PHAR 255 - Tuberculosis

Question 1

What is Tuberculosis?

Answer 1

Infection caused by mycobacterium tuberculosis (MTB) which is an aerobic, non-spore forming, non-motile bacilli
- Slow growing bacteria that can cause issues with timely diagnosis
- Genetic variability of the organsim worldwide

Question 2

Who Does TB Primarily Affect?

Answer 2

Anyone can get TB, Although it disproportionally impacts…
- People born outside Canada
- Inuit, first nations and metis populations (worse social conditions, overcrowding, access to care)

Question 3

Pathogenesis:

How Does TB Spread and Cause an Infection?

Answer 3

Spread person to person by airborne droplets (remain suspended in the air for several hours) → enters the upper airway mucosa and is taken up by immune cells called alveolar macrophages → The bacteria proliferates within these macrophages and causes localized infection within the lungs

Question 4

Pathogenesis:

Primary Infection can be signs of infection after exposure, mild symptoms, or asymptomatic…What occurs a few weeks after primary infection?

Answer 4

Cell-mediated processes occur:
Granuloma → wall of bacteria to prevent spreading
- Causes fibrosis, calcification, and scar rissue in lungs (this is all visible on CXR)

THEN Bacteria are either killed off, move to latency, or move to active infection

Question 5

What is it called when TB moves from the lungs to other tissues in the body?

Answer 5

Miliary TB

Question 6

Once Infected With TB What are the 3 Possible Outcomes?

Answer 6

1. Latent TB (~90%) → Have infection but is kept in dormant state by immune system and does not pass onto others (may have positive skin/blood tests or CXR evidence of stable granulomas)
2. Subclinical Infection → Disease without overt symptoms but is detectable and transmissible
3. Active TB Infection (~5%) → Have symptoms, can transmit to others

Question 7

Risk Factors For Developing Active TB

Answer 7

Immunocompromised
- Old age
- Genetics
- HIV
- Transplant
- Prolonged corticosteroid use
- Chemotherapy
- TNF antagonists
- Malnutrition
- Diabetes

Question 8

What is Active TB?

Answer 8

Bacteria erodes the airway and forms cavities (cavitating disease)
- TB bacteria proliferate within this space
- Source of transmission

Question 9

What is the Most Common Mechanism that Leads to Active TB?

Answer 9

Reactivation of latent TB
- Patients have large inoculum or are immunocomrpomised
- Granulomas containing bacteria emerge and multiply extracellularly

Question 10

Signs and Symptoms of TB

Answer 10

• Cough
• Fever
• Weight loss
• Night sweats
• Malaise
• Hemoptysis
• Dullness-percussion on chest exam
• Nodular infiltrates and cavitation on CXR

Question 11

How is TB Diagnosed?

Answer 11

Mantoux Test (TB Skin Test) → Uses purified protein derivative (PPD), intradermal and measure bump after 48-72hrs
Sputum culture and sensitivity → 3 separate samples on 3 consecutive days
Imaging → CXR
Risk Factor Assessment → Known exposure, travel, family history, country of origin, immunosuppression, etc.

Question 12

Goals of Therapy for TB

Answer 12

1. Eradicated TB infection by end of treatment duration
2. Prevent development of drug-resistant bacteria - ongoing
3. Ensure patients are adherent to treatment regimens - ongoing
4. Prevent adverse effects associated with drug therapy - ongoing

Question 13

Prevention of Transmitting TB

Answer 13

• Patients with active TB should be in private, isolated rooms (negative air pressure and adequate ventilation)
• Proper PPE for patients and HCPs (N95s)

Question 14

Treatment of TB:

Why is Multi-Drug Therapy Used in TB?

Answer 14

Treatment of Active TB Requires combination therapy (minimum 2 drugs) because patients are infected with a large number of TB bacilli and Bacterial mutations to any of the drugs can occur spontaneously
- There could be small amounts of TB developing drug resistance to each first line drug (but resistance to 2 or 3 drugs is highly unlikely, thats why we use more than one)

Question 15

Treatment of TB:

2 Phases of Drug Therapy

Answer 15

Intensive Phase → 3 or 4 drugs for 2 months, dosed daily
Continuation Phase → minimum 2 drugs used, trtmt an vary depending on drug regimen (intermittent 3x/week, directly observed therapy OR daily which is preferred)

Question 16

Treatment of TB:

What 6 Drugs Can be Used in TB Treatment?

Answer 16

1. Isoniazid (INH)
2. Pyridoxine (Vit B6)
3. Rifamycin Class (Rifampin)
4. Pyrazinamide
5. Ethambutol
6. Fluoroquinolones (moxifloxacin and levofloxacin)

Question 17

Treatment of TB:

Isoniazid (INH)

Answer 17

Cornerstone of therapy → early bactericidal activity and prevents drug resistance
MOA → inhibits bacterial wall synthesis
AEs → Asymptomatic increases in hepatic aminotransferases and bilirubin and clinical hepatitis, peripheral neuropathy (give pyridoxine to reduce)

MUST Take on Empty Stomach

Question 18

Treatment of TB:

Pyridoxine (Vitamin B6)

Answer 18

Routinely added to INH treatment for people at risk of peripheral neuropathy (some prescribers may add to all patients)
- Diabetes
- CKD
- HIV
- Malnutrition
- Seizure disorder
- Substance misuse
- Pregnant/breastfeeding

Question 19

Treatment of TB:

Rifamycin Class (Rifampin)

Answer 19

Most important First-Line TB Drug
- Good bactericidal activity and prevents drug resistance and relapse
- 6 months with rifampin, without rifampin treatment can be 12-18 months)

MOA → Inhibits RNA synthesis
AEs → Orange discolouration of body fluids, rash/uticaria

Administer on and Empty Stomach

Question 20

Treatment of TB:

Pyrazinamide

Answer 20

Provides most benefit when part of multidrug regimen in the first 2 months of therapy (intensive phase only)
- Offers minimal protection against drug resistance and relapse and no benefit in continuation phase

AEs → Hepatotoxicity, rash, acute gout, GI and hematologic effects

Question 21

Treatment of TB:

Ethambutol

Answer 21

Started for all patients in the intensive phase until drug susceptibility testing completed
- Inhibits growth (least bactericidal activity of all drugs)
- Prevents drug resistance

AEs → Optic neuropathy (decreased visual acuity/colour changes), rash, hematologic, neurologic, GI

Question 22

Treatment of TB:

Fluoroquinolones (moxifloxacin and levofloxacin)

Answer 22

Alternative meds when a patient must stop another first-line drug due to adverse effects
- core component when organism is resistant to INH or multiple drugs

Drug susceptibility testing must be completed prior to initiation

Question 23

Preferred Active TB Regimen

Answer 23

Initial Phase: Quadruple Therapy → INH, RMP, PZA, EMB daily for 2 months
Continuous Phase INH, RMP, EMB daily for 4 months

Question 24

What is Intermittent Therapy?

Answer 24

Continuation phase is give 3 times per week AND must be used in combination with Direct Observed Therapy (DOT) in order to ensure medication adherence

If the patient is not undergoing DOT and is self-administering → change to daily regimen

Question 25

Latent TB (Preventative) Treatment (aka TPT)

Answer 25

Development of active TB occurs the most in first 2 years after infection - Must rule out active TB disease before starting TPT Two Regimens: - Rifapentine + isoniazid once weekly for 3 months (DOT) - Rifampin once daily for 4 months (self-administered)

Question 26

**Drug Interactions:** Isoniazid

Answer 26

- Warfarin - Phenytoin - Carbamazepine - Acetaminophen - Valproic Acid

Question 27

**Drug Interactions:** Rifampin

Answer 27

- Potent p450 inducer - P-glycoprotein efflux transporters - Oral contraceptives - Levothyroxine - SSRIs - Corticosteroids - DOACs - Warfarin - Methadone - Antiseizure meds - HIV meds