13. Anti-TB Drugs

Mycobacterium tuberculosis is the leading infectious cause of death worldwide. Over ___ _______ people have already been infected. Infections result in the formation of ____ growing, _____________ lesions that cause tissue destruction anywhere in the body.

two billion

slow

granulomatous

What do Mycobacterium tuberculosis cell walls contain?

Mycolic acids - very long chain, β-hydroxylated fatty acids

According to their clinical utility, anti-TB drugs can be divided into 2 groups. List and describe them.

1. First line: high anti-TB efficacy; low toxicity; used routinely

2. Second line: either low anti-TB efficacy or higher toxicity or both; used as reserve drugs

List first line anti-TB drugs.

1. Isoniazid (H)

2. Rifampin (R)

3. Pyrazinamide (Z)

4. Ethambutol (E)

5. Streptomycin (S)

Which anti-TB drug is an essential component of all anti-TB regimens, unless the patient is not able to tolerate it/resistant?

Isoniazid (H)

Which anti-TB drug is the cheapest?

Isoniazid (H)

What does the H abbreviation in INH (isoniazid) stand for?

Highlights the hydrazide component of molecule; antitubercular activity

Describe the mechanism of action of isoniazid (H).

Inhibition of synthesis of mycolic acids (unique fatty acid components of mycobacterial cell wall)

List the adverse effects of isoniazid (H).

1. Well tolerated

2. Peripheral neuritis

3. Hepatitis (rare in children, more common in older people and alcoholics)

What is given prophylactically to prevent neurotoxicity with isoniazid (H)?

Pyridoxine (10mg/day)

Which anti-TB drug is a first-line oral agent for TB?

Rifampin (R)

Describe the mechanism of rifampin (R).

Interrupts RNA synthesis

List the other uses of rifampin (R).

1. Leprosy

2. Prophylaxis of meningococcal and H. influenzae meningitis

3. Second/third choice drug for MRSA

List an adverse effect of rifampin (R).

Hepatitis; occurs in patients w/pre-existing liver disease, dose-related

What harmless side effect may occur due to rifampin (R)?

Urine and secretions may become orange-red

Describe rifabutin and its uses.

• Derivative of rifampin

• Recommended in patients coinfected with HIV (less potent inducer of CYP enzymes than rifampin)

• Preferred for TB patients coinfected w/HIV who are receiving protease inhibitors (PIs) or several non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Describe pyrazinamide (Z).

1. Synthetic

2. Orally effective short-course agent; used in combination with isoniazid, rifampin, and ethambutol

3. Mechanism is unclear

4. Weakly tuberculocidal

5. More active in acidic medium

6. Most clinical benefit occurs early in treatment; highly effective during first 2 months of therapy when inflammatory changes present; discontinued after 2 months of 6-month regiment

List the adverse effects of pyrazinamide (Z).

May contribute to liver toxicity; uric acid retention is common

Describe the mechanism of ethambutol (E).

Inhibits enzyme important for synthesis of the mycobacterial cell wall

List the adverse effect of ethambutol (E).

Optic neuritis (diminished visual acuity and loss of ability to discriminate between red and green)

Which patients should ethambutol (E) be used with caution and why?

Patients with gout because ethambutol decreases uric acid excretion

Describe streptomycin (S) and its effectivity.

1. Aminoglycoside

2. Tuberculocidal

3. Less effective than INH or rifampin

4. Used only as alternative or in addition to other 1st line anti-TB drugs due to need for IM injections and lower margin of safety (ototoxicity and nephrotoxicity in elderly and those w/impaired renal function)

5. Use restricted to max. 2 months; thus labeled as a ‘supplemental’ 1st line drug

_______ and ________ are the most efficacious drugs; their combination is ____________; duration of therapy shortened from > ______ months to ____ months. Addition of ____________ for the initial 2 months further reduces the treatment to ___ months. A single _____ dose of all anti-TB drugs is preferred.

Isoniazid

rifampin

synergistic

twelve

nine

pyrazinamide

six

daily

Describe the ‘directly observed therapy short course.'

• Introduced by WHO in 1995

• 6-8 month multidrug regimens

• For initial empiric treatment, 4 drug regimen: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin

• Once TB isolate known to be fully susceptible, ethambutol or streptomycin can be discontinued

• New patient (therapy given for minimum 6 months)

• Acceptable if DOT ensured:

  • H + R + Z + E for 2 months, followed by H + R thrice weekly for 4 months

When does drug resistance - TB develop?

1. Patients do not complete course of treatment

2. Health care providers prescribe wrong treatment, dose, or duration

3. Supply of drugs not always available

4. Drugs are of poor quality

5. Poor compliance

What are the 2 types of drug resistant TB?

1. Multidrug resistant TB (MDR-TB)

2. Extensively drug-resistance TB (XDR-TB)

Describe multidrug resistance TB (MDR-TB).

Resistance to isoniazid and rifampicin with or without resistance to other anti-TB drugs

Describe extensively drug-resistant TB (XDR-TB).

Resistance to isoniazid and rifampicin + 1 fluoroquinolone + 1 of the 3 injectable 2nd line drugs (amikacin, kanamycin, or capreomycin)

Treatment of MDR and XDR: treatment regimens are based on patient’s ______ status and the results of ____________ testing, and require 18-24 _______ of treatment with _______ -line drugs.

health

susceptibility

months

second

Which second-line drugs are used to treat MDR and XDR?

1. Ethionamide

2. Cycloserine

3. Streptomycin

4. Capreomycin

5. Other aminoglycosides

6. Para-amino salicylic acid (PAS)

Which drugs are specifically used to treat XDR?

1. Clarithromycin

2. Clofazimine

3. Linezolid

4. Amoxicillin/clavulanate

5. Imipenem/cilastatin