ID - Tuberculosis

Question 1

What bacteria causes tuberculosis?

Answer 1

Mycobacterium tuberculosis (MTB)

Question 2

How is tuberculosis transmitted?

Answer 2

Inhalation of aerosolized droplet nuclei

Question 3

TB transmission depends on what factors? (4)

Answer 3

1. Living conditions
2. Immune system function
3. Exposure
4. Bacterial burden

Question 4

With TB, up to __% do not develop any active disease in their lifetime

Answer 4

90

Question 5

What is the morphology of Mycobacterium tuberculosis

Answer 5

Aerobic, non-spore forming bacillus

Question 6

What is TB primary disease?

Answer 6

In those unable to contain infection (often young children and immunocompromised individuals) progression of disease and complications may occur in 2 – 6 months

Question 7

What does latent TB infection mean? (2)

Answer 7

1. After 3-8 weeks, most immunocompetent individuals develop bacilli-specific immunity, leading lymphocytes to activate macrophages that surround the tuberculosis foci and contain the infection
2. 90% of all cases do not develop any disease, 5% may have TB reactivation

Question 8

How does TB reactivation occur? (4)

Answer 8

1. Occurs years to decades after initial infection and presents as pulmonary or extrapulmonary disease
2. MTB escapes granuloma and begins to multiply extracellularly
3. Immune response, release of cytokines and lysozymes into infected foci leads to tissue damage and necrosis
4. Foci becomes unstable, liquefies (caseous necrosis), and infection spreads

Question 9

How is TB reinfection distinct from reactivation?

Answer 9

Reinfection: repeat exposure leads to new MTB infection, distinct from reactivation
- More common in highly endemic areas, uncommon cause of active TB cases in Canada

Question 10

How does pulmonary TB (most common one) present (signs and symptoms) (4)

Answer 10

Weight loss, fatigue, fever, night sweats, hemoptysis, pleural pain, hoarseness, cough lasting longer than 2 weeks with/without blood and/or phlegm
2. Dyspnea (dyspnea requires ventilation/perfusion mismatch, but TB kills both lung and blood vessels, so dyspnea only seen in late stage of TB)
3. Patchy/nodular infiltrates in apical areas of upper lobes of lung or cavitary lesions
4. Dullness to chest percussion, rales

Question 11

What are some risk factors for TB exposure? (6)

Answer 11

1. Men 2x more than women
2. Location and place of birth (e.g., sub-Saharan Africa, India, Southeast Asia, China)
3. Recent travel to areas of high prevalence
4. Crowded conditions with poor air quality and ventilation
5. Poor access to medical care
6. Close contacts, residents and employees of high-risk congregate settings: correctional facilities, homeless shelters, some healthcare facilities (e.g., nursing homes, long-term care facilities for the elderly), residential facilities for AIDS patients

Question 12

What are some risk factors for having an active TB infection after exposure? (9)

Answer 12

1. Decreased immunity (e.g. use of immunosuppressants, chemotherapy)
2. Co-morbidities (e.g. HIV/AIDS, diabetes, hematologic/head and neck cancers, silicosis, renal disease)
3. Children < 2 and elderly > 65
4. Recent TB infection
   5.Tuberculin skin test conversion within 2 years
5. Smoker or use illicit drugs
6. Underweight
7. Heavy drinker
8. Once infected, lifetime risk of active TB is ~10% where the highest risk within first 2 years of infection

Question 13

Why does HIV/TB co-infection hold negative clinical impacts for both disease states? (2)

Answer 13

1. Declining immunity (reduced CD4) increases risk for TB progression and complications
2. TB may accelerate progression to AIDS and death

Question 14

Why does HIV lead to greater TB risk?

Answer 14

HIV leads to depletion of TB-fighting lymphocytes and macrophages, increasing immunosuppression

Question 15

What is the mantoux skin test (or tuberculin skin test) for TB diagnosis? (4)

Answer 15

1. Assists in the diagnosis of latent TB, also used as epidemiological tool
2. Tuberculin purified protein derivative is injected intracutaneously, results in 48-72 hours
3. Positive test interpreted based on size of induration or “bump/wheal” and individual risk factors
   - False negatives (e.g. very elderly, severe illness, immunocompromised)
   - False positives (e.g. BCG vaccination)
4. Interferon-gamma release assays (IGRAs) are also used to support TB diagnosis

Question 16

What drug category can cause reactivation of latent TB infection?

Answer 16

Immunosuppressants
- e.g., MABs and biologicals (e.g., TNF-alpha inhibitors, infliximab)

Question 17

What are the goals of therapy for TB? (6)

Answer 17

1. Eliminate Mycobacterium tuberculosis (MTB) infection
2. Prevent disease progression
3. Prevent complications and death
4. Reduce transmission with proper isolation precautions
5. Prevent TB reactivation
6. Prevent drug resistance by using effective combination regimen

Question 18

What are the first-line drug therapy options for latent TB infection (LTBI)? (2)

Answer 18

1. Rifampin 10 mg/kg (up to 600 mg) daily x 4 months (preferred in elderly patients)
   OR
2. Isoniazid 15 mg/kg (up to 900 mg) + rifapentine WEEKLY x 3 months
   - Rifapentine is not approved in Canada

Question 19

What is the 2nd-line drug therapy option for latent TB infection?

Answer 19

Isoniazid daily x 9 months

Question 20

What is an important thing to know about using single agents in active pulmonary TB infection?

Answer 20

Do not use a single agent to treat active TB or add single agent to failing regimen

Question 21

What are some things to know about drug therapy and pathogens/epidemiology for active pulmonary TB? (3)

Answer 21

1. Combination drug therapy with emphasis on adherence
2. Eliminate organisms and prevent development of resistant MTB
   strains
3. Important to know epidemiology of resistance to existing therapies

Question 22

What are the 2 phases of therapy for active pulmonary TB infection?

Answer 22

1. Therapy begins with initial intensive phase:
   - 2 months of intensive bactericidal therapy to rapidly eliminate the majority of organisms and prevent drug resistance
2. Then, continuation (sterilizing) phase:
   - 4-7+ months to eradicate dormant organisms and prevent relapse

Question 23

What are dose adjustments based on for active pulmonary TB infection? (2)

Answer 23

1. Based on susceptibility data (typically 1-2 month delay until available)
2. Based on patient factors (e.g. low BMI, renal disease)

Question 24

In active pulmonary TB infection ________ based regimen is standard of care

Answer 24

rifampin

Question 25

Should know the 2 drug therapy regimens for the intensive phase of active pulmonary TB infection (RIPE)

Answer 25

Intensive phase: early bactericidal action on extracellular organisms to render patient non-infective 1. INH + RMP + pyrazinamide (PZA) ± ethambutol (EMB) daily x 2 months - EMB added if isoniazid resistance ≥4% or unknown local susceptibilities, can D/C if full sensitivity shown on susceptibility results 2. INH + RMP + EMB daily x 2 months (for patients >75 years)

Question 26

What is the drug therapy for the continuation phase of active pulmonary TB infection?

Answer 26

Continuation phase: slow killing of dormant organisms to completely eradicate infection and decrease duration of treatment 1. INH + RMP daily or 3x weekly x 4-7 months

Question 27

Why might pyridoxine (vitamin B6) be used in TB therapy? (2)

Answer 27

1. Given to prevent peripheral neuropathy in high-risk populations (e.g. malnourished, substance-use disorders, diabetes, HIV infection, pregnant/breastfeeding, renal dysfunction) 2. Consider supplementation in all patients receiving INH

Question 28

In active TB infection, what is Direct Observed Therapy? (DOT) (3)

Answer 28

1. Standard of care to improve adherence and treatment completion 2. Requires clinicians/trained individuals to directly observe ingestion of medication 3. Consider specifically in high-risk populations: history of treatment failure and TB relapse, drug resistance, HIV co-infection, substance abuse, mental health disorders, individuals without a fixed address

Question 29

BCG vaccine to help prevent TB. Yay or nay?

Answer 29

Nay - The BCG vaccine is not routinely used in Canada, only 51% effective in preventing TB

Question 30

In what situation do we refer to TB expert?

Answer 30

If treatment interruption, failure/relapse, and multiple drug resistance

Question 31

What to know about active TB and HIV co-infection when it comes to drug therapy?

Answer 31

1. At least 8 months of therapy required if patient not on antiretrovirals (ARVs) 2. Rifamycins (e.g. RMP) decreases [C] of many ARVs – protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Consider using rifabutin (least potent inducer) instead of RMP - Monitor drug therapy and make dose adjustments as needed 3. Immediate (i.e. < 2 weeks after TB therapy started) initiation of ART suggested (UNLESS CNS TB, where delayed ART > 2 weeks should be used)

Question 32

What to know about treatment of active TB in pregnancy and lactation? (4)

Answer 32

1. Do not withhold therapy as the risk of untreated TB outweighs risks to newborn 2. INH + RIF + EMB → no teratogenicity 3. Pyrazinamide → less data, unlikely to be teratogenic, controversy in use 4. Avoid aminoglycosides and REFER to TB expert in drug-resistant cases

Question 33

What to know about treatment of latent TB in pregnancy and lactation? (2)

Answer 33

1. Avoid pregnancy if receiving LTBI treatment (if possible) 2. Case by case assessment if pregnant - If low risk: withhold treatment until 3 months postpartum to reduce risk of hepatotoxicity - Rifampin 4 month regimen preferred - If rifampin resistant, consider INH with monitoring for hepatoxicity - Pyridoxine supplementation recommended

Question 34

What to know about breastfeeding and the TB medications?

Answer 34

Breastfeeding is safe with INH, RMP, PZA, EMB and pyridoxine

Question 35

What are 4 main drug toxicities associated with TB treatment?

Answer 35

1. GI upset 2. Rash 3. Fever **4. Hepatitis**

Question 36

What to know about hepatitis and TB drug treatment? (5)

Answer 36

1. AST >3-5 times the normal limit 2. Stop all potential drug causes 3. Initiate LESS hepatotoxic TB drug regimen 4. Drug Risk: PZA>INH>RIF>EMB 5. Moxifloxacin, linezolid, amikacin, clofazimine, etc other options

Question 37

What are the side effects of isoniazid? (3+)

Answer 37

1. N/V, GI upset, drug-induced lupus, skin rash, mood changes, drug fever, encephalopathy, drowsiness, gynecomastia, pancreatitis, lymphadenopathy 2. Hematologic side effects, peripheral neuropathy (dose-related) 3. Hepatotoxicity: monitor carefully and educate patients on symptoms (ranges from asymptomatic liver enzyme elevations to hepatitis)

Question 38

What are the side effects of rifamycins (rifampin and rifabutin)? (4+)

Answer 38

1. GI upset, flu-like symptoms, metallic taste, myalgia, hepatotoxicity, neutropenia, leukopenia, discolouration of bodily fluids, rash (usually minor – petechial rash may suggest thrombocytopenia) 2. RMP specifically: confusion, ataxia, visual toxicity, acute interstitial nephritis **3. Major P450 enzyme inducer, monitor therapy and dose adjust** 4. Rifabutin is a less potent inducer than RMP (use in patients on PIs/NNRTIs)

Question 39

What are the side effects of pyrazinamide? (3+)

Answer 39

1. Hepatotoxicity (rare if only using for 2 months) 2. GI upset, polyarthralgia (common), hyperuricemia (usually asymptomatic), drug fever 3. Hematologic (e.g. thrombocytopenia, leukopenia)

Question 40

What are the side effects of ethambutol?

Answer 40

GI upset, headache, dizziness, confusion, hallucinations, rash (SJS/TENS), hematologic, optic neuritis (monitor visual acuity at baseline and monthly), red/green vision change due to retrobulbar neuritis (dose related but rare → immediate notification/discontinuation), separate dosing from aluminum hydroxide by 4h

Question 41

What are some common drug classes that interact with rifampin? (9)

Answer 41

Since rifampin is 3A4 inducer, it will reduce the levels of: 1. CCBs 2. Statins 3. Azole antifungals 4. Opioids 5. Levothyroxine 6. Calcineurin inhibitors 7. Anticoagulants 8. Anticonvulsants 9. Oral contraceptives