in the general population and so high in hospital patients?

Probably fecal oral transmission from hospital personel

Detail: What is the recent emergent virulent strain?

What is the pathogenesis of Clostridium difficile?

Antibiotic-induced suppression of normal flora >> C. diff proliferates and produces two distinct toxins: exotoxin A and B

Explain the function of toxin A and B in C. difficile.

A binds to gut receptor B is cytotoxin that damages colonic mucosa and causes diarrhea (sometimes bloody) (B is a ADP-ribosylating Rho GTP binding protein

What is that all too famous inflammation caused by C. diff that we learned in pathology?

pseudomembrane formation

What are the clinical syptoms of C. diff?

diarrhea (usually watery, sometimes bloody) with yellowish-white plaque pseudomembranse on colonoscopy

What is the Dx for C. diff?

History of antibiotic use Exotoxin B in stool samples ELISA to detect toxin Sigmoidoscopy with Pseudomembrane

What is the Tx for C. diff?

Stop offending antibiotics (usually ampicillin, cephalosporins, or clindamycin Treat with Metronidazole, Vancomycin, or Fidaxomicin Fecal transplantation

Bonus question: Why... Metronidazole? Vancomycin? Fidaxomicin?

Metronidazole: anaerobic Vancomycin: G + multi-resistant enterococcus Fidoxomicin: a drug that stays in the intestines (doesn't absorb into the blood) and is great for C. diff

What is prophylaxis for C. diff?

PRUDENT USE OF ANTIBIOTICS | isolation in case of outbreak and more consistent hand-washing

What are the major and minor illnesses caused by Clostridium perfringens? What is the hallmark of infection?

1) GAS GANGRENE (histotoxinc clostridia) 2) food poisoning Hallmark: TISSUE NECROSIS Note: many species of Clostridium can cause gas gangrene. Clostridium perfringens is the most common. Gas production Gangrene from closed off blood vessels.

What is the aerobic status, invasive status, gram stain, shape, and speed of growth of Clostridium perfringens?

Anaerobic, INVASIVE, gram + rod, grows VERY rapidly

What is the natural environment of Clostridium perfrinngens?

soil human GI vagina

What is the general pathogenesis of Gas Grangrene Clostridium perfringens? (details follow)

synthesize many toxins and enzymes which lyse host cells and tissues: necrosis

What are the lysogenic toxins and enzymes that are produced by Clostridium perfringens?

Lecithinase: an alpha toxin that damages host cell membrane (including capillary and host erythrocytes) Collagenase: degrades ECM Hyaluronidase: degrades ECM

What is lecithinase?

An alpha toxin that damages host cell membrane inclusing capillary and host erythrocytes

Does Clostridium perfringens a slow growing or fast growing organism?

Grows RAPIDLY in anaerobic environments usually requiring surgery to remove the infected tissues RAPIDLY FATAL if not treated

What are the byproducts of fast growing Clostridium perfringens?

H2 and CO2 gas

What are the clinical syndromes of gas gangrene Clostridium perfringens (name 4 progressive syndromes)?

1) cellulitis 2) necrotizing cellulitis (invasion of the dermis and underlying capillaries) 3) necrotizing cellulitis (invasion of facia around muscle) 4) myositis or myonecrosis (invasion into the muscle)

What is Dx of Gas Gangrene Clostridium perfringens? | Name three major and three minor Dx criteria

CREPITUS of due to gas in subcutaneous tissue DISCOLORATION and edema of skin EXTREME PAIN ``` also... dark serous exudates gram stain of exudates culture of wound X-ray ```

What is the Tx for Gas Gangrene Clostridium perfringens?

SURGICAL wound debridement penicilin (G+) to kill remaining bacteria hyperbaric oxygen

What is the pathogenesis of Clostridium perfringens with regard to food poisoning… (these seem like unecessary details) How many spores are required? Where is the enterotoxin found on the bacteria? What food is usually infected?

Needs lots of bacteria to cause infection (10^8) Enterotoxin is associated with the spore coat and the toxin is released into the intestine Usually found in meat

What are the clinical symptoms of Clostridium perfringens food poisoning?

Abdominal cramps watery diarrhea for 8-22 hours resolves within 24 hours note: this is the 2nd or 3rd common cause of food poisoning

What is the Dx for food poisoning Clostridium perfringens?

ELISA enterotoxin in feces or implicated food

Explain how Gas Gangrene development is dependent on location.

Myositis is in muscle Fascitis is in fascia Cellulitis is is dermis and skin

Flow chart of tests to perform if you suspect anaerobic infection…

1) Metronidazole senstive 2) Gram stain 3) + do microscopy and Nagler reaction, lactose egg yolk agar, gas liquie chromatography of fatty acid in culture of supernatants of bacteria 3) - suspect Bacteriodes, then do gas liquie chromatography of fatty acid in culture of supernatants of bacteria