Clostridia

Clostridia species comprise a group of spore-forming, obligate anaerobic, gram-positive bacilli. Major pathogenic species include Clostridium perfringens (C. perfringens), which is associated with gas gangrene; Clostridioides difficile, which is associated with pseudomembranous colitis; C. tetani, which causes tetanus; and C. botulinum, which causes botulism. Clostridium perfringens (C. perfringens), Clostridioides difficile, C. tetani, and C. botulinum have broad-spectrum invasiveness and clinical manifestations that are summarized below. Note that Clostridium difficile has been reclassified as Clostridioides difficile. However, exams will likely not have the updated genus for several years.

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Classification

Gram-positive bacteria:
Most bacteria can be classified according to a lab procedure called Gram staining.
Bacteria with cell walls that have a thick layer of peptidoglycan retain the crystal violet stain utilized in Gram staining but are not affected by the safranin counterstain. These bacteria appear as purple-blue on the stain, making them gram positive. The bacteria can be further classified according to morphology (branching filaments, bacilli, and cocci in clusters or chains) and their ability to grow in the presence of oxygen (aerobic versus anaerobic). The cocci can also be further identified. Staphylococci can be narrowed down based on the presence of the enzyme coagulase and on their sensitivity to the antibiotic novobiocin. Streptococci are grown on blood agar and classified based on which form of hemolysis they employ (a, b, or g). Streptococci are further narrowed based on their response to the pyrrolidonyl-β-naphthylamide (PYR) test, their sensitivity to specific antimicrobials (optochin and bacitracin), and their ability to grow on sodium chloride (NaCl) media.

Image by Lecturio.

General Characteristics

Basic features of Clostridium species

  • Gram-positive bacilli
  • Spore-forming organisms
  • Obligate anaerobes
  • Habitat:
    • Soil, fresh water, marine sediments
    • Intestinal tract of humans and animals
    • Cervical-vaginal flora
    • Spores can be airborne.
  • Pathogenesis:
    • Infection can be exogenous (from outside) or endogenous.
    • Cause disease by exotoxins or enterotoxin production

A cartoon showing the general structure of the gram-positive Clostridia bacteria

Image by Lecturio.

Pathogenic species

  • C. perfringens (20%–40% of all isolates)
  • Clostridioides difficile
  • C. tetani
  • C. botulinum
Table: Compare and contrast Clostridia species
C. botulinumClostridioides difficile C. perfringensC. tetani
Habitat
  • Soil 
  • Marine sediments
  • Intestinal flora
  • Soil 
  • Intestinal flora
  • Soil 
  • Intestinal flora
Virulence
  • Botulinum toxin
  • Enterotoxin A
  • Toxin B
  • Alpha toxin
  • Enterotoxin
  • Tetanus toxin (tetanospasmin)
TransmissionIngestion of:
  • Spores
  • Preformed toxin
Via spores:
  • Nosocomial infection (poor handwashing)
  • Opportunistic intestinal flora
Via spores:
  • Traumatic wounds
  • Food ingestion
Via spores:
  • Traumatic wounds
  • Umbilical cord contamination during delivery
Clinical presentation
  • Flaccid paralysis
  • Botulism
  • Infants: floppy baby syndrome
  • Nosocomial diarrhea
  • Pseudomembranous colitis
  • Food poisoning
  • Localized cellulitis
  • Clostridium myonecrosis
  • Spastic paralysis
  • Trismus
  • Risus sardonicus
  • Opisthotonos
  • Neonatal tetanus

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Clostridium botulinum

Epidemiology

  • Foodborne botulism:
    • In the United States, most common in Alaskan Natives (via ingestion of aged fish)
    • Overall national rate is 0.0068 per 100,000
  • Infant botulism:
    • Ingestion of spores:
      • From raw honey
      • From environmental dust
    • Highest incidence in Utah, Pennsylvania, and California
  • Wound botulism: in injection drug users

Transmission

  • Adults ingest preformed toxin from food
    • Associated with improper canning
    • Sometimes from fermented beverages (e.g., moonshine)
  • Infants ingest spores: toxin then produced in vivo
  • Wound botulism:
    • Wound contamination with spores
    • Germination and toxin production in vivo

Pathogenesis

  • Botulism is a potentially life-threatening neuroparalytic disease.
  • Botulinum neurotoxin:
    • Protease that cleaves soluble N-ethylmaleimide sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) proteins
    • Inhibits release of stimulatory acetylcholine (ACh)
    • Causes depletion of ACh in neuromuscular junctions
    • Results in flaccid paralysis

Pathophysiological mechanism caused by Clostridium botulinum
Introducing the pathogen with its toxin causes hyperexcitation since part of the toxin blocks the motor end-plate from releasing its neurotransmitters into the synapse

Image by Lecturio.

Clinical presentation

Adults:

  • Prodromal symptoms: 
    • Nausea/vomiting
    • Abdominal pain
    • Diarrhea
    • Dry mouth
    • Sore throat
  • Early symptoms:
    • Diplopia
    • Ptosis
    • Dysphagia
  • Descending, flaccid paralysis
  • Severity may vary.

Infants (floppy baby syndrome):

  • Hypotonia
  • Feeding difficulties
  • Weak cry
  • Drooling
  • Irritability

Six-week-old infant with botulism
Marked loss of muscle tone, especially in the region of the head and neck

Image: “PMC3223485_eplasty11e47_fig5” by Chopra K, Conde-Green A, Folstein MK, Knepp EK, Christy MR, & Singh DP. License: CC BY 2.0.

Identification

  • Toxin identification from:
    • Serum
    • Stool
    • Vomitus
    • Food
  • Enzyme-linked immunosorbent assay (ELISA) test
  • Mouse bioassay
  • Quantitative polymerase chain reaction (PCR): detects toxin genes in the organism

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Clostridium (Clostridioides) difficile

Epidemiology

  • Most common cause of antibiotic-induced colitis (especially associated with clindamycin)
  • Carrier rate:
    • In healthy adults: 3%
    • In hospitalized/institutionalized adults: 8%–10%
  • New exposures more likely to result in symptomatic disease

Transmission

  • Fecal-oral spore transmission
  • Spores transmitted from person to person (poor handwashing)

Pathogenesis

  • Produces 2 potent exotoxins
  • Inactivate Ras homologous (Rho) guanosine triphosphate (GTP) enzymes (GTPases):
    • Enterotoxin A:
      • Targets brush border enzymes
      • Alters fluid secretion
      • Causes watery diarrhea
    • Toxin B (10 times more potent):
      • Depolymerizes actin 
      • Disrupts cytoskeleton of enterocytes
      • Causes pseudomembranous colitis
  • Dipicolinic acid in spore core: highly resistant to heat and chemicals

Clinical presentation

Pseudomembranous colitis:

  • Abdominal pain
  • Profuse watery diarrhea (may occasionally be bloody)
  • Leukocytosis
  • Associated with recent antibiotic use

Pathologic specimen showing pseudomembranous colitis

Image: “Pseudomembranous colitis” by the pathologist at work. License: Public domain.

Identification

  • Toxin antigen detection in stool
  • PCR for Clostridioides difficile deoxyribonucleic acid (DNA)

Clostridium perfringens

Epidemiology

  • Food poisoning:
    • 2nd most common cause of foodborne illness
    • Estimated 1 million cases each year in the United States
  • Soft-tissue infections:
    • 30%–80% of open wounds are contaminated with Clostridium species.
    • 80% of traumatic gas gangrene cases
    • Spontaneous gas gangrene is usually caused by another species: C. septicum.

Transmission

  • Spores in the soil: wound contamination
  • Spores in reheated meats: food poisoning

Pathogenesis

Myonecrosis (gas gangrene):

  • Alpha toxin:
    • Hemolytic toxin; essential for disease manifestations and mortality
    • Has phospholipase C and sphingomyelinase activity
    • Degrades tissue and cell membranes
    • Causes small vessel thrombosis and tissue ischemia
    • Ischemia creates anaerobic environment → further propagation of C. perfringens
    • Also depresses cardiac output and contributes to systemic shock
  • Theta toxin (perfringolysin O):
    • Pore-forming cytolysin
    • Cytotoxic to vascular and immune cells 
    • Not essential for mortality

Food poisoning:

  • Caused by type A strains
  • Spores survive cooking temperatures and propagate in improperly stored foods.
  • Enterotoxin:
    • Disrupts ion transport in the ileum
    • Results in watery diarrhea

Clinical presentation

  • Foodborne illness:
    • Slow-onset watery diarrhea with abdominal cramping
    • Vomiting and fever are uncommon.
    • 12–24 hours after food consumption
    • Self-limiting, resolves in 1–3 days
  • Myonecrosis:
    • Severe pain 
    • Tissue crepitus (from gas formation)
    • Edema, blisters, and bullae
    • Purplish skin discoloration
    • Fever, change in mental status

Gas gangrene of the right leg and pelvis

Image: “Gas gangrene” by Engelbert Schröpfer, Stephan Rauthe, and Thomas Meyer. License: CC BY 2.0.

Identification

  • Gram stain and culture of the tissues/blister fluid
  • Blood cultures
  • Stool cultures for foodborne illness
  • Distinctive growth characteristics:
    • Egg yolk agar: forms a cloudy zone
    • Catalase negative
    • Oxidase negative
    • Double zone of hemolysis on blood agar
    • Non-motile
    • Encapsulated

Clostridium tetani

Epidemiology

  • Causes tetanus: a nervous system disorder
  • Very rare in resource-rich countries due to widespread vaccination
  • Remains endemic in resource-limited countries

Transmission

  • Via spores
  • Associated with skin puncture wounds:
    • Rusty nails
    • Barbed wire
    • Construction workers
  • Will not grow in healthy tissues
  • Predisposing factors:
    • Localized ischemia
    • Devitalized tissue
    • Foreign body
    • Co-infection with other bacteria 

Pathogenesis

  • Average incubation period: 8 days
  • Retrograde transport of toxin to the central nervous system (CNS)
  • Tetanus toxin or tetanospasmin (A/B toxin):
    • Protease that cleaves the SNARE protein
    • Blocks exocytosis of inhibitory neurotransmitters (gamma-aminobutyric acid (GABA) and glycine) from Renshaw cells in the spinal cord
    • Causes accumulation of ACh
    • Results in spastic paralysis

Pathophysiological mechanism caused by Clostridium tetani
Tetanospasmin blocks the binding of neurotransmitters (GABA/glycine) to their receptors on the postsynaptic membrane; thus, inhibitory neurotransmission

Image by Lecturio.

Clinical presentation

  • Generalized:
    • Spastic paralysis
    • Risus sardonicus 
    • Trismus (lockjaw)
    • Opisthotonus 
  • Local:
    • Only 1 extremity or part of the body involved
    • Often progresses to generalized
  • Cephalic:
    • Predominant involvement of cranial nerves
    • May progress to generalized
  • Neonatal:
    • Results from contamination of the umbilical cord at delivery
    • Rare in developed countries

Risus sardonicus in a patient with generalized tetanus

Image: “PMC4946959_cureus-0008-000000000644-i01” by Zunga PM, Tarfarosh SF, Farooq O, Dar IH, Rashid S, & Yaseen U. License: CC BY 3.0.

Identification

  • Grows at neutral or alkaline pH
  • On different anaerobic media:
    • Thioglycolate
    • Casein hydrolysate
    • Blood agar

Prevention

  • Toxoid vaccine
  • For clean wounds, give vaccine:
    • If < 3 previous doses 
    • If last dose > 10 years ago
  • For contaminated wounds:
    • Give vaccine if last dose > 5 years ago.
    • Give human tetanus immune globulin if < 3 doses of toxoid vaccine.

References

  1. Brooke I. (1988). Clostridium species (Clostridium perfringens, C. butyricum, C. clostridioforme, C. innocuum, C. ramosum, C. septicum, C. sordellii, C. tertium). http://antimicrobe.org/b90.asp
  2. Knapp, S. (2020). Clostridium botulinum. https://biologydictionary.net/clostridium-botulinum/ 
  3. Lamont J.T., Kelly C.P., Bakken J.S. (2020). Clostridioides (formerly Clostridium) difficile infection in adults: Clinical manifestations and diagnosis. UpToDate. Retrieved December 25, 2020, from https://www.uptodate.com/contents/clostridioides-formerly-clostridium-difficile-infection-in-adults-clinical-manifestations-and-diagnosis?search=clostridium%20difficile&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2 
  4. LaRocque R., & Harris J.B. (2019). Causes of acute infectious diarrhea and other foodborne illnesses in resource-rich settings. UpToDate. Retrieved December 23, 2020, from https://www.uptodate.com/contents/causes-of-acute-infectious-diarrhea-and-other-foodborne-illnesses-in-resource-rich-settings?search=clostridium%20perfringens&source=search_result&selectedTitle=2~40&usage_type=default&display_rank=2
  5. Pegram P.S., & Stone S.M. (2020). Botulism. UpToDate. Retrieved December 25, 2020, from https://www.uptodate.com/contents/botulism?search=botulism&source=search_result&selectedTitle=1~68&usage_type=default&display_rank=1
  6. Sexton D.J., & Thwaites L. (2020). Tetanus. UpToDate. Retrieved December 25, 2020, from https://www.uptodate.com/contents/tetanus?search=tetanus&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H16
  7. Stevens D.L, & Bryant A. (2020). Clostridial myonecrosis. UpToDate. Retrieved December 23, 2020, from https://www.uptodate.com/contents/clostridial-myonecrosis?search=clostridium%20perfringens&source=search_result&selectedTitle=1~40&usage_type=default&display_rank=1

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