Antimycobacterials Flashcards
What makes tuberculosis very difficult to treat?
- It is only susceptible to bactericidals when metabolically active.
- It is exceedingly slow-growing.
- Therapy takes months to years.
- It may be intracellular.
- Disease is well-established prior to symptoms.
How many drugs are typically involved in an active TB treatment regimen? Why?
At least 2 or 3. Resistance occurs in one per 107 organisms; less than the number in a typical granuloma. Multiple drugs will reduce this.
What unique structures are found in Mycobacterium Tuberculosis**?
What drugs target them?
Mycolic acid and arabinogalactan (in the outer layer, make it very resistant to dessication).
Isoniazid, Ethambutol, and Pyrazinamide specifically block the synthesis of these molecules.
Isoniazid
What is its mechanism of action?
What are its indications?
How is it resisted?
Isoniazid
It is activated by KatG (a peroxidase) and targets InhA (a carrier protein in mycolate synthesis).
It is bactericidal for actively growing bacilli. It is used in combination for active TB, and alone for latent TB.
Mutations in KatG and InhA (1 in 106).
Izoniazid
How is it metabolized?
What are its adverse effects?
Isoniazid
It is metabolized by N-AcetylTransferase (NAT-2). Note that there are known polymorphisms for this enzyme.
Neurotoxicity (eg peripheral neuritis, better with B6), Hepatotoxicity (worse with age, due to acetylhydrazine).
Rifampin
What is its mechanism of action?
What are its indications?
What are its adverse effects?
Rifampin
It inhibits bacterial RNA Pol.
It is bactericidal against both intra- and extracellular forms of TB (highly lipophilic). It is also used to treat MAC/Leprosy.
Hepatotoxicity, heavy CYP induction, and discoloration of bodily fluids.
Ethambutol
What is its mechanism of action?
What are its indications?
What are its adverse effects?
Ethambutol
It interferes with arabinosyl transferase.
It is tuberculostatic (yet doesn’t block cidal action). It is used in some MAC regimens.
Side effects are mild; some optic neuritis.
Pyrazinamide
What is its mechanism of action?
What are its indications?
What are its adverse effects?
Pyrazinamide
Inhibits FAS-I to block mycolate synthesis.
It is bactericidal (usually) against TB, and is used in combo short-term therapy of TB (especially with CNS involvement).
Hepatotoxicity, worse when combined with Rifampin.
Streptomycin
What is its mechanism of action?
What are its indications?
What are its adverse effects?
Streptomycin
It is an aminoglycoside; it binds the bacterial ribosome to cause mRNA misreads and release.
It is reserved for serious TB infections.
Ototoxicity (usually irreversible), nephrotoxicity (usually reversible)
Distinguish between the treatment regimens for uncomplicated TB, disseminated TB, and latent TB.
Uncomplicated: Isoniazid+Rifampin (6+ months) and pyrazinamide (2 months).
Disseminated: Isoniazid+Rifampin (up to 2 years) and pyrazinamide+ethambutol (2 months).
Latent: Isoniazid (9 months).
Distinguish between MDR and XDR TB. What are the guidelines for treating either?
MDR resists at least INH+Rif and will require 4+ drugs.
XDR resists nearly all TB drugs. Referral to treatment center.
What causes “atypical” mycobacterial infections? How serious is it?
Mycobacterium Avium Complex (MAC). It is less fatal than TB.
Rifabutin
What is its mechanism of action?
What are its indications?
What are its adverse effects?
Rifabutin
Same as rifampin.
Single-agent prophylaxis of MAC in AIDS patients. Interchangable with rifampin in most antimycobacterial treatment regimens.
Like rifampin, but less severe. For example, less CYP induction.
Clarithromycin
What is its mechanism of action?
What are its indications?
What are its adverse effects?
Clarithromycin
It is a macrolide: It binds the 50S subunit and blocks translocation.
For treatment of MAC in AIDS patients (prophylaxis too). It appears to be bactericidal, somehow.
Inhibition of CYP3A4 (true of most macrolides).
How are Leprosy cases treated? Lepromatous vs Tuberculoid?
Referral to a specialized program, and drug regimens such as:
Lepromatous: Dapsone + Clofazimine + Rifampin daily for 2 years.
Tuberculoid: Dapsone + Rifampin daily for 1 year.
