Tuberculosis ethionamide

Ethionamide monooxygenase EtaA Physiological substrates unidentified Mycobacterium tuberculosis 200447... 

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. 

Ethionamide is active with respect to Mycobacterium tuberculosis and Mycobacterium leprae, but it does not have an effect on other microorganisms. It enhances phagocytosis at the center of tuberculous inflammation, which facilitates its decomposition. However, it frequently causes side effects associated with the gastrointestinal tract as well as a hepa-totoxic effect in approximately 5% of patients. Synonyms of this drug are trecatil, ethimide, thiomid, tuberin, tuberoid, and others. 

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. 

Mycobacterium tuberculosis Isoniazid + rifampin + ethambutol + pyrazinamide Streptomycin, moxifloxacin, amikacin, ethionamide, cycloserine, PAS, linezolid... 

Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 < g/mL, or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 g/mL. Serum concentrations in plasma and tissues of approximately 20 g/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum. A 1 g/d dosage, although effective in the treatment of tuberculosis, is poorly tolerated because of the intense gastric irritation and neurologic symptoms that commonly occur. Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine. 

A Banerjee, E Dubnau, A Quemard, V Balasubramanian, KS Um, T Wilson, D Collins, G de Lisle, WR Jacobs Jr. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263 227-230, 1994. 

A number of drugs—aminosalicylic acid [a mee noe sal i SIL ik], ethionamide [e thye on AM ide], cycloserine [sye kloe SER een]— are considered second-line drugs because they are no more effective than the first-line agents and their toxicities are often more serious. Streptomycin, the first antibiotic effective in the treatment of tuberculosis, has been discussed wth the aminoglycosides (see p. 314). Its action is directed against extracellular organisms. 

Sharma GS, Gupta PK, Jain NK, Shanker A, Nanawati V. Toxic psychosis to isoniazid and ethionamide in a patient with pulmonary tuberculosis. Tubercle 1979 60(3) 171-2. 

Schwartz WS. Comparison of ethionamide with isoniazid in original treatment cases of pulmonary tuberculosis. XIV. A report of the Veterans Administration—Armed Forces cooperative study. Am Rev Respir Dis 1966 93(5) 685-92. 

Samtsov VS. [Treatment of patients with pulmonary tuberculosis, complicated by peptic ulcer, with ethionamide and prothionamide.] Probl Tuberk 1973 51(7) 67-70. 

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. 

Patients with CNS tuberculosis usually are treated for longer periods (9 to 12 months instead of 6 months) (Table 110-4). In general, isoniazid, pyrazinamide, ethionamide, and cycloserine penetrate the cerebrospinal fluid (CSF) readily, but rifampin, ethambutol, and streptomycin have variable CNS penetration." Of the quinolones, levofloxacin may be preferred based on current data. Extrapulmonary TB of the soft tissues can be treated with conventional regimens. 

Zhu M, Namdar R, Stambaugh JJ, et al. Population pharmacokinetics of ethionamide in patients with tuberculosis. Tuberculosis 2002 82 91-96. 

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, which has bacteriostatic actions against M. tuberculosis (0.5 to 1 g/day in divided doses) is indicated in the treatment of tuberculosis where first-line drugs such as isoniazid and rifampin have failed. The side effects of ethionamide may include nausea and vomiting, diarrhea, metallic taste, hepatitis, jaundice, stomatitis, depression, drowsiness, asthenia, peripheral neuritis, olfactory disturbances, diplopia, blurred vision, optic neuritis, convulsions, postural hypotension, thrombocytopenia, gynecomastia, impotence, menorrhagia, or diabetes mellitus. 

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. 

M. tuberculosis Isoniazid -1- rifampin - -pyrazinamide -1- ethambutol or streptomycin Moxifloxacin or gatifloxacin cycloserine capreomycin kanamycin amikacin ethionamide clofazimine aminosalicylic acid... 

Drugs for tuberculosis Pyridines Isoniazid Ethionamide, pyrazinamide... 

The synthesis of analogues of isonicotinamide resulted in the discovery of ethionamide and a homologue in which the ethyl group is replaced with a propyl (prothionamide). Both compounds have proven to be bactericidal against Mycobacterium tuberculosis and Mycobacterium leprae. 

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