Anti-Mycobacterial Therapies (Fan) - 5/3/16

Question 1

Describe mycobacterial-specific cell wall features pertinent to chemotherapy.

Answer 1

Thick cell wall!

Outer membrane:

• Long acyl lipids
• Mycolate (C54-C78) (target of INH, ETA, PAS)
• Arabinogalactan (target of EMB)

Question 2

State proper TB treatment durations for culture-positive and culture-negative patients free of HIV infection

Answer 2

Culture positive: RIF + INH + PZA + EMB (26 weeks of treatment - 6 mo.)

Culture positive: RIF + INH + EMB (39 weeks of treatment - 9 mo.)

Active TB = ALWAYS multiple drug therapy; NO CROSS-RESISTANCE AMONG FOUR MAJOR DRUGS USED IN TREATMENT

Culture negative:
Initial phase - RIF + INH + PZA + EMB (2 mo)
Continuation phase - RIF + INH (2 mo)

Question 3

Name first-line and second-line anti-TBs (and abbreviations, when applicable) under CDC guidelines

Answer 3

First-line (6):

• Isoniazid (INH)
• Rifampin (RIF)
• Rifabutin
• Rifapentine
• Pyrazinamide (PZA) - inhibits protein synthesis in dormant bacteria
• Ethambutol (EMB)

Second-line (10):

• Ethionamide (ETA)
• p-Aminosalicylic acid (PAS)
• Cycloserine
• Streptomycin* (WHO lists streptomycin as first line drug)
• Amikacin/kanamycin (aminoglycoside)
• Capreomycin
• Levofloxacin
• Moxifloxacin
• Gatifloxacin
• Bedaquiline

Question 4

Challenges in treating TB?

Answer 4

1. Dormant or slow-growing intracellular infection
   - Bacteria live and hide within macrophages
   - Slow growth –> less sensitive to drugs that target actively growing cells
   - 4-9 mo. treatment is needed
2. MT readily accumulate mutations that cause drug resistance (chromosomal mutation)
   - Which is why multiple drug approach is important!
3. Doctor/patient compliance (exacerbates resistance!)
4. Strong lipid-rich cell wall
5. TB (drug-resistant TB) and HIV/AIDS often co-exist (double trouble!)

Question 5

Name geographical areas with particularly high resistance rates to anti-TBs

Answer 5

Eastern Europe! (15.7-45.3%)

Question 6

Name first-line anti-TBs that target both extracellular and intracellular dormant Mtb

Answer 6

Isoniazid

Question 7

Name the drug(s) that specifically target dormant Mtb

Answer 7

PZA

Question 8

Define de facto mono therapy and describe its possible causes

Answer 8

De Facto Monotherapy - responsible for development of resistance in patients treated w/ multiple drugs

Possible causes:

1. Pre-existing resistance
2. Poor distribution of certain drugs to fibrotic tissues
3. Differential targeting of bacterial forms (active growing vs. dormant bacteria in LTBI)

Question 9

State the significance of direct observed treatment.

Answer 9

Helps with patient compliance since treatments are lengthy! (6-9 mo)

Question 10

List the indications for second-line anti-TBs

Answer 10

• Multi-resistant TB (MDR-TB, resistance to both isoniazid and rifampin)
• Extensively drug-resistant TB (XDR-TB: MDR + resistance to a fluoroquinolone + injectable amino glycoside)
• Cases in which first line drugs are effective but can’t be used due to toxicities

Question 11

List general properties of second-line anti-TBs

Answer 11

• Less effective than first-line drugs
• Significant toxic side-effects
• Expensive

Question 12

Name the active forms of INH and PZA, and the enzymes that catalyze the activation reaction

Answer 12

Active form: INH-NAD
Catalyst: Bacterial KatG (catalase peroxidase)

Active form: Pyrazinoic acid

Question 13

Describe the reason and management of major neurological side effects of INH

Answer 13

Peripheral neuropathy due to pyridoxine deficiency

Mild form:

• Sensory abnormalities: temporary numbness, tingling, prickling sensations (paresthesia), sensitivity to touch
• Muscle weakness

Severe form:
- Burning pain (especially at night)
- Muscle asting, paralysis
Organ or gland dysfunction: maldigestion, low BP, abnormal sweating, sexual dysfunction, breathing difficulties

Question 14

Describe INH metabolic mechanism, and implication of its variation within population for therapeutic regimen

Answer 14

High probability of resistance - almost always used with other drugs

Pro-drug activated by bacterial KatG (catalase peroxidase)
- INH + NAD = active drug

Mycolic Acid Biosynthesis:
Fatty acids are synthesized in two stages in mtb:
- FAS-I = synthesizers chains up to C16-C26 using CoA as carrier
- FAS-II = multi-enzyme system that lengthens fatty acid chains to > C52.

INH-NAD inhibits Fab1 (InhA) of FAS-II:

• Fab1 carries out last step in FAS-II cycle
• Fab1 = NADH-dependent-enoyl-ACP reductase
• Fab1 binds inhibitor INH-NAD tightly within a NADH-binding pocket

Resistance mechanisms:

• Mutations of KatG so INH-NAD can’t be formed
• Mutations in NADH binding pocket of Fab1 that reduce binding affinity for INH-NAD
• Mutations that increase expression of Fab1

Question 15

Name the enzyme that RIF inhibits.

Answer 15

Blocks departure of bacterial RNAP from gene promoters –> prevents RNA exit from polymerase by interacting with large (beta) subunit of bacterial RNAP –> directly blocks path of growing RNA

Human RNAPs do not bind rifampin and are not inhibited.

Question 16

Describe the potential advantages of rifabutin and rifapentin over RIF

Answer 16

Higher potencies

Longer 1/2 lives

Better membrane permeability (getting inside macrophages more efficiently)

Less active in CYP3A induction (particularly rifabutin) –> better compatibility with other medications (e.g., for HIV and arrhythmia)

Question 17

Describe effects of rifampin on excreted body fluids

Answer 17

Induces expression of cytochrome P450 members including CYP3a –> increases elimination of other drugs (anticoagulants, HIV protease inhibitors, contraceptives)

So how do you address this? dosage adjustment or a RIF substitute may be needed

Question 18

Describe the impact of PZA on TB treatment duration (related to Objective 2)

Answer 18

Reduce chemotherapy from 9 mo. to 6 mo.

Mechanism: inhibits trans-translation

But needs to be used in combo with at least two more other drugs to avoid de facto mono therapy!

Question 19

Describe the rationale for not prescribing EMB to young children.

Answer 19

Blocks EmbA and EmbB arabinosyl transferases that incorporate arabinose into arinogalactan layer –> weakening cell wall and making M. tuberculosis susceptible to damage

Adverse effets: optic neuritis and red-green color blindness

Question 20

List two principles governing TB treatment in HIV-infected patients.

Answer 20

6-10% TB patients in US = HIV-positive

Use more aggressive regimen (-12 mo. treatment… even for LTBI)

No once weekly treatment for active TB disease

Note: Adverse interaction of RIF with antiretrovirals - so give patients rifabutin as substitute