Ethionamide resistance

Ethionamide (Trecator) is a derivative of isonicotinic acid and is chemically related to isoniazid. It is a secondary agent used in combination when primary agents are ineffective or contraindicated it is a bacteriostatic antituberculosis agent. Its exact mechanism of action is unknown but is believed to involve inhibition of oxygen-dependent mycolic acid synthesis. It is thought that mutations in the region of the (tnhA) gene that are involved in mycolic acid synthesis can cause both isoniazid and ethionamide resistance. 

Rifampin-, isoniazid-, streptomycin-, ethambutol-, and ethionamide-resistant strains have been found that are virtually untreacable with existing antibiotics cases have increased 28% since the 1980s. 

DeBarber A, K Mdluli, M Bosman, L-G Bekker, CE Barry (2000) Ethionamide activation and sensitivity in multidrug resistant Mycobacterium tuberculosis. Proc Natl Acad USA 97 9677-9682. 

Resistance The use of ethionamide alone in the treatment of tuberculosis results in rapid development of resistance. 

Lactation Because no information is available on the excretion of ethionamide in breast milk, administer to nursing mothers only if the benefits outweigh the risks. Children Investigations have been limited do not use in pediatric patients younger than 12 years of age except when the organisms are definitely resistant to primary therapy and systemic dissemination of the disease, or other life-threatening complications of tuberculosis, is judged to be imminent. 

Ethionamide is an analog of isoniazid and also inhibits mycolic acid synthesis. Its usefulness is limited by the rapid development of resistance. It can cause intense gastric pain and, like isoniazid, may also be neurotoxic. 

Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo. There can be low-level cross-resistance between isoniazid and ethionamide. 

Alternative or reserve drugs are used where there are problems of drug intolerance and bacterial resistance. They are in this class because of either greater toxicity or of lesser efficacy and include ethionamide (gastrointestinal irritation, allergic reactions), capreomycin (nephrotoxic), and cycloserine (effective but neurotoxic). Quinolone antibiotics such as ciprofloxacin and the more recently introduced macrolides such as clarithromycin and azithromycin also have useful activity against mycobacteria. 

Phototoxicity occurred in four of nine patients with multidrug-resistant tuberculosis treated with a combination of sparfloxacin (400 mg/day), ethionamide, and kana-mycin (initially for 3-4 months) (16). It occurred after several months of treatment and was presumably due to... 

Singla R, Gupta S, Gupta R, Arora VK. Efficacy and safety of sparfloxacin in combination with kanamycin and ethionamide in multidrug-resistant pulmonary tuberculosis patients preliminary results. Int J Tuberc Lung Dis 2001 5(6) 559-63. 

Ethionamide is considered a secondary drug for the treatment of tuberculosis. It is used in the treatment of i.soniazid-resistant tuberculosis or when the patient i.s intolerant to Iso-niazid and other drugs. Because of its low potency, the highest tolerated dose of ethionamide i.s usually recommended. Ga.strointestinal intolerance is the most common side effect associated with its use. Visual disturbances and hcpatotoxic-iiy have also been reported. 

The final step in each round of fatty acyl elongation in E. coli is the NADH-dependent reduction of the trans double bond, catalyzed by the homotetrameric (subunit mass of 29 kDa) NADH-dependent enoyl-ACP reductase I (encoded by fabl). The Fabl amino acid sequence is similar (34% identical) to the product of a gene (called inhA) from mycobacteria. InhA is involved in mycolic acid biosynthesis (A. Banerjee, 1994). The synthesis of these unusual 70-80 carbon mycobacterial acids requires a pathway composed of enzymes essentially identical to those of fatty acid synthesis. Missense mutations within the inhA gene result in resistance to the anti-tuberculosis drugs, isoniazid and ethionamide. The crystal structures of Fabl and InhA have been solved, and are virtually superimposable for most... 

Ethionamide is an antituberculosis agent that causes inhibition of peptide synthesis in susceptible organisms. It is indicated in the treatment of tuberculosis, in combination with other agents, in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance to other antituberculous agents. 

Ethionamide is a congener of INH, but cross-resistance does not occur. The major disadvantage of ethionamide is severe gastrointestinal irritation and adverse neurologic effects at doses needed to achieve effective plasma levels. 

It may be used alone to clear the sputum of mycobacteria within a span of 12 weeks in many cases, but bacterial resistance usually takes place in 35% of cases, and thus leading to frequent relapses. Therefore, it is employed in combination with isoniazid, pyrazinamide, cycloserine or ethionamide-such relapses are uncommon. 

The major problem in tuberculosis therapy is the buildup of resistance to the drug in use. Attempts at overcoming this difficulty took the form of additives such as substituted phenothiazines and acridines to retard emergence of resistance to INH 3i qj, combinations of drugs such as INH plus ethionamide, pyrazinamide, cycloserine or ethoxide . The biophysical aspects of the interaction of amino acridines with nucleic acids were reviewed 3,... 

Figure 25.3 Antitubercular agents small fragment-like molecules used as drugs (isoniazid, pyrazinamide, ethionamide, and ethambutoi) bedaquiline is recently approved for the treatment of multidrug-resistant TB PA824 and SQ109 are in clinical trial.

Tuberculosis remains a major cause of mortality and morbidity killing each year more than two million people. The emergence of multidrug-resistant strains of Mycobacterium tuberculosis, stresses the need for alternative therapies. Ethionamide (ETH), a second-line antibiotic, is used to treat multidrug-resistant tuberculosis. ETH is a prodrug and needs to be activated by the mycobacterial enzyme EthA in order to inhibit InhA, the enoyl-acyl ACP reductase involved in mycolic acid biosynthesis. We demonstrated that the limited effectiveness of ethionamide is due to the transcriptionnal repression of ethA by the bacterial regulator EthR. 

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