Drug-resistant tuberculosis ethambutol

Ethambutol is a water-soluble, heat-stable compound that acts by inhibition of arabinosyl transferase enzymes that are involved in cell wall biosynthesis. Nearly all strains of M tuberculosis and M. kansasii and most strains of Mycobacterium avium-intracellulare are sensitive to ethambutol. Drug resistance relates to point mutations in the gene (EmbB) that encodes the arabinosyl transferases that are involved in mycobacterial cell wall synthesis. 

The most commonly used regimen for drug-susceptible tuberculosis consists of isoniazid, rifampin, and pyrazinamide daily for 2 months, followed by isoniazid and rifampin daily or two to three times a week for 4 months. If isoniazid resistance is suspected, ethambutol or streptomycin should be added to the regimen until the susceptibility of the mycobacterium is determined. This... 

Rifampin, usually 600 mg/d (10 mg/kg/d) orally, is administered together with isoniazid, ethambutol, or another antituberculous drug in order to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin is given twice weekly. Rifampin 600 mg daily or twice weekly for 6 months also is effective in some atypical mycobacterial infections and in leprosy when used together with a sulfone. Rifampin is an alternative to isoniazid prophylaxis for patients who are unable to take isoniazid or who have had close contact with a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain. 

Patients with inactive tuberculosis who have not received adequate therapy should be considered for 1 year of isoniazid treatment. HIV-infected intravenous drug abusers with a positive PPD test have 8% chance per year of developing active tuberculosis. Isoniazid prophylaxis in HIV-infected persons appears to be as effective as in non-immunocompromised persons. The CDC recommends that isoniazid prophylaxis be continued for 12 months. Persons infected with HIV who are exposed to multidrug-resistant tuberculosis should receive prophylaxis with rifampin and pyrazinamide (with close monitoring for hepatic toxicity) or high-dose ethambutol and pyrazinamide, with or without a fluoroquinolone. 

Mycobacterium tuberculosis (extensively drug-resistant) Lung Drug combinations (strepto-mycin/isonicotinyl/ hydrazine/rifampin/ ethambutol/pyrazinamide/ moxifloxacine/cycloser-ine/imipenem/co-amoxi-clav/clofazimine/ prochlorperazine/ metronidazole), PA-824 and R207910... 

Mycobacterium tuberculosis Add streptomycin or ethambutol as a fourth drug in a regimen containing isoniazid (INH), rifampin, and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH or rifampin resistance is very low. Streptomycin also is indicated for therapy of tuberculosis when one or more of the above drugs is contraindicated because of toxicity or intolerance. 

Use of PAS has diminished over the years following the introduction of more effective drugs, such as rifampin and ethambutol. At present, therapy with PAS is limited to the treatment of MDR tuberculosis. Problems with primary resistance, poor compliance due to GI intolerance, and lupuslike reactions have further discouraged its use. 

Streptomycin (Boxes 20-B, 20-H) was introduced into clinical use against tuberculosis in about 1943. However, resistant mutants always survived until newer drugs were developed. Isonicotinylhydrazide (isoniazid) is especially effective in combinations with suitable antibiotics and other drugs.8 The four-drug combination isoniazid, rifampicin (Box 28-A), pyrazinamide, and ethambutol is often used. Nevertheless, bacteria resistant to all of these have developed. 

Isoniazid (INH), rifampin, pyrazinamide, ethambutol, and streptomycin are the five first-line agents for treatment of tuberculosis (Table 47-1). Isoniazid and rifampin are the two most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95-98% of cases of tuberculosis caused by susceptible strains. The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy (Table 47-2). In practice, therapy is initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin until susceptibility of the clinical isolate has been determined. Neither ethambutol nor streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if either drug is used), but they do provide additional coverage should the isolate prove to be resistant to isoniazid, rifampin, or both. Unfortunately, such resistance occurs in up to 10% of cases in the United States. Most patients with tuberculosis can be treated entirely as outpatients, with... 

Ethambutol [e THAM byoo tole] is bacteriostatic and specific for most strains of M- tuberculosis and M- kansasii. Resistance is not a serious problem if the drug is employed with other antituberculous agents. Ethambutol can be used in combination with pyrazinamide, isoniazid, and rifampin to treat tuberculosis. Absorbed on oral administration, ethambutol is well distributed throughout the body. Penetration into the central nervous system (CNS) is therapeutically adequate in tuberculous meningitis. Both parent drug and metabolites are excreted by glomerular filtration and tubular secretion. The most important adverse effect is optic neuritis, which results in... 

As a rule, a regimen of two, three, or four of the five first-line antituberculosis drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin) is used in tuberculosis (1). The 6-month short-course regimen consists of isoniazid, rifampicin, and pyrazinamide for 2 months, followed by isoniazid and rifampicin for 4 months (1). It may be advisable to include ethambutol in the initial phase when isoniazid resistance is suspected or if the prevalence of primary resistance to isoniazid is over 4% in new cases. A 9-month regimen consisting of isoniazid and rifampicin is also highly successful (1). Treatment should always include at least two drugs to which the mycobacteria are susceptible. 

Unfortunately, MAC is resistant to the standard drugs used for tuberculosis, such as isoniazid and pyrazinamide. Multiple agents such as rifampin, rifabutin (ansamycin), clofazimine, imipenem, amikacin, ethambutol, ciprofloxacin, clarithromycin, and azithromycin have varying degrees of in vitro anti-MAC activity. Controversy formerly existed as to whether treatment for MAC is beneficial, but data indicate that an aggressive therapeutic approach decreases symptoms... 

Infections caused by Mycobacterium tuberculosis are treated with combination therapy. The primary drugs used are isoriazid, rifampin, ethambutol, and pyrazinamide. Highly resistant organisms may require the use of additional agents. Backup drugs include aminoglycoside, fluoroquinolones, capreomycin, and cycloserine. 

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