Antimycobacterials Flashcards
Latent TB infection
TB bacilli live dormant inside the lung, but do not cause destruction of organs
No signs/symptoms of disease
NOT infections
TB disease
TB bacilli progressively invade and damage a part(s) of the body
Signs and symptoms of disease appear
Can be infectious
TB symptoms
*(Night) cough for > 3 weeks
*Profuse night sweats
*Weight loss
Extreme tiredness
Fever
No appetite
Is tuberculosis: A. Gram positive B. Gram negative C. Acid fast D. None of the above
Acid fast based on cell wall components
TB replication time
Slow - 15-20 hours
Because of that, they can sense, change, adapt during replication cycle so drug resistance is a problem
TB is a facultative intracellular parasite, usually of the _________.
Macrophages.
Not just limited to lungs, can affect really any part of the body where macrophages are present.
What two components of the mycobacterium cell well are unique?
Mycolic Acid and Arabinogalactan
TB drugs target these components
These components are what make them “acid fast” bacteria
First line drugs for TB
*Isoniazid
*Rifampin
*Pyrazinamide
*Ethambutol
(Streptomycin and Rifabutin) are back ups to these first four
ALWAYS use in combo - never monotherapy
Remember the patient is “RIPE” for treatment
What makes something a “second line” drug
Not as effective and more toxic
CAN be used in cases of resistance, but won’t work as well as the front line and may kill the pt
What does MDR mean?
Multi drug resistant TB - resistant to both Isoniazid and Rifampin
What does XDR mean?
Extreme Drug Resistance - resistant to Isoniazid, Rifampin and some some second line drugs (ie fluroquinolone)
For a healthy individual with active TB the treatment regime is…
All four front line for TWO months (Isoniazid, Rifampin, Pyrazinamide, and Ethambutol), followed by FOUR months of Isoniazid and Rifampin alone (to reduce resistance)
For Latent TB (contracted, harbor bacteria, but not symptomatic) can be treated with…
Either Isoniazid OR Rifampin monotherapy
MOA for Isoniazid
Inhibits biosynthesis of mycolic acid (mycobacterium cell wall)
Prodrug that requires enzyme KatG within bacillus to activate the drug
Possible site of resistance to Isoniazid
Mutation of KatG (because KatG is required to active Isoniazid, which is a prodrug)
Isoniazid prophylaxis
For post-exposure to TB
Weigh benefits of prophylaxis v risks of INH-associated hepatic, esp in patients >35 years
Is Isoniazid bacteriostatic or bactericidal?
Static, unless combined with Rifampin
Doesn’t really matter - you’ll treatment regardless
Metabolism of Isoniazid
By acetylation —> inactivated the drug
Metabolic rate of INH is depended on genetic makeup. There are Rapid and Slow metabolizers. About 1/2 of whites and blacks in the US are “slow”. Many eskimos, native Americans, and Asians are “rapid” acetylators.
Slow acetylators —> more likely to develop peripheral neuritis
Rapid acetylators —> more likely to develop hepatitis
Doesn’t change the dosage though
Primarily excreted through urine
Main toxicities for Isoniazid
- **Hepatitis - monitor LFTs MONTHLY, look for jaundice. More common with fast acetylators
- *Peripheral neuritis (esp with slow acetylators) - antagonized by Pyridoxine B6)
- Hemolysis in patients with G6PD (not a contraindication but caution)
- Lupus-like Syndrome (it’s the I in the “HIP” drugs: hydralazine, INH, procainamide)
MOA for Rifampin
Inhibits DNA dependent RNA polymerase (rpoB subunit) —> inhibits transcripts
**rpoB mutations confer resistance
Rifampin primarily used for TB but also effective against…
Leprosy
Most G+ cocci and some G- microbes, chlamydia and pox viruses
Rifampin toxicities
Generally fairly well tolerated (no hepatotoxicity)
Potent INDUCER of CYP3A4 - lots of drug interactions (NOT Recommended for HIV pt)
Orange color to urine, sweat, tears, contacts
Decrease effectiveness of birth control b/c induces liver metabolism of progestin
MOA for Ethambutol
Inhibits arabinosyl transferases (embCAB) involved in the synthesis of arabinogalactan (AG) - bacteriostatic
Which frontline TB drug can penetrate the CNS?
Ethambutol
Ethambutol toxicities
Decrease in visual acuity and loss of GREEN-RED perception (usually reversible with discontinuation)
• Not recommended in children <13; Monitor for vision changes
Also beware in renal insufficiency - give smaller doses
MOA for Pyrazinamide
Prodrug - mechanism unknown
Active at acidic pH - optimal for Mtb within macrophages (which have low pH)
Greatest activity against dormant organisms
Oral, well absorbed, good penetration
Pyrazinamide use
Must be used in combo with INH and rifampin for 2 months
Critical first line drug - responsible for reducing therapy to current standard of 6 months
If hepatic dysfunction, remove PZA before INH (both contribute synergistically, but remove PZA first)
Streptomycin
Aminoglycoside, inhibitor of 30s ribosomes
Bactericidal, Parenteral
Dose-related oto- and nephrotoxicity
Not used often but helpful for MDR/XDR
Rifabutin
Same family as rifampin but LESS POTENT INDUCER of p450s - so helpful if you’re worried about drug interactions (esp HIV-TB coinfections)
Same orange colored secretions as with rifampin
Mycobacterium avium complex (MAC)
M. avium and M. intracellulare
Common environmental pathogen; infection following inhalation (similar to pulmonary TB) or swallowing bacteria (GI distress, diarrhea)
Intrinsically resistant to anti-TB/antimicrobials
Treatment with 2 or 3 antimicrobials for 12 MONTHS
Co-infection with HIV is prevalent
Treatment for Mycobacterium avium complex (MAC)
- Include either clarithromycin or azithromycin
- Include ethambutol
- Add third oral drug (Rifabutin, rifampin, ciprofloxacin)
Inclusion of I.V. Amikacin in certain cases (if resistance to clarithromycin)
Mycobacterium leprae
Leprosy
Multi drug therapy necessary - treatment with only one antileprosy drug will always result in development of resistance (NEVER monotherapy)
Treating PB leprosy (1-5 patches)
Rifampin and dapsone for 6 months
Treating MB leprosy (>5 patches)
Rifampin and Dapsone for 6-12 months
Dapsone
Most widely use and least expensive anti-leprosy drug
MOA - similar to sulfonamides (think PABA antagonist) but other sulfas aren’t effective
Oral administration with rapid absorption and slow excretion
Dapsone toxicities
Common - nausea, vomiting, HA etc
***Nasal obstructive (severe): improves in 3-6 months (need pt ed)
Thalidomide use in leprosy
NOT for treating the mycobacterium, but for treating the leprosy related ENL (erythema nodosum leprosum)
Orphan drug status b/c of teratogenicity - very heavily regulated
