Anti-TB Therapeutics Flashcards
Which age group has the largest number of tuberculosis cases?
25-34 year olds (greater than 74 year olds)
What are the risk factors for tuberculosis?
Elderly, poverty, malnutrition, alcoholism, immunosuppression, AIDS, diabetes
How is tuberculosis acquired?
Person-to-person transmission of airborne droplets of organisms from an active case to a susceptible host
What occurs in a patient with a primary infection of tuberculosis?
Most often asymptomatic as regional lymph node spread and bacteremia
Usually controlled by the development of cellular immunity.
How can latent tuberculosis be detected?
Positive tuberculin skin test, no disease
How can active tuberculosis be detected?
Latent infection that was reactivated
Clinical signs and symptoms, radiographic evidence and bacteriological evidence
What are the signs and symptoms of tuberculosis?
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.)
What are the infectious agents that cause?
Mycobacterium tuberculosis (acid fast, high lipid content, gram negative, slow growing) and mycobacterium bovis (cows and milk, oropharyngeal and intestinal tuberculosis)
How can tuberculosis be reactivated?
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
What can lead to tuberculosis treatment failure and drug resistance?
Long duration needed for treatment and poor adherence
What is the standard length of treatment for tuberculosis?
6 months
What is the length of treatment for tuberculosis meningitis?
9-12 months
What are the first line drugs for tuberculosis?
Isoniazid, rifampin, pyrazinamide and ethambutol
Use combination therapy
How does isoniazid work?
Inhibits cell wall synthesis by inhibiting mycolic acid synthetase.
Bactericidal in extracellular area with high oxygen concentration. Important in prevention of resistance.
How does rifampin work?
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
What does pyrazinamide do?
Sterilizes semi-dormant and dormant bacteria by inhibiting mycolic acid synthesis. Active in acidic environment. Only beneficial for 2 months (while inflammation is present)
What does ethambutol do?
Inhibits arabinosyl transferase which stops arabinogalactan chain elongation and mycobacterial wall synthesis
Bacteriostatic
Prevents resistance to rifampin when primary resistance to isoniazid is present
When should ethambutol not be used?
Discontinue if the organism is sensitive to isoniazid.
Do not use in children or renal failure.
What occurs during the intensive phase of tuberculosis treatment? When does it occur?
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.
What occurs during the continuation phase of tuberculosis treatment? When does it occur?
2-6 months
Sterilize the lungs by killing dormant and semi-dormant organisms to prevent relapse
Intermittent therapy allowed if directly observed therapy
What is the drug regime during the intensive phase of tuberculosis treatment?
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
What is the drug regime during the continuation phase of tuberculosis treatment?
Directly observed therapy (DOT) of isoniazid and rifampin twice weekly
How can the duration of pansensitive tuberculosis treatment change?
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.
What is the therapy for latent tuberculosis?
Isoniazid daily for 9 months or rifampin daily for 4 months.
What are some adverse effects of isoniazid?
Peripheral neuropathy due to interference with pyridoxine metabolism (occurs in B6 deficiency)
Seizures, rash, hepatic toxicity (hepatitis, increase in LFTs), drug interactions
How can resistance to isoniazid occur?
Due to decreased drug uptake
How can resistance to rifampin occur?
Rapid resistance due to alteration in DNA-dependent RNA polymerase structure causing decreased drug binding
What are some adverse effects of rifampin?
Uncommon
Hepatotoxiity, discolouration of urine/sweat, rash, oral pain, “flu-like”, thrombocytopenia, dose dependent interference with bilirubin uptake causing unconjugated hyperbilirubinemia or jaundice
What are some drug interactions with rifampin?
Concentration of rifampin is decreased by HIV protease inhibitors
Decreased efavirenz
Decreased raltegravir
All HIV drugs
What are some adverse effects of pyrazinamide?
Hepatotoxicity, hyperuriaenemia which could cause gout. arthralgias, GI effects, rash
How can resistance against pyrazinamide occur?
Due to loss of pyrazinamidase which decreases the conversion to pyrazinoic acid
What are the adverse effects of ethambutol?
Loss of visual acuity, loss of colour discrimination (green), GI upset
How do we monitor the microbiological response to TB therapy?
Sputum at 2 months and sputum at completion of therapy
How do we monitor the laboratory response to TB therapy?
Check AST, ALT, bilirubin and CBC
Twice weekly in the first 2 weeks then monthly at 1 month
How can pregnancy change tuberculosis therapy?
Can continue therapy as usual. First line drugs are safe in pregnancy and lactation
What are the abnormal LFTs that a patient may develop while on TB therapy?
AST/ALT is 5x the upper limit of normal asymptomatic or AST/ALT is 3x the upper limit of normal, symptomatic or jaundice
What should be done if a patient develops abnormal LFTs on tuberculosis therapy?
Hold TB meds until ALT returns to
How does TB treatment change in patients with pre-existing liver disease?
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
How does TB treatment change in patients with cirrhosis?
Rifampin, ethambutol and fluoroquinolone
How does TB treatment change in patients with renal insufficiency?
Dose adjust pyrazinamide and ethambutol if creatine levels are
How does multi-drug resistant tuberculosis (MDR-TB) emerge?
Course of antibiotics is interrupted or the levels of drug are insufficient to kill bacteria
What is multi-drug resistant tuberculosis (MDR-TB)?
Patients (4%) who are resistant to refampin and isoniazid and potentially other drugs.
Who is more likely to develop MDR-TB?
Patients with weakened immune systems (HIV, immunosuppressant drugs), areas poverty and lack of healthcare
What is extensively drug resistant tuberculosis?
A form of MDR-TB that is resistant to ridampin and isoniazid, any quinolone and any injectable 2nd line agent
Makes TB untreatable
What are some alternative treatment regimes for a patient who is isoniazid resistant?
Rifampin and pyrazinamide and ethambutol or streptokinase for 6-9 months
Rifampin and ethambutol for 12 months
Fluoroquinolone or aminoglycosides may be added
How is MDR-TB treated?
Combinations of 5-7 drugs
Isoniazid, rifampin, pyrazinamide, ethambutol, an aminoglycoside, a fluoroquinolone and one of: cycloserine, ethionamide or aminosalicylic acid
What is the MDR-TB therapy regime?
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.
How are MDR-TB drug regime decided?
Individual regimes are guided by Drug Susceptibility Testing (DST)
How does bedaquiline work?
New MDR-TB drug
Inhibits mycobacterium ATP synthase
Used in combination with rifampicin and pyrazinamide
What are the safety issues with bedaquiline?
Liver toxicity, prolonged QT, chest pain, hemoptysis and nausea/headache
