Anti-Mycobacterial Therapies Flashcards
name the first-line anti-TB drugs and their abbreviations (under US guidelines) - 6
RIPPPE:
1. Rifampin (RIF)
2. Rifabutin (RFB)
3. Rifapentine (RPT)
4. Isoniazid (INH)
5. Pyrazinamide (PZA)
6. Ethambutol (EMB)
*note that RIF, RFB, and RPT are all under one category - Rifamycins
what anti-TB drug is considered second-line in the US but first-line by WHO? what is the reason for this discrepancy?
Streptomycin: considered 2nd-line in US because of toxic side effects and administration by injection (expensive)
when would we use 2nd-line anti-TB drugs in the US? (3 situations)
2nd-line are less effective, have significant toxic side-effects, and are expensive
indications:
1. multi-resistant TB (MDR-TB): resistant to both isoniazid and rifampin
2. extensively drug-resistant TB (XDR-TB): MDR + resistant to a fluoroquinolone and an aminoglycoside
3. cases in which first-line drugs are effective but cannot be used due to toxicities
multi-resistant TB vs. extensively drug-resistant TB
MDR-TB: resistant to both isoniazid and rifampin
XDR-TB: MDR + resistance to a fluoroquinolone and an aminoglycoside
which 3 first-line anti-TB drugs target mycolate (mycolic acid) in the mycobacterium cell wall? give name and abbreviation
- Isoniazid (INH)
- Ethambutol (ETA)
- Pyrazinamide (PAS)
which first-line anti-TB drug targets arabinogalactan of the mycobacterium cell wall? give name and abbreviation
Ethambutol (EMB)
why does anti-TB therapy take 4-9 months?
dormant or slow-growing intracellular infection is less sensitive to drug that actively growing cells
time frame depends on culture status and drug combination
how method of drug therapy is recommended for TB?
multi-drug: ALWAYS use 4 first-line drugs for initial treatment in absence of contradictions or evidence of resistance
this is because there is no cross-resistance among the four major first-line drugs (INH, RIF/RFB/RPT, PZA, EMB)
What are the 2 treatment phases of TB therapy with anti-mycobacterial drugs? Specify for both microbiologically-confirmed cases (high bacillus loading) and smear-neg. and culture neg. TB disease.
- Intensive phase (8 weeks): 4 drug combo and susceptibility testing
- Continuation phase: 18 weeks for high bacillus loading, 8 weeks for smear/culture negative TB; drugs used depends on prior susceptibility testing
what is a social services practice that greatly increases the effectiveness of anti-TB therapy?
DOT: directly observed treatment (send social worker to the home to make sure they take the drug)
*lack of compliance exacerbates resistance!
describe administration and absorption of Isoniazid (INH)
small, water soluble - taken orally, absorbed from GI tract
pro-drug activated by bacterial enzyme KatG (catalase-peroxidase) —> INH-NAD is active drug
high probability of resistance, always use with other drugs
describe pharmacokinetics and mechanism of Isoniazid (INH)
pro-drug activated by bacterial enzyme KatG (catalase-peroxidase) —> INH-NAD is active drug
INH-NAD inhibits bacterial FAS II required for fatty acid synthesis
what is Isoniazid (INH) bactericidal against, and what are its adverse effects?
INH: bactericidal against both extracellular and intracelular mycobacteria
notable adverse effects: hepatitis, peripheral neuropathy (via pyridoxine/B6 deficiency), possible CNS toxicity (seizures, psychosis, memory loss)
how is Isoniazid (INH) metabolized?
liver metabolism via acetylation by N-acetyltransferase
[recall there are slow and rapid acetylaters, which will affect therapeutic outcome]
what are 2 mechanisms of mycobacterial resistance to Isoniazid (INH)?
mutations in KatG (enzyme necessary to activate prodrug) prevents INH-NAD formation
or mutation/overexpression of Fab1 (component of FAS II complex targeted by INH-NAD)
what type of bacteria is Rifampin (RIF, aka rifampicin) bactericidal for?
broad spectrum: bactericidal for Gram +/- bacteria, mycobacteria, and chlamydiae, but reserved for sole use against mycobacteria as much as possible
[isolated from Streptomyces, inhibitor of RNA synthesis]
describe how Rifampin (RIF), aka rifampicin, inhibits bacterial RNA synthesis
how does mutation arise?
RIF inhibits bacterial transcription elongation - prevents RNA exit by binding beta-subunit of bacterial RNA pol
resistance via mutation in rpoB, gene encoding beta subunit
[note there is cross-resistance with rifampin derivatives - rifabutin (RFB) and rifapentine (RPT)]
describe the administration and pharmacokinetics of Rifampin (RIF)
taken orally, penetrates cerebrospinal fluid if meninges are inflamed
oxidatively deacetylated but metabolite is still active
excreted via feces
describe the adverse effects of Rifampin (RIF)
flu-like symptoms if taken less frequently (believed to be drug allergic reaction, antibody allowed to accumulate)
induces cytochrome P450 members including CYP3A —> increases elimination of other drugs!
harmless red or purple color to urine, sweat, tears
what is different about Rifabutin (RFB) and Rifapentine (RPT), as compared to Rifampin (RIF)?
more potent, longer half life, better membrane permeability (enters macrophages more easily)
*less CYP3A induction —> more compatible with other medications
Pyrazinamide (PZA) is structurally similar to Isoniazid (INH) but mechanistically different - explain
PZA is also a prodrug, but it is converted to active form by bacterial PcnA enzyme
resistance via PcnA mutation, emerges rapidly
[recall that INH is activated by KatG]
what are the specific advantages of Pyrazinamide (PZA)?
works synergistically with rifampin, no cross-resistance with other TB drugs, oral administration and inexpensive
sterilizer - bactericidal specifically against dormant Mtb, but not replicating bacteria (must be used with 2+ other drugs because this doesn’t count as the first bactericidal against replicating bacteria, and >1 must be used at all times)
can reduce chemotherapy from 9 months to 4-6 months!
what are the adverse effects of Pyrazinamide (PZA)?
hepatotoxicity, hyperuricemia, N/V, drug fever
what is the mechanism of action of Ethambutol (EMB), a first-line anti-TB drug?
blocks EmbA and EmbB arabinosyl transferases which incorporate arabinose into arabinogalactan layer —> weaken cell wall
inhibits fast growing extracellular Mtb (less effective against intracellular)
EMB blocks EmbA and EmbB!
why would Ethambutol (EMB) + Pyrazinamide (PZA) be a bad combination of anti-TB therapy?
you always need 2+ drugs targeting Mtb in TB therapy
however, PZA targets dormant Mtb while EMB targets rapidly growing extracellular Mtb
these are 2 different populations of Mtb, so you essentially are treating each with only 1 drug! (“de facto monotherapy”)
describe administration and pharmacokinetics of Ethambutol (EMB)
taken orally, half excreted in urine unchanged (high excretion rate)
accumulates in renal failure patients! reduce dosage
crosses BBB only if meninges are inflamed
resistance emerges easily, always use in combination
why is Ethambutol (EMB) usually avoided in young children?
adverse effects include optic neuritis and red-green color blindness - avoid in children because it is difficult to test vision
how does TB therapy change for a patient with HIV?
patients with HIV have less T cells, so must increase dosage regimen! 3x/week is MINIMUM during continuation phase
if patient is not on ART, add 3 months to treatment regimen
*note that Rifampin (RIF) adversely interacts with antiretrovirals - swap with Rifabutin (RFB) or 2x/3x antiretroviral drug dosage if first option not possible
which drugs are used to treat MAC (Mycobacterium avium complex)?
MAC (M. avium, M. intracellulare, M. paratuberculosis, etc) infections occur in AIDS or other immunocompromised patients
MAC much less susceptible to anti-TB therapies
Rx: azithromycin (or clarithromycin), ciprofloxacin, ethambutol, and rifabutin
can be used prophylactically
