Toxigenic Bacteria Flashcards
Primary site of infection for Corynebacterium diphtheriae? For Bordatella Pertussis?
Both have primary infection site in upper respiratory tract
What is the evidence that diphtheria toxin is the most important virulence determinant of the organism?
Diphtheria toxin is THE cause of the manifestations of diphtheria infection. There are other properties of this organism that allow it to grow in mucous membranes in upper respiratory tract (e.g. pili), but they are not well characterized and are not responsible for the potentially fatal properties of the organism.
Here’s the big evidence: the toxin attacks the heart, peripheral nerves and the kidneys while the organism is restricted to the upper respiratory tract or skin: it does NOT invade beyond the URT. Furthermore, just one molecule of toxin is sufficient to kill one eukaryotic cell.
Need more evidence? If you have anti-toxin in your blood, you are protected
How is the toxin used in the prevention of diphtheria? Why should antibiotics NOT be used as the ONLY therapeutic agent for diphtheria
The diphtheria toxin is the antigen of interest – establishing antibodies to this toxin prior to any diphtheria infection is what confers immunity. Thus, the vaccine against diphtheria is comprised of a toxoid (a non-toxic derivative) of the diphtheria toxin. Diphtheria toxoid is made from purified toxin that has been treated with formaldehyde. This process destroys the toxicity of this toxin, but not its immunogenicity (the ability to induce an immune response).
Horse antitoxin is given to all patients clinically diagnosed as having diphtheria. If a patient is allergic to horse products then he or she must be desensitized. Antitoxin made from human antibodies is not available. If more than 4 days pass between the time of disease onset and administration of antitoxin the death rate (~20%) is as high as in untreated patients. This is why the antitoxin cannot always prevent mortality, and why you must GIVE ANTITOXIN IMMEDIATELY upon suspecting diphtheria infection!
Anyone who has had close contact with someone diagnosed as having diphtheria should be vaccinated and given antibiotics. If a contact is clinically suspected of having Diphtheria then he/she should also be given diphtheria antitoxin.
How safe/effective are current vaccines against diphtheria and whooping cough?
Vaccines against Diphtheria and Pertussis come in a trivalent format that also includes Tetanus. The diphtheria toxoid and the tetanus toxoid portion part of the vaccine are about the most perfect vaccines that have been ever made. However, previous vaccines against pertussis, which used whole-cell merthiolate-killed virulent pertussis organisms, caused some major problems. Concerns about the safety of whole-cell pertussis vaccines prompted development of acellular vaccines (aP) that are less likely to provoke adverse events because they contain only purified antigenic components of Bordetella pertussis.
Three Diphtheria and Tetanus toxoids and acellular Pertussis (DTaP) vaccines (ACEL-IMUNE®, Tripedia®, and Infanrix) have now been licensed. They are safe and effectives. Also available is a DTaP vaccine that includes Haemophilus influenzae tybe b vaccine, and one that has DTaP in combination with H. influenzae and polio.
How do the vaccines protect against diphtheria and whooping cough?
Diphtheria – make antibodies against diphtheria toxin = neutralize the toxin before it can cause problems.
Pertussis – two-component acellular pertussis vaccines are more effective than monocomponent vaccines.
• Pertussis toxoid + antigenic components of the pertussis organism (filamentous hemagglutinin, fimbriae)
• The addition of pertactin increases efficacy still more
o Pertactin: outer membrane protein that promotes adhesion to tracheal epithelial cells
• This wasn’t clearly stated, but from these facts I’m assuming that the pertussis vaccine elicits both antibodies to the pertussis toxin AND a cell-mediated immune response to the organism itself.
o Makes sense since the disease is caused by both the disseminated toxin and antigenic factors on the bacteria.
What are virulence factors of C. diphtheriae and B. pertussis besides the toxin and their possible roles of disease (if known)
C. diphtheriae – pretty much just the toxin.
o There are other properties of this organism that allow it to grow in mucous membranes in upper respiratory tract (such as pili), but they are not well characterized.
B. pertussis – this bugger has lots!!
• Pertussis toxin
o Most important virulence factor
o Increases cAMP levels
Note: for Boards, pneumonic cAMP for the bugs that increase cAMP levels!
• C = Cholera
• A = Anthrax (edema factor)
• M = Monteczuma’s Revenge (ETEC, heat labile toxin)
• P = Pertussis
No, I was not clever enough to come up with that on my own. Tragic.
o Anyway, the pertussis toxin also has mitogenic activity, effects the circulation of lymphocytes, and serves as an adhesin for bacterial binding to respiratory ciliated cells.
• Filamentous hemagglutinin
o A component of the cell wall
o Mediates surface attachment of pertussis to host cells
• Pertactin
o An outer-membrane protein
o Mediates surface attachment of pertussis to host cells
• Fimbriae
o Bacterial appendages that play a role in bacterial attachment
o These are the major antigens against which agglutinating antibodies are directed
• Tracheal cytotoxin
o Causes respiratory epithelial damage
• Adenylate cyclase toxin
o Impairs host immune-cell function
o Also increases cAMP levels (by inhibiting Gi)
• Dermonecrotic toxin
o May contribute to respiratory mucosal damage
• Lipooligosaccharide (similar to other gram-negative bacterial endotoxins)
Should physician always wait for lab diagnosis before treating diphtheria/pertussis? Why/why not?
No- diphtheria is severe and it takes at least >5 days to get laboratory diagnosis, so it is usually made clinically.
- Treatment administered before final laboratory diagnosis is made (i.e. toxin testing)–antibodies can’t reverse effects of toxin once bound to eukaryotic cell receptor of the toxin, so the sooner unbound toxin is neutralized the less likely it is to cause damage
What environmental factors, if any, influence the expression of the virulence factors of C. diphtheriae and B. pertussis?
- many virulence factors not always expressed-tight regulation and expressed under very specific environmental conditions
Diphtheria: none besides toxin have been identified for C diphtheriae. Toxin primarily affects heart, kidneys, and peripheral nerves
Pertussis:
- tracheal cytotoxin destroys ciliated epithelial cells in upper respiratory tract. Part of murein cell wall called peptidoglycan and not a protein
- Adenyl cyclase toxin–adverse effects on macrophage trafficking
- Filamentous Hemagglutinin (FHA)–attachment to ciliated respiratory epithelial cells
What is the value of antibiotic useage in Diphtheria and Whooping Cough when the major manifestations of these diseases are due to toxins, against which antibiotics have no effect?
The drug of choice for both organisms is erythromycin. You can also use penicillin for C. diphtheriae but not for B. pertussis.
Diphtheria: Give erythromycin to eradicate the organism (so it stops making that damn toxin!) and to prevent spread
Pertussis: The bug itself causes a lot of problems, and the only way to get it to stop making the toxin is to kill it!
o Erythromycin early in the disease (catarrhal stage) will ameliorate the disease
o Abx after the catarrhal stage can’t help
Antibiotics Summary (more eloquently stated):
o Abx can eliminate carriage and subsequent transmission of these organism
o Abx reduce the bacterial load that is producing the toxins, thereby they may reduce the severity of the disease
o Abx are critical to prophylactic treatment of persons who have been in contact with someone who has the disease
Who should NOT be vaccinated with the whole cell pertussis vaccine? What are the differences between the current pertussis vaccines (i.e. acellular) and the whole cell pertussis vaccine?
Whole-cell pertussis vaccines are no longer used in the U.S. – says so in bold on page 8 of the notes.
Whole-cell pertussis vaccines are prepared through the heating, chemical inactivation, and purification of whole B. pertussis organisms. Although effective, whole-cell pertussis vaccines are associated with adverse events: o Common: o Fever o Injection-site pain o Erythema and swelling o Irritability
Uncommon:
o Febrile seizures
o Hypotonic hyporesponsive episodes
Alleged associations with encephalopathy, sudden infant death syndrome, and autism, although not substantiated, have spawned an active anti-immunization lobby. The development of acellular pertussis vaccines, which are effective but fewer side effects, has greatly alleviated concerns about the inclusion of pertussis vaccine in the combined infant immunization series.
Although whole-cell vaccines are still used extensively in developing regions of the world, acellular pertussis vaccines are used exclusively for childhood immunization in much of the developed world. In North America, acellular pertussis vaccines for children are given as a three-dose primary series at 2, 4, and 6 months of age, with a reinforcing dose at 15–18 months of age and a booster dose at 4–6 years of age
What is purpose of vaccinating prego women with TdaP in 3rd trimester?
Want to protect babies so that they have some immunity after they are born as well as prevent the mom from passing it to her kid.
Why has whooping cough increased >10 fold in last 10 years?
Increased recognition/diagnosis of mild cases of pertussis
- the acellular vaccine used now is NOT as effective as previously used whole vaccine
- possible to have emergence of new strain of mutant Bordatella pertussis NOT covered by current vaccine
Diphtheria
Laboratory diagnosis based on isolation of C. diphtheriae and demonstration of toxin production.
- Requires special media; easy to grow but have to distinguish from nl flora
- Bram- positive bacilli often appearing with rods clubbed at 1 or both ends
Diphtheria toxigenicity tests
To establish laboratory diagnosis, have to produce Diphtheria toxin–tests usually done at state health lab or CDC in Atlanta
-Immune status of case contacts needs to be assessed and may need to treat with prophylactic antibiotics/possibly vaccinated
Pertussis
Gram-negative coccobacillus that grows VERY slow (3-5 days) on rich media
