Corynebacterium diphtheriae

Background

History

• Derived from the Greek word for leather

Microbiology

• 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

Pathophysiology

• Contains a polypeptide exotoxin that is cleaved into segment A, the active segment, and B, which binds receptors on susceptible cells (heparin-binding epidermal growth factor receptor)
• Segment A enters the cytosol after B binds, and inactivates mammalian tRNA translocase (elongation factor 2), which stops protein synthesis
  • Affects all cells, but heart, nerves, and kidneys are particularly sensitive
• In the respiratory tract, causes the formation of a necrotic coagulum of fibrin, WBCs, RBCs, and epithelial cells
  • Appears clinically as a pseudomembrane

Epidemiology

• 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

Diphtheria

• Clinical syndrome of pharyngeal infection with systemic toxicity caused by C. diphtheriae and C. ulcerans

Clinical Manifestations

• 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

Myocarditis

• 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

Neurotoxicity

• 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
  • Generally fully resolves with time

Tubular necrosis

• Caused by both the toxin itself and the septic shock

Differential Diagnosis

• Infectious mononucleosis
• Streptococcal or viral pharyngitis
• Vincent angina
• Acute epiglottitis

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
• Can confirm with culture and Gram stain ("Chinese characters")
• PCR for the toxin gene exists

Management

• Treat presumptively while awaiting confirmation of the diagnosis
• Start with with diphtheria antitoxin (DAT)
  • Antiserum made in horses
  • 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
• Adults
  • Penicillin G 600,000 units IM q12h
  • Pencillin V 250 mg
  • Erythromycin 500 mg qid
  • Duration 14 days
• Culture 2 weeks after treatment for test-of-cure

Infection Control

• Must be in isolation throughout therapy and until two negative cultures at 24 hour intervals

Complications and Prognosis

• Suffocation from aspiration of the pseudomembrane
• Rarely, bacteremia, endocarditis, and arthritis from hematogenous spread
• Mortality 3-12% even now, usually from asphyxiation or myocarditis, but is rare in immunized patients

Cutaneous Diphteria

• Can also cause chronic non-healing ulcers with dirty-gray membrane, often with concommitant Staph. aureus or group A streptococci
• Generally not invasive and can cause immunity, but also contribute to the organism's reservoir

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
• Should be treated to prevent infection with benzathine penicillin G 600,000 to 1,200,000 units IM once

Prophylaxis

• Healthcare workers, close contacts, etc. regardless of immunization status
• Collect culture specimens before treatment (for public health tracing)
• Treated to prevent infection with benzathine penicillin G 600,000 to 1,200,000 units IM once
• Immunize if not immunized