Clostridium tetani

Microbiology and Structure

• Medical Microbiology 9e, p. 349
• Quick Compendium of Clinical Pathology 5e

Epidemiology

• Spores are ubiquitous in soil and in the feces of horses and other animals; they survive in adverse conditions for very long periods.
• C. tetani transiently colonizes the GI tracts of humans and animals without causing disease.
• Disease is rare in vaccinated populations (only ~33 cases in the US in 2017), but remains a major cause of death in developing countries, with an estimated >1 million cases worldwide and mortality rates of 30-50%.
• At least half of all tetanus deaths occur in neonates.
• Risk is greatest in people with inadequate vaccine-induced immunity; importantly, natural infection does not confer immunity.
• Medical Microbiology 9e, p. 350

Toxins

Mechanism of Action of Tetanospasmin

1. Synthesis: Tetanospasmin is produced during the stationary phase of bacterial growth and released upon cell lysis. The single 150-kDa peptide is cleaved by an endogenous protease into:
   • Heavy chain (100 kDa, B subunit) - binding and translocation
   • Light chain (50 kDa, A subunit) - enzymatic activity The two chains are held together by a disulfide bond.
2. Binding: The carboxyl-terminal domain of the heavy chain binds polysialoganglioside (sialic acid) receptors and adjacent glycoproteins on the surface of lower motor neurons at the neuromuscular junction.
3. Internalization and retrograde transport: The toxin is internalized in endosomal vesicles and transported retrograde along motor neuron axons to the motor neuron soma in the spinal cord and brainstem.
4. Transcytosis: The toxin then undergoes trans-synaptic spread to the presynaptic terminals of inhibitory interneurons (both glycinergic and GABAergic).
5. Cleavage of synaptobrevin (VAMP2): Within the inhibitory neuron, endosomal acidification causes a conformational change in the heavy chain N-terminus that inserts into the membrane, releasing the light chain into the cytosol. The light chain is a zinc endopeptidase that cleaves synaptobrevin (VAMP2), a SNARE protein required for docking of neurotransmitter vesicles onto the presynaptic membrane.
6. Result: Release of the inhibitory neurotransmitters glycine and GABA is blocked. Motor neurons lose inhibition, causing unregulated excitatory activity → spastic paralysis and uncontrolled muscle spasms.

The toxin binding is irreversible - recovery depends on the formation of new axonal terminals.

• Medical Microbiology 9e, pp. 350-351
• Jawetz, Melnick & Adelberg's Medical Microbiology 28e, p. 194

Pathogenesis

• Necrotic tissue
• Calcium salts
• Associated pyogenic infections

Clinical Forms of Tetanus

1. Generalized Tetanus (most common)

• Incubation: Days to weeks; shorter incubation = worse prognosis
• Progression: Trismus (lockjaw, masseter spasm) is the most common presenting sign → risus sardonicus (sardonic smile from sustained facial muscle contraction) → opisthotonos (persistent spasms of the back muscles)
• Any external stimulus can precipitate generalized tetanic spasm
• Autonomic involvement in severe disease: cardiac arrhythmias, fluctuating blood pressure, profound sweating, dehydration
• Patient remains fully conscious; pain can be intense
• Death is typically from respiratory failure

Risus sardonicus: facial spasm in tetanus. (From Cohen, J., Powderly, W.G., Opal, S.M., Infectious Diseases, 3rd ed.)

Opisthotonos: persistent arching of the back from back muscle spasms in a child with tetanus. (From Emond, R.T., Colour Atlas of Infectious Diseases, 3rd ed.)

2. Localized Tetanus

• Muscle rigidity confined to the site of primary infection
• Generally better prognosis

3. Cephalic Tetanus

• Primary infection site is the head (e.g., ear infection, facial wound)
• Involves short cranial motor nerves; very poor prognosis

4. Neonatal Tetanus (Tetanus neonatorum)

• Entry via infected umbilical stump (unsterile cord cutting in developing countries)
• Progresses to generalized tetanus
• Mortality >90%; developmental defects in survivors
• Almost exclusively a disease of developing countries

Diagnosis

• Microscopy and culture are insensitive (culture positive in only ~30% of cases)
• Tetanus toxin is not detectable in blood (it binds irreversibly to neurons)
• Antibodies to the toxin are also typically absent
• Differential diagnosis: strychnine poisoning (also blocks glycine receptors, clinically identical)
• Confirmatory test (reference labs only): mouse toxin neutralization assay

Treatment

Why prefer metronidazole over penicillin? Penicillin is a GABA antagonist, similar in mechanism to tetanus toxin itself, potentially worsening CNS excitability. Metronidazole avoids this issue and has equivalent antimicrobial activity.

Prevention

• Primary series: 3 doses of tetanus toxoid (as part of DTaP or Td)
• Booster: Every 10 years
• Vaccination is highly effective and the most important preventive measure
• For wound prophylaxis in unvaccinated or incompletely vaccinated individuals: both toxoid and HTIG may be given simultaneously

Summary Table