Toxigenic Bacteria

Question 1

Diphtheria toxin as most important virulence factor

Answer 1

• Toxin affects heart, peripheral nerves, and kidneys
• Disease caused by strains that release diphtheria toxin
• Abs cannot reverse effects of toxin
• Erythromycin helps eradicate organism and prevent transmission but does not stop disease in vivo
• Must give antitoxin early to prevent disease from progressing

Question 2

Diphtheria toxin in prevention of diphtheria

Answer 2

• Toxin given as a vaccine along with tetanus in DTap or Tdap vaccine
  
  • Made from purified toxin treated with formaldehyde, which destroys toxicity but not immunogenicity
• Antitoxin from horse Abs is necessary for treatment of active diphtheria and must be given ASAP
• > 4 days before antitoxin - death rate as high as in untreated patients (20%)
• Must get antitoxin from state health dept or CDC

Question 3

Safety & efficacy of DTap/Tdap vaccines

Answer 3

• Diphtheria vaccine = safe and effective
• Whole cell pertussis vaccine (no longer used):
  
  • Series of nasty side effects
  • Including neurological sequelae, death
• Acellular pertissus vaccines (aP)
  
  • Less likely to provoke adverse events

Question 4

20 year old with all childhood DPT vaccines but none since - what amount of disease would they develop?

Answer 4

• Would probably be somewhat protected but still get a mild case of the disease, as immunity wanes
• This is why aP is included with DT vaccine recommended every 10 years
• Bigger issue may be transmission of mild disease to immunocompromised individuals like infants
• Diphtheria is rare in US, so chance of encountering infected individual is miniscule

Question 5

MOA of diphtheria and pertussis vaccines protection against disease

Answer 5

• Diphtheria:
  
  • Toxoid made from purified toxin treated with formaldehyde
  • Conveys immunogenicity to recipient without toxicity
  • Host makes anti-toxin Ab
• Pertussis:
  
  • Merthiolate, heat, or formalin-killed cells from fully virulent B. pertussis used
  • Host makes Ab to many of the toxins

Question 6

Other virulence factors of B. pertussis

Answer 6

• Pertussis toxin:
  
  • A portion transferse ADP-ribose of NAD onto inhibitory subunit of adenylyl cyclase –> constitutive activation –> increased cAMP
  • Cholera toxin is similar, but stimulates S subunit of adenylyl cyclase
• Tracheal cytotoxin:
  
  • Activates iNOS in nearby cell that kills off cilia (hence coughing)
  • Part of murein cell wall
• Adenylyl cyclase toxin
  
  • Adverse effect on trafficking of macrophages
• Filamentous hemagglutinin (FHA)
  
  • Role in attachment to ciliated respiratory epithelial cells

Question 7

Problems encountered in making lab/clinical diagnosis of Diphtheria/Pertussis

Answer 7

• Both are slow-growing
• Don’t wait for diphtheria diagnosis - give antitoxin based on clinical suspicion (wet mouse smell) before lab results
• Antimicrobials given early in stage of whooping cough can ameliorate disease

Question 8

Wait for lab diagnosis of diphtheria/pertussis before treating?

Answer 8

• NO
• Patient may die if they have diphtheria
• And better outcomes if erythryomycin is given in catarrhal stage of pertussis

Question 9

Environmental factors influencing expression of C. diphtheriae and B. pertussis toxins

Answer 9

• Diphtheria toxin:
  
  • Regulated by iron
  • Increase in iron in environment will shut off toxin synthesis
• Pertussis toxin:
  
  • Virulence regulated by genes in a locus called vir
  • Vir is master regulator that can swithc on and off expression of virulence factors
  • On-off switch of vir locus (phase variation) + environmental factors (modulation) control expression of virulence factors

Question 10

Value of abx usage in diphtheria/pertussis

Answer 10

• Even though major manifestations are due to toxins, treatment with abx:
  
  • Can eliminate carriage and subsequent transmission
  • Can reduce bacterial load producing toxins (may reduce severity of disease)
  • Are critical prophylactic treatment for contacts
• Give erythromycin (B. pertussis is suceptible to penicillin but it can’t reach the site of infection)

Question 11

People who should not be vaccinated with whole cell pertussis vaccine

Answer 11

• Whole cell pertussis vaccine no longer available
• Likely contraindicated for those with compromised immune systems or who had previously had a serious adverse event (e.g. seizure)
• Acellular vaccine probably less efficacious, but has been shown to have fewer adverse side effects and is safer for all ages