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Review Question - QID 100820

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QID 100820 (Type "100820" in App Search)
A 30-year-old man is diagnosed with multi-drug resistant tuberculosis after a recent trip to Eastern Europe. After drug susceptibility testing is completed, he is given a regimen of antibiotics as treatment. He returns two weeks later complaining of decreased visual acuity and color-blindness. Which drug of the following is the mechanism of action of the drug that is most likely to cause this side effect?

Inhibition of mycolic acid synthesis

11%

26/245

Inhibition of arabinogalactan synthesis

71%

174/245

Binding to ergosterol and formation of a transmembrane channel

5%

12/245

Inhibition of RNA synthesis

6%

14/245

Inhibition of RNA translation

2%

5/245

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The patient is presenting with ethambutol toxicity, of which side-effects include retrobulbar neuritis that results in color-blindness, decreased visual acuity, and central scotoma. Ethambutol is a bacteriostatic agent that works by obstructing the formation of the tubercular cell wall through its inhibition of arabingalactan synthesis.

Ethambutol is commonly used along with isoniazid, rifampicin, and pyrazinamide in the initial treatment of tuberculosis. Multi-drug resistant tuberculosis (MDR-TB) is commonly treated with a regimen that contains ethambutol as long as the tuberculosis has been shown to be susceptible to this drug. MDR-TB, by definition, is resistant to at least isoniazid and rifampicin. Treatment of MDR-TB should be guided by drug susceptibility testing. Other side-effects of ethambutol include peripheral neuropathy, arthralgia, hyperuricemia, and vertical nystagmus.

Chugn et al. detail the toxicity of ethambutol. They note that ethambutol exposure results in vacuole formation in cultured retinal cells. Addition of zinc to the ethambutol aggravates the toxicity while the addition of zink chelators reduces vacuole formation.

Inge et al. detail treatment strategies for active tuberculosis. It is advisable to initiate combination therapy with isoniazid, rifampin, pyrazinamide, and ethambutol for two months followed by isoniazid and a rifamycin product for four-to seven-months.

Incorrect answers:
Answer 1: Isoniazid inhibits mycolic acid synthesis. The main side effects of this drug include hepatitis, peripheral neuritis due to vitamin B6 deficiency, sideroblastic anemia, and systemic lupus erythematosus.
Answer 3: Amphotericin B binds to ergosterols in fungi and forms a transmembrane channel. It is not used in the treatment of tuberculosis and has toxicities that include fever/chills, hypotension, nephrotoxicity, arrhythmias, and anemia. Visual symptoms however are rare.
Answer 4: Rifampin inhibits RNA synthesis. It's side-effects include hepatitis and red-orange body secretions (non-hazardous).
Answer 5: Pyrazinamide is thought to inhibit fatty acid synthesis and RNA translation, although the exact mechanism of action is thus far unknown. Hepatitis and hyperuricemia are side effects of pyrazinamide.

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