Corynebacterium diphtheriae

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Corynebacterium diphtheriae / (Redirected from Diphtheria)



  • The name diphtheria is derived from the Greek word for leather, based on the appearance of the pseudomembrane that the organism produces


  • Non-spore-forming, pleomorphic, unencapsulated, nonmotile Gram-positive bacillus with clubbed ends
  • Needs to be cultured on special media, so notify the lab
    • On Loeffler medium, outgrows other throat flora by 12 to 18 hours
  • Classic "Chinese character" appearance on Gram stain (pallisading) of all corynebacteria
  • Metachromatic granules on methylene blue
  • Four biovars: gravis, intermedius, mitis, and belfanti
    • Based on morphology, fermentation, and hemolysis, but now more often based on PCR ribotyping
    • Not clinically significant
  • Exotoxin production is provided by the tox gene
    • The gene is carried by bacteriophages, which convert non-toxigenic strains into toxigenic ones
    • Toxin production is not necessary for the life cycle


  • Toxigenic strains produce a polypeptide exotoxin that is cleaved into two segments, which comprise three domains
    • Segment B contains the receptor-binding and transmembrane domains, and facilitates binding to heparin-binding epidermal growth factor receptor
    • Segment A is the active segment, which enters the cytosol after B binds and inactivates mammalian tRNA translocase (elongation factor 2), thus stopping protein synthesis and killing the cell
      • A single molecule is enough to kill a cell
  • The exotoxin affects all cells, but heart, nerves, and kidneys are particularly sensitive
  • In the respiratory tract, exotoxin causes the formation of a necrotic coagulum of fibrin, WBCs, RBCs, and epithelial cells
    • Appears clinically as a pseudomembrane
  • The lethal dose may be as low as 100 ng/kg body weight


  • Spread by droplets and direct contact, and via fomites
  • Mostly occurs in colder months
  • Asymptomatic carriage is an important reservoir for the organism, with 3-5% carriage rates in endemic areas
    • May also be carried by horses, cattle, and domestic cats
  • Disease is rare in immunized populations
  • Risk factors include travel or residence within an epidemic or endemic setting, and a history of inadequate vaccination
    • Currently, the highest rates are seen in India, and particularly in Kerala state in people older than 10 years
  • Maternal antibodies provide immunity until about 6 months

Clinical Manifestations


  • Clinical syndrome of pharyngeal infection with systemic toxicity caused by C. diphtheriae and C. ulcerans
  • Incubation period of 2 to 4 days
  • Low-grade fever, hoarseness, pain, and laryngeal pseudomembrane that can cause stridor and obstruction
    • Pseudomembrane starts white but later dirty gray with patches of green or black
    • Bleeding if membrane is removed
    • Can have a bullneck appearance
  • Can also have serosanguineous nasal discharge and cervical lymphadenopathy
  • Palatal paralysis and cranial nerve defects may cause dysphagia
  • Systemic symptoms related to extent of local disease
  • Occurs in 10-25% of cases
  • Can range from acute heart failure and cardiogenic shock to more subacute heart failure and dilatation
    • Can be monitored with AST (?and troponin?)
  • ECG may show ST-T wave changes and first-degree heart block, which can progress to complete heart block
    • Mortality is higher with ECG changes, and highest with AV blocks and LBBB
    • Can be permanent
    • Monitor for arrhythmias
  • Acutely, can manifest as paralysis of the soft palate and posterior pharynx, causing dysphagia
    • Followed by cranial nerve defects
  • After 10 days to 3 months, can develop a peripheral motor neuropathy from demyelination
    • Typically descending paralysis by can still be confused with Guillain-Barré syndrome
    • Generally fully resolves with time
Acute Tubular Necrosis
  • Caused by both the toxin itself and the septic shock

Complications and Prognosis

  • Suffocation from aspiration of the pseudomembrane
  • Rarely, bacteremia, endocarditis, and arthritis from hematogenous spread
  • Can have post-infectious, autoimmune-mediated complications including neuropathy and carditis
  • Mortality 3-12% even now, usually from asphyxiation or myocarditis, but is rare in immunized patients

Cutaneous Diphtheria

  • Usually caused by non-toxigenic strains
  • Can also cause chronic non-healing ulcers with dirty-gray membrane (or not), often with concomitant Staphylococcus aureus or Streptococcus pyogenes
  • Generally not invasive and can cause immunity, but also contributes to the organism's reservoir

Asymptomatic Carrier State

  • C. diphtheriae not particularly invascive and can colonize the respiratory tract and skin
  • Common in areas that do not vaccinate, as well as inner cities and rural areas

Non-Toxigenic Strains

  • As well as cutaneous diphtheria, these strains can also cause bacteremia and endocarditis, particularly in those with chronic alcohol use, dental disease, and intravenous drug use

Differential Diagnosis


  • Clinical diagnosis based on:
    • Mildly painful tonsilitis or pharyngitis with a membrane, especially if the memrane extends to the uvula and soft palate
    • Adenopathy and cervical swelling, especially if assocaited with memranous pharyngitis and signs of systemic toxicity
    • Hoarseness and stridor
    • Palatal paralysis
    • Serosanguineous nasal discharge with associated mucosal membrane
    • Temperature not over 102.5ºF (39ºC)
    • History of travel to endemic country
  • Collected specimens from nose or throat, and any mucosal or cutaneous lesions
    • Ideally collected from below the pseudomembrane
    • Can also collect a piece of pseudomembrane
    • Notify lab, who will use modified Tinsdale agar or cystine-tellurite blood agar
    • Gram stain should show classic coryneform "Chinese letter" appearance, which may be dismissed as normal respiratory flora unless specific testing for diphtheria is requested
  • Culture requires Tinsdale medium (contains teluride and cysteine), inhibits non-pathogenic Corynebacterium
  • PCR for the toxin gene exists, and is followed by serology to demonstrate toxin production
  • Serology is done for tox gene positive strains using the Elek test


Pharyngeal Diphtheria

  • Supportive management, with a focus on airway protection
    • Preemptive intubation is recommended in most situations
    • May require tracheotomy if severe
    • May be useful to add carnithine to improve myocardial function
  • If concern for pharyngeal diphtheria, then need to treat presumptively with antitoxin and penicillin while awaiting confirmation of the diagnosis
  • Start with with equine-derived diphtheria antitoxin (DAT)
    • Prevents toxin from entering the cell
    • First must rule out horse protein hypersensitivity
      • History of allergy
      • Scratch test: drop of 1:1000 dilution applied to superficial scratch; if no wheal in 15 minutes, inject 0.02 mL of 1:1000 dilution intracutaneously
        • Epipen at the ready!
    • Dose depends on duration of symptoms
      • ≤48 hours: 20,000-40,000 units
      • ≥3 days: 80,000-120,000 units, including anyone with neck swelling
      • Nasopharyngeal: 40,000-80,000 units
    • Diluted in 250-500 mL NS and infused over 60-120 minutes
    • 10% risk of serum sickness
  • Also treat with a 14-day course of an appropriate antibiotic
  • Test of cure should be done at least 24 hours after completing treatment, with two cultures from both nose and throat at least 24 hours apart
    • If still positive, extend treatment for another 10 days
  • After acute illness, still need to vaccinate since infection does not generate long-term immunity

Cutaneous Diphtheria

  • Treated with a 14-day course of antibiotics, as above
  • Test of cure should be done at least 24 hours after completing treatment, with two cultures from cutaneous lesions at least 24 hours apart

Asymptomatic Carrier State

  • Should be treated to prevent transmission to others
  • Benzathine penicillin G 600,000 units (<6 years) to 1,200,000 units (≥6 years) IM once, or erythromycin 40 mg/kg/day (max 1 g) for 7 to 10 days
  • If cultures still positive after treatment, do another 10-day course of erythromycin (more effective than penicillin)


Infection Control

  • Contact precautions for cutaneous diphtheria, contact and droplet precautions for pharyngeal diphtheria
  • Must be in isolation until treatment is completed and until two negative cultures collected at least 24 hours apart


  • Indicated for healthcare workers exposed to nasopharyngeal secretions, household contacts, other habitual close contacts, people sharing utensils or kitchen facilities, and childcare workers
    • Indicated regardless of immunization status
    • Even if the contact is transient, but excludes those who were wearing appropriate PPE at the time
  • Procedure
    • Monitor for symptoms for 7 days
    • Collect culture specimens before treatment
    • Antimicrobial prophylaxis with either benzathine penicillin G 600,000 units (<30 kg) to 1,200,000 units (≥30 kg) IM once, or erythromycin 40 mg/kg/day (max 1 g) for 7 to 10 days
    • Repeat culture after treatment, and repeat a 10-day course of erythromycin if still positive (more effective than penicillin)
  • If previously vaccinated, give a Td/Tdap booster if it's been more than 5 years from last dose
  • If not fully vaccinated, complete the vaccine series


  • The available vaccine is against diphtheria toxin, so protects against the harmful effects of infection but does not directly prevent infection
    • Asymptomatic carriage still occurs, though at a lower population level
  • Diphtheria toxoid vaccine is given as a ≥3-dose series in childhood
    • Typically in combination with others (e.g. DTaP-IPV-HiB at 2, 4, 6, and 18 months)
    • Adult catch-up schedule would be Tdap followed 4 weeks later by Td followed 6 to 12 months later by another Td
  • Adults should get a Tdap booster in adulthood at least once, and Td booster every 10 years