4. Anti-Tuberculosis Agents

Question 1

Active TB treatment

Answer 1

2-months intensive phase of daily rifampicin, isoniazid, pyrazinamide & ethambutol (RIPE) followed by 4-months continuation phase of daily rifampicin and isoniazid

Question 2

MOA of rifampicin

Answer 2

Inhibits the gene transcription of mycobacteria by blocking the DNA-dependent RNA polymerase → prevents the bacillus from synthesising mRNA and protein → cell death
→ bactericidal

Question 3

Resistance to rifampicin

Answer 3

Mutations in the gene which encodes the RNA polymerase beta chain

Question 4

Drug-drug interaction in rifampicin

Answer 4

Induce certain cytochrome P450 enzymes → increase the metabolism of drugs (warfarin, corticosteroids, hormonal contraceptives, HIV protease inhibitors)

Question 5

Adverse effects of rifampicin

Answer 5

1. Cutaneous syndrome: flushing, pruritus, with or without rash, often with redness and watering of the eyes
2. Flu-like syndrome: fever, chills, malaise, headache, bone pain
3. Respiratory syndrome: shortness of breath
4. Severe immune-mediated reactions (rare): thrombocytopenic purpura, haemolytic anemia, acute renal failure
5. Hepatitis
6. Drug-drug interaction: induction of cytochrome P450
7. Orange discolouration of bodily fluids

Question 6

MOA of isoniazid

Answer 6

Isoniazid → prodrug → activated by the catalase-peroxidase enzyme of M. tuberculosis → produces oxygen-derived free radicals → inhibit formation of mycolic acids of bacterial cell wall, cause DNA damage → death

→ bactericidal

Question 7

Resistance to isoniazid

Answer 7

1. Mutations to the catalase-peroxidase enzyme

2. Mutations to the regulatory genes involved in mycolic acid synthesis

Question 8

Adverse effects of isoniazid

Answer 8

1. Isoniazid interferes competitively with pyridoxine metabolism by inhibiting the formation of the active form of vitamin B6 → peripheral neuropathy → prevent by supplemental pyridoxine
2. Hepatitis
3. Toxic psychosis, convulsions, haematologic reactions, lupus-like syndrome, hypersensitivity reaction (rarely)
4. Drug interactions → inhibitor of CYP450 → increase the plasma conc. of anticonvulsants such as phenytoin, and oral anticoagulants

Question 9

MOA of pyrazinamide

Answer 9

Pyrazinamide enters the bacillus passively → converted into pyrazinoic acid by pyrazinamidase → reaches high conc. in the bacterial cytoplasm → decrease intracellular pH to levels that cause the inactivation of critical pathways necessary for the survival of the bacteria

→ bactericidal

Question 10

Resistance to pyrazinamide

Answer 10

Mutations in the gene which encodes for the pyrazinamidase enzyme → prevents pyrazinamide from being converted into its active from

Question 11

Adverse effects of pyrazinamide

Answer 11

1. Gastrointestinal symptoms → nausea and vomiting
2. Photosensitivity
3. Hepatotoxicity
4. Hyperuricemia and arthralgia
5. Exanthema and pruritus

Question 12

MOA of ethambutol

Answer 12

1. Inhibits the arabinosyltransferase enzyme encoded by the embB gene and interferes with the polymerisation of arabinose into arabinogalactan, the principle polysaccharide on the myobacterial cell wall
2. This affects the integrity of the M. tuberculosis cell wall and thus facilitates the entry of lipophilic abs like rifampicin and levofloxacin

→ bacteriostatic

Question 13

Resistance to ethambutol

Answer 13

Mutation in the embB gene

Question 14

Adverse effects of ethambutol

Answer 14

1. Visual toxicity → decrease in visual acuity, red-green colour blindness, blurring, central scotoma (greater risk in patients with kidney failure and in elderly individuals)
   - toxicity is dose-dependent → recovery dependent on early withdrawal of the drug
   - caution in young children → visual acuity is difficult to evaluate
2. Hyperuricemia / gout

Question 15

Drug-drug interaction in ethambutol

Answer 15

Antacids can reduce the maximum serum conc. of ethambutol → separated by at least 2 hours

Question 16

Clinical indication for streptomycin

Answer 16

May be used as the fourth drug in place of ethambutol

Question 17

Multi-drug resistance TB

Answer 17

TB resistant to rifampicin and isoniazid

Question 18

Extensively drug resistant TB

Answer 18

MDR TB + additional resistance to any fluoroquinolone and second line injectable agent, which are the key second-line drugs in MDR-TB treatment regimens

Question 19

Cure of TB

Answer 19

1. Demonstration of negative sputum smear or culture in the last month of treatment and on at least one previous occasion
2. Nonconversion of sputum cultures at 2 months is a good surrogate marker for risk of relapse

Question 20

Treatment failure for TB

Answer 20

Positive sputum bacteriology at or after 5 months of treatment