Anti-Mycobacterial Therapies

Question 1

name the first-line anti-TB drugs and their abbreviations (under US guidelines) - 6

Answer 1

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

Question 2

what anti-TB drug is considered second-line in the US but first-line by WHO? what is the reason for this discrepancy?

Answer 2

Streptomycin: considered 2nd-line in US because of toxic side effects and administration by injection (expensive)

Question 3

when would we use 2nd-line anti-TB drugs in the US? (3 situations)

Answer 3

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

Question 4

multi-resistant TB vs. extensively drug-resistant TB

Answer 4

MDR-TB: resistant to both isoniazid and rifampin

XDR-TB: MDR + resistance to a fluoroquinolone and an aminoglycoside

Question 5

which 3 first-line anti-TB drugs target mycolate (mycolic acid) in the mycobacterium cell wall? give name and abbreviation

Answer 5

1. Isoniazid (INH)
2. Ethambutol (ETA)
3. Pyrazinamide (PAS)

Question 6

which first-line anti-TB drug targets arabinogalactan of the mycobacterium cell wall? give name and abbreviation

Answer 6

Ethambutol (EMB)

Question 7

why does anti-TB therapy take 4-9 months?

Answer 7

dormant or slow-growing intracellular infection is less sensitive to drug that actively growing cells

time frame depends on culture status and drug combination

Question 8

how method of drug therapy is recommended for TB?

Answer 8

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)

Question 9

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.

Answer 9

1. Intensive phase (8 weeks): 4 drug combo and susceptibility testing
2. Continuation phase: 18 weeks for high bacillus loading, 8 weeks for smear/culture negative TB; drugs used depends on prior susceptibility testing

Question 10

what is a social services practice that greatly increases the effectiveness of anti-TB therapy?

Answer 10

DOT: directly observed treatment (send social worker to the home to make sure they take the drug)

*lack of compliance exacerbates resistance!

Question 11

describe administration and absorption of Isoniazid (INH)

Answer 11

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

Question 12

describe pharmacokinetics and mechanism of Isoniazid (INH)

Answer 12

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

Question 13

what is Isoniazid (INH) bactericidal against, and what are its adverse effects?

Answer 13

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)

Question 14

how is Isoniazid (INH) metabolized?

Answer 14

liver metabolism via acetylation by N-acetyltransferase

[recall there are slow and rapid acetylaters, which will affect therapeutic outcome]

Question 15

what are 2 mechanisms of mycobacterial resistance to Isoniazid (INH)?

Answer 15

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)

Question 16

what type of bacteria is Rifampin (RIF, aka rifampicin) bactericidal for?

Answer 16

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]

Question 17

describe how Rifampin (RIF), aka rifampicin, inhibits bacterial RNA synthesis

how does mutation arise?

Answer 17

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)]

Question 18

describe the administration and pharmacokinetics of Rifampin (RIF)

Answer 18

taken orally, penetrates cerebrospinal fluid if meninges are inflamed

oxidatively deacetylated but metabolite is still active

excreted via feces

Question 19

describe the adverse effects of Rifampin (RIF)

Answer 19

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

Question 20

what is different about Rifabutin (RFB) and Rifapentine (RPT), as compared to Rifampin (RIF)?

Answer 20

more potent, longer half life, better membrane permeability (enters macrophages more easily)

*less CYP3A induction —> more compatible with other medications

Question 21

Pyrazinamide (PZA) is structurally similar to Isoniazid (INH) but mechanistically different - explain

Answer 21

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]

Question 22

what are the specific advantages of Pyrazinamide (PZA)?

Answer 22

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!

Question 23

what are the adverse effects of Pyrazinamide (PZA)?

Answer 23

hepatotoxicity, hyperuricemia, N/V, drug fever

Question 24

what is the mechanism of action of Ethambutol (EMB), a first-line anti-TB drug?

Answer 24

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!

Question 25

why would Ethambutol (EMB) + Pyrazinamide (PZA) be a bad combination of anti-TB therapy?

Answer 25

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”)

Question 26

describe administration and pharmacokinetics of Ethambutol (EMB)

Answer 26

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

Question 27

why is Ethambutol (EMB) usually avoided in young children?

Answer 27

adverse effects include optic neuritis and red-green color blindness - avoid in children because it is difficult to test vision

Question 28

how does TB therapy change for a patient with HIV?

Answer 28

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

Question 29

which drugs are used to treat MAC (Mycobacterium avium complex)?

Answer 29

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