1
Q
True or False? Tuberculosis is not curable, only preventable.
A
False - it is both curable and preventable
2
Q
In Canada, who is most affected by tuberculosis?
A
Canadian-born Indigenous peoples
3
Q
What is the causative organism of tuberculosis?
A
Mycobacterium tuberculosis
4
Q
How is M. tuberculosis spread? (4)
A
- Airborne via coughing or sneezing
- Host inhales droplet nuclei
- Close contacts most likely to be infected
- With prolonged contact - risk of infection can be up to 30%
5
Q
What is the morphology of M. tuberculosis?
Growing rate?
A
- Acid fast bacillus (Ziehl-Neelson stain)
- Impervious to gram-staining (can appear weakly gram +) - Slow growing (doubling time = 20 hours)
6
Q
What are the risk factors for tuberculosis? (7)
A
- Foreign born from highly endemic areas
- Canadian Indigenous people
- Close contacts
- Homelessness
- Incarceration
- Alcoholism, IVDU, malnutrition
- Co-infection with HIV-TB and HIV act synergistically
7
Q
Once infected with M. tuberculosis - lifetime risk of active TB is approximately 10%.
What are the age and immunosuppression risk factors here? (2 each)
A
- Greatest risk is during first 2 years after infection
- < 2 years old and >65 years old - 2-5x greater risk of active disease
- Immunosuppression - 4-16x risk of active disease
- HIV-infected - 100x risk of active disease
8
Q
The likelihood of a tuberculosis transmission event will depend on what 2 things?
A
- The number of infectious droplet nuclei per volume of air (infectious particle density)
- Length of time that the uninfected individual spends breathing that air
9
Q
The probability of tuberculosis transmission increases with the following: (7)
A
- Bacterial burden (smear positivity) in the source patient
- Cavitary or upper lung-zone disease on chest radiograph in the source patient
- Laryngeal disease in the source patient
- Amount and severity of cough in the source patient
- Duration of exposure of the contact
- Crowding and poor room ventillation
- Delays in diagnosis and/or effective treatment of the source patient
10
Q
What is the pathophysiology of tuberculosis? (more like, what is the immune response?) (4)
A
- Controlling infection requires T-lymphocyte response - mainly CD4+ cells
- T-lymphocytes activate macrophages that engulf and kill mycobacterium
- TNF-alpha and TNF-gamma are important cytokines in coordinating immune response
- Organism has many mechanisms for evading host immune response
11
Q
Primary infection of tuberculosis occurs by inhalation of droplet nuceli which reach alveoli. Progression to clinical disease depends on: (3)
A
- Infecting dose (# of organisms inhaled)
- Virulence of the organism
- Cell-mediated immune response
12
Q
Macrophages can either kill, or fail to kill the tuberculosis organism. What happens in either case?
A
- If macrophages inhibit or kill bacteria - infection is controlled
- If organism is not killed, macrophages eventually ruptures, spilling bacteria which are then phagocytized until immune response generated
13
Q
In approximately 3 weeks after infection, T-lymphocytes are presented with M. tuberculosis antigen. What happens from there? (4)
A
- T-cells become activated and secrete INF-gamma
- This stimulates macrophages to become -cidal
- Large number of -cidal macrophages surround the solid caseous tuberculosis foci
- Process of creating activated microbiocidal macrophages is called cell mediated immunity (CMI)
14
Q
During tuberculosis infection, DTH (delayed-type hypersensitivity) occurs at the same time. What is this/what’s happening? (4)
A
- This is a cytotoxic immune process that kills nonactivated immature macrophages that allow bacillary replication
- Occurs via T-lymphocytes
- Bacteria released from immature phagocytes are killed by activated macrophages
- Macrophages begin to form granulomas which contain organisms
15
Q
Once tuberculosis infection is largely under control and replication declines, what occurs next ? (4)
A
- Inflammatory response can produce tissue necrosis, calcification and lymph node enlargement
- Positive tuberculin skin test occurs when activated lymphocytes reach an adequate number and tissue hypersensitivity results
- 90% of pts have no further clinical manifestations
- 5% progressive primary disease - pneumonia with spread to meninges or other organs
16
Q
Reactivation disease (tuberculosis) occurs in about 10% of cases. What is happening here? (4)
A
- Most often in apices of the lungs (high oxygen content and poor local immunity)
- Orgnanisms within granuloma emerge and multiply extracellularly
- Caseating granulomas which liquefy and spread, producing cavities
- If untreated, destroy the lung - hypoxia, respiratory acidosis and death
17
Q
What extrapulmonary regions are most affected in tuberculosis infection? (2)
A
- Lymphatic and pleural disease are most common
- Bone (often the vertebrae), joint, genitourinary and meningeal
18
Q
What is miliary TB?
A
Massive numbers of organisms in the bloodstream causing widely disseminated TB - medical emergency
19
Q
What is the mechanism by which HIV increases the risk of tuberculosis disease?
A
As CD4+ cells multiply in response to TB, HIV multiplies within these cells and destroys them thereby depleting the cells that control TB
20
Q
What are the signs and symptoms of tuberculosis? (7)
A
- Gradual onset
- Weight loss
- Fever
- Cough
- Fatigue
- Nightsweats
- Frank hemoptysis
21
Q
With tuberculosis, people may not seek medical attention until __________ occurs. At that point, what’s already happening?
A
hemoptysis
Large cavities and large number of organisms - not looking too good for the patient
22
Q
Tuberculosis exams:
What is seen during a chest exam?
WBCs?
Chest x-ray?
A
- Chest exam - dullness to percussion, rales
- Moderated increase in WBCs - lymphocyte predominance
- CXR - nodular infiltrates (apices), cavitation
23
Q
How is TB diagnosed? (3)
A
- Mantoux test - TB skin test
- Uses purified protein derivative (PPD) - Read in 48-72 hours
- Measure the bump, not the redness
24
Q
What is done during treatment of tuberculosis? (4)
A
- Isolation to prevent spread
- Drugs to cure
- Adherence - DOT: directly observed therapy
- Identification of contacts
25
___________ therapy is required for active TB
Combination
26
TB has 3 subpopulations of microorganisms with different susceptibility to drugs. What are these 3 subpopulations?
1. Extracelluar - rapidly dividing; within cavities
2. Within granulomas; semidominant with occasional bursts of metabolic activity
3. Intracellular within macrophages
27
For the extracellular subpopulation of TB microorganism, what are the best drugs to treat? (3)
1. Isoniazid (INH)
2. Rifampin
3. Streptomycin
28
For the 'within granulomas' subpopulation of TB microorganism, what are the best drugs to treat? (3)
1. Pyrazinamide best drug
2. Rifampin
3. Isoniazid
29
For the 'intracellular within macrophages' subpopulation of TB microorganism, what are the best drugs to treat? (3)
1. Rifampin
2. Isoniazid
3. Quinolones
30
Treatment of latent TB infection reduces lifetime risk from __% to _%
10; 1
31
What are the drug treatments of latent TB infection? For how long? (2)
1. Rifampin daily x 4 months (4R)
2. Rifapentine and INH once weekly x 3 months (3HP)
32
If unable to use a rifamycin based regimen for treatment of latent TB infection, what then, is used? (2)
1. INH daily for 9 months (9H)
2. When 9H cannot be used - 6 month daily INH (6H)
33
Treatment of active TB infection - 2 main drugs are _________ and ________ - used together whenever possible
isoniazid; rifampin
34
What is standard treatment of active TB infection? (Know the drugs involved (4) and the timeline)
Isoniazid, rifampin, pyrazinamide and ethambutol for 2 months followed by INH and RMP for 4 months - 6 months total
35
Treatment of active TB infection - if sensitive to INH and RMP, what can be done?
Ethambutol can be stopped at any time
36
Treatment of active TB infection - without pyrazinamide, how long is treatment?
A total of 9 months of RMP and INH required
37
What is the intensive phase of active TB infection?
3-4 effective drugs given daily for 2 months
38
What is the continuation phase of active TB infection?
Minimum of 2 effective drugs; daily dosing is preferred but option of intermittent (thrice weekly) therapy with DOT
- Thrice weekly not recommended for HIV-positive patients
39
When INH and RMP cannot be used, treatment duration of active TB infection becomes:
2 years or more
40
What is MDR-TB?
Multidrug resistant TB - resistant to at least INH and RMP
41
What is XDR-TB?
Extensively drug-resistant - resistance to 2nd line drugs (including quinolones and injectables)
42
What is the MOA of isoniazid (INH)?
Inhibit bacterial wall synthesis
- Powerful early bactericidal activity
43
How should isoniazid and rifampin be taken?
On an empty stomach
44
What does speed of acetylation (genetics) determine when using isoniazid?
Slow acetylators = higher risk of neurotoxicity
45
What are 5 side effects of isoniazid?
1. Hepatotoxicity (1%)
2. Neurotoxicity - peripheral neuropathy
3. GI
4. Rash
5. Hematologic
46
What are the DIs seen with isoniazid? (6)
Inhibits metabolism of:
1. Phenytoin
2. Carbamazepine
3. Primidone
4. Warfarin
5. Acetaminophen
6. Valproic acid
47
What is the MOA of rifampin (RMP)?
Inhibits bacterial RNA synthesis by binding to the beta subunit of DNA-dependent RNA polymerase, blocking RNA transcription
48
What are the side effects of rifampin? (9)
1. Elevation in liver enzymes (10-15%)
2. Hepatotoxicity (<1%)
3. Fever
4. GI
5. Colors body-secretions orange-red*
6. Allergic reaction - especially with intermittent dosing
7. Flu-like symptoms
8. Hemolytic anemia
9. Acute renal failure
49
Rifampin is a potent ________ of CYP___
inducer; 3A4
50
What are some DIs of rifampin? (4)
1. Methadone
2. Warfarin
3. Phenytoin
4. Oral contraceptives
(A lot more, but not listed)
51
What is the main benefit of rifabutin?
When is it preferred?
1. Fewer DIs than rifampin
2. Preferred with some antiretrovirals and immunosuppressives (solid organ transplant)
52
What are 2 common side effects of rifabutin?
1. Arthralgia
2. Myalgia
53
What are the less common side effects of rifabutin? (5)
1. Uveitis
2. Hepatotoxicity
3. Neutropenia
4. Thrombocytopenia
5. Rash
54
What is the major difference between rifapentine and rifampin?
Rifapentine has a longer half-life
55
What are the side effects of rifapentine? (5)
1. Rash
2. Hematologic
3. Arthralgias
4. Increased liver enzymes
5. More hypersensitivity reactions
56
The main benefit of pyrazinamide in TB treatment is? (2)
1. When used in first 2 months, shortens duration of therapy to 6 months
2. Significant sterilizing activity
57
What are the side effects of pyrazinamide? (4)
1. GI
2. Arthralgias
3. Increased uric acid
4. Hepatotoxicity - major SE and dose-related
58
What is the purpose of ethambutol in TB treatment?
Generally bacteriostatic; prevents drug resistance
59
What are the side effects of ethambutol? (2)
1. GI - avoid concurrent antacids
2. Retrobulbar neuritis - decreased visual acuity, or inability to see green, or both
- Need eye exams
60
When are fluoroquinolones used in TB treatment?
Alternatives when a first-line agent has to be ds/c
61
What are the common side effects of fluoroquinolones? (5)
1. Nausea
2. Headache
3. Diarrhea
4. Dizziness
5. Insomnia
62
What are the serious side effects of fluoroquinolones? (3)
1. Tendinopathy
2. QT prolongation
3. Blood glucose alterations
63
What are the 2nd line agents used in TB treatment? (6)
1. Streptomycin
2. P-aminosalicylic acid
3. Cycloserine
4. Ethionamide
5. Clofazamine
6. Quinolones
64
BCG vaccine for TB. Yay or nay?
Nay for the most part. Not routinely given in Canada with some exceptions
65
The primary benefit of the BCG vaccine for TB is?
Prevention of severe forms of TB in children
66
In terms of division of scope, what is the TB pharmacist doing? (4)
1. TB meds + relevant adverse effect management
2. Check interactions
3. Efficacy
4. Safety
67
In terms of division of scope, what is the community pharmacist doing? (2)
1. Directly Observed Therapy (DOT) or self-administered therapy (SAT)
2. Manage NEW interactions (Rx and OTC) and report
68
Drug interactions with rifamycins:
How to manage interaction between hormone therapy (contraception) and rifamycins?
Add a barrier method of contraception
69
Drug interactions with rifamycins:
How to manage interaction between levothyroxine and rifampin?
Monitor TSH; may require levothyroxine dose increase
70
Drug interactions with rifamycins:
How to manage interaction between SSRIs and rifampin?
Moderate risk of interaction; may require SSRI dose increase
71
Drug interactions with rifamycins:
How to manage interaction between corticosteroids and rifamycins?
Monitor clinically; may require a 2-3 fold corticosteroid dose increase
72
Drug interactions with rifamycins:
How to manage interaction between novel oral anticoagulants (-xabans) and rifampin?
Some combos contraindicated; check individual monographs
73
Drug interactions with rifamycins:
How to manage interaction between warfarin and rifamycins?
Monitor prothrombin time (INR); may require 2-3 fold warfarin dose increase
74
Drug interactions with rifamycins:
How to manage interaction between methadone and rifamycins?
May require methadone dose increase, rifabutin rarely implicated
75
Drug interactions with rifamycins:
How to manage interaction between anticonvulsants (phenytoin and lamotrigine) and rifamycins?
May require anticonvulsant dose increase
76
Drug interactions with rifamycins:
How to manage interaction between antiretrovirals (ARVs) and rifamycins?
Complex; Rifabutin usually preferred drug with ARVs
77
What is patient monitored for initially when beginning TB treatment? (5)
1. Physical exam
2. Weight
3. Visual acuity
4. Color vision testing
5. Chest X-ray
78
What baseline labs are taken for patient monitoring of TB treatment? (7)
1. CBC
2. ALT/AST
3. Bilirubin
4. Creatinine
5. HIV serology
6. Hep C virus serology
7. HbA1C
79
The most important patient monitoring parameter of TB treatment is?
Adherence - DOT
80
How often should sputum smears be done in TB patient? For how long?
1. For efficacy - sputum smears every 1-2 weeks until 2 consecutive negatives; should occur by the end of 2 months
2. Monthly sputum cultures until 2 consecutive negatives; should occur in 2-3 months
