Anti-TB Therapeutics

Question 1

Which age group has the largest number of tuberculosis cases?

Answer 1

25-34 year olds (greater than 74 year olds)

Question 2

What are the risk factors for tuberculosis?

Answer 2

Elderly, poverty, malnutrition, alcoholism, immunosuppression, AIDS, diabetes

Question 3

How is tuberculosis acquired?

Answer 3

Person-to-person transmission of airborne droplets of organisms from an active case to a susceptible host

Question 4

What occurs in a patient with a primary infection of tuberculosis?

Answer 4

Most often asymptomatic as regional lymph node spread and bacteremia
Usually controlled by the development of cellular immunity.

Question 5

How can latent tuberculosis be detected?

Answer 5

Positive tuberculin skin test, no disease

Question 6

How can active tuberculosis be detected?

Answer 6

Latent infection that was reactivated

Clinical signs and symptoms, radiographic evidence and bacteriological evidence

Question 7

What are the signs and symptoms of tuberculosis?

Answer 7

Cough, fever, night sweats, pulmonary cavitation, mycobacteria dissemination, presence of bacilli in sputum (increased, at first mucoid then purulent), malaise, anorexia, extrapulmonary effects (liver, bone marrow, etc.)

Question 8

What are the infectious agents that cause?

Answer 8

Mycobacterium tuberculosis (acid fast, high lipid content, gram negative, slow growing) and mycobacterium bovis (cows and milk, oropharyngeal and intestinal tuberculosis)

Question 9

How can tuberculosis be reactivated?

Answer 9

Loss of balance between the immune system and bacilli, most often occurs in the lungs but can happen in lymph nodes, kidneys, gut
Symptomatic and infectious

Question 10

What can lead to tuberculosis treatment failure and drug resistance?

Answer 10

Long duration needed for treatment and poor adherence

Question 11

What is the standard length of treatment for tuberculosis?

Answer 11

6 months

Question 12

What is the length of treatment for tuberculosis meningitis?

Answer 12

9-12 months

Question 13

What are the first line drugs for tuberculosis?

Answer 13

Isoniazid, rifampin, pyrazinamide and ethambutol

Use combination therapy

Question 14

How does isoniazid work?

Answer 14

Inhibits cell wall synthesis by inhibiting mycolic acid synthetase.
Bactericidal in extracellular area with high oxygen concentration. Important in prevention of resistance.

Question 15

How does rifampin work?

Answer 15

Inhibits DNA-dependent RNA polymerase only in mycobacteriu, inhibiting RNA synthesis
Bactericidal in extracellular areas, including fibrotic areas.
Very important, without it treatment would last 18 months

Question 16

What does pyrazinamide do?

Answer 16

Sterilizes semi-dormant and dormant bacteria by inhibiting mycolic acid synthesis. Active in acidic environment. Only beneficial for 2 months (while inflammation is present)

Question 17

What does ethambutol do?

Answer 17

Inhibits arabinosyl transferase which stops arabinogalactan chain elongation and mycobacterial wall synthesis
Bacteriostatic
Prevents resistance to rifampin when primary resistance to isoniazid is present

Question 18

When should ethambutol not be used?

Answer 18

Discontinue if the organism is sensitive to isoniazid.

Do not use in children or renal failure.

Question 19

What occurs during the intensive phase of tuberculosis treatment? When does it occur?

Answer 19

0-8 weeks
Goal is to quickly kill the rapidly dividing organism to control disease and render the patient non-infectious and prevent the emergence of drug resistance.

Question 20

What occurs during the continuation phase of tuberculosis treatment? When does it occur?

Answer 20

2-6 months
Sterilize the lungs by killing dormant and semi-dormant organisms to prevent relapse
Intermittent therapy allowed if directly observed therapy

Question 21

What is the drug regime during the intensive phase of tuberculosis treatment?

Answer 21

Isoniazid, rifampin, pyrazinamide and ethambutol daily for 8 weeks
First nations use 3 times weekly after the patient has had 14 daily doses and is smear negative
Ethanmbutol can be dropped if the organism is pansensitive

Question 22

What is the drug regime during the continuation phase of tuberculosis treatment?

Answer 22

Directly observed therapy (DOT) of isoniazid and rifampin twice weekly

Question 23

How can the duration of pansensitive tuberculosis treatment change?

Answer 23

Required number of doses should be given (may have to extend duration to get them all in)
If pyrazianmide wasn’t used in first 2 months, treatment will be 9 months.
If culture is positive at 2 months, treatment is 9 months.

Question 24

What is the therapy for latent tuberculosis?

Answer 24

Isoniazid daily for 9 months or rifampin daily for 4 months.

Question 25

What are some adverse effects of isoniazid?

Answer 25

Peripheral neuropathy due to interference with pyridoxine metabolism (occurs in B6 deficiency) Seizures, rash, hepatic toxicity (hepatitis, increase in LFTs), drug interactions

Question 26

How can resistance to isoniazid occur?

Answer 26

Due to decreased drug uptake

Question 27

How can resistance to rifampin occur?

Answer 27

Rapid resistance due to alteration in DNA-dependent RNA polymerase structure causing decreased drug binding

Question 28

What are some adverse effects of rifampin?

Answer 28

Uncommon Hepatotoxiity, discolouration of urine/sweat, rash, oral pain, "flu-like", thrombocytopenia, dose dependent interference with bilirubin uptake causing unconjugated hyperbilirubinemia or jaundice

Question 29

What are some drug interactions with rifampin?

Answer 29

Concentration of rifampin is decreased by HIV protease inhibitors Decreased efavirenz Decreased raltegravir All HIV drugs

Question 30

What are some adverse effects of pyrazinamide?

Answer 30

Hepatotoxicity, hyperuriaenemia which could cause gout. arthralgias, GI effects, rash

Question 31

How can resistance against pyrazinamide occur?

Answer 31

Due to loss of pyrazinamidase which decreases the conversion to pyrazinoic acid

Question 32

What are the adverse effects of ethambutol?

Answer 32

Loss of visual acuity, loss of colour discrimination (green), GI upset

Question 33

How do we monitor the microbiological response to TB therapy?

Answer 33

Sputum at 2 months and sputum at completion of therapy

Question 34

How do we monitor the laboratory response to TB therapy?

Answer 34

Check AST, ALT, bilirubin and CBC | Twice weekly in the first 2 weeks then monthly at 1 month

Question 35

How can pregnancy change tuberculosis therapy?

Answer 35

Can continue therapy as usual. First line drugs are safe in pregnancy and lactation

Question 36

What are the abnormal LFTs that a patient may develop while on TB therapy?

Answer 36

AST/ALT is 5x the upper limit of normal asymptomatic or AST/ALT is 3x the upper limit of normal, symptomatic or jaundice

Question 37

What should be done if a patient develops abnormal LFTs on tuberculosis therapy?

Answer 37

Hold TB meds until ALT returns to

Question 38

How does TB treatment change in patients with pre-existing liver disease?

Answer 38

Be aware that treatment may elevate AST/ALT | If ALT is more than 3x the upper limit of normal is not related to TB, avoid pyrazinamide

Question 39

How does TB treatment change in patients with cirrhosis?

Answer 39

Rifampin, ethambutol and fluoroquinolone

Question 40

How does TB treatment change in patients with renal insufficiency?

Answer 40

Dose adjust pyrazinamide and ethambutol if creatine levels are

Question 41

How does multi-drug resistant tuberculosis (MDR-TB) emerge?

Answer 41

Course of antibiotics is interrupted or the levels of drug are insufficient to kill bacteria

Question 42

What is multi-drug resistant tuberculosis (MDR-TB)?

Answer 42

Patients (4%) who are resistant to refampin and isoniazid and potentially other drugs.

Question 43

Who is more likely to develop MDR-TB?

Answer 43

Patients with weakened immune systems (HIV, immunosuppressant drugs), areas poverty and lack of healthcare

Question 44

What is extensively drug resistant tuberculosis?

Answer 44

A form of MDR-TB that is resistant to ridampin and isoniazid, any quinolone and any injectable 2nd line agent Makes TB untreatable

Question 45

What are some alternative treatment regimes for a patient who is isoniazid resistant?

Answer 45

Rifampin and pyrazinamide and ethambutol or streptokinase for 6-9 months Rifampin and ethambutol for 12 months Fluoroquinolone or aminoglycosides may be added

Question 46

How is MDR-TB treated?

Answer 46

Combinations of 5-7 drugs Isoniazid, rifampin, pyrazinamide, ethambutol, an aminoglycoside, a fluoroquinolone and one of: cycloserine, ethionamide or aminosalicylic acid

Question 47

What is the MDR-TB therapy regime?

Answer 47

An injectable is used daily for the first 2-6 months then stepped down to 3 times a week, ideally for 8 months. Must have daily directly observed therapy Duration of therapy is total 20 months.

Question 48

How are MDR-TB drug regime decided?

Answer 48

Individual regimes are guided by Drug Susceptibility Testing (DST)

Question 49

How does bedaquiline work?

Answer 49

New MDR-TB drug Inhibits mycobacterium ATP synthase Used in combination with rifampicin and pyrazinamide

Question 50

What are the safety issues with bedaquiline?

Answer 50

Liver toxicity, prolonged QT, chest pain, hemoptysis and nausea/headache