Ethambutol infection

Treatment of disseminated MAC infections 600 mg/day in combination with ethambutol at the recommended daily dose of 15 mg/kg. 

A triple therapy regimen with combinations of clarithromycin or azithromycin plus ethambutol plus rifabutin is the current standard of care. However rifabutin may be omitted in HIV-infected patients on protease inhibitors because of significant interactions (Table 19). 

Ethambutol has replaced aminosalicylic acid as a first-line antitubercular drug. It is commonly included as a fourth drug, along with isoifiazid, pyrazinamide, and rifampin, in patients infected with MDR strains. It also is used in combination in the treatment of M. avium-intracellulare infection in AIDS patients. 

Quinolones are important recent additions to the therapeutic agents used against M. tuberculosis, especially in MDR strains. Clinical trials of ofloxacin in combination with isoniazid and rifampin have indicated activity comparable to that of ethambutol. In addition, quinolones, particularly ciprofloxacin, are used as part of a combined regimen in HIV-infected patients. 

M avium complex Pulmonary disease in patients with chronic lung disease disseminated infection in AIDS Amikacin, azithromycin, clarithromycin, ciprofloxacin, ethambutol, rifabutin... 

Ethambutol Inhibits mycobacterial arabinosyl transferases, which are involved in the polymerization reaction of arabinoglycan an essential component of the mycobacterial cell wall Bacteriostatic activity against susceptible mycobacteria Given as four-drug initial combination therapy for tuberculosis until drug sensitivities are known also used for atypical mycobacterial infections Oral t mixed clearance (half-life 4 h) dose must be reduced in renal failure Toxicity Retrobulbar neuritis... 

The mechanism of ethambutol (Myambutol) is not fully understood. This drug apparently suppresses RNA synthesis in susceptible bacteria, but it is not known how this occurs. Ethambutol is primarily effective against M. tuberculosis infections and is a secondary agent in the treatment of tuberculosis.61 Adverse effects associated with this drug include joint pain, nausea, skin rash and itching, and CNS abnormalities (dizziness, confusion, hallucinations). 

Not all mycobacterial infections are caused by M. tuberculosis or M. leprae. These atypical mycobacteria require treatment with secondary medications as well as other chemotherapeutic agents. For example, M. marinum causes skin granulomas, and effective drugs in the treatment of infection are rifampin or minocycline. Mycobacterium fortuitum causes skin ulcers and the medications recommended for treatment are ethambutol, cycloserine, and rifampin in combination with amikacin. 

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. 

The incidence of disseminated MAC infection has increased dramatically with the AIDS epidemic. Treatment regimens for patients with a positive culture for MAC from a sterile site should include two or more drugs, including clarithromycin. Prophylaxis against disseminated MAC should be considered for patients with a CD4 cell count of less than 50 X 10 /1 (11). In a randomized, open trial in 37 patients with HIV-associated disseminated MAC infection, treatment with clarithromycin -I- ethambutol produced more rapid resolution of bacteremia, and was more effective at sterilization of blood cultures after 16 weeks than azithromycin + ethambutol (12). 

A 35-year old Caucasian man with AIDS and multiple opportunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 4—5 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, mod-ified-release oral morphine, pseudoephedrine, diphenhydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal. 

Ward TT, Rimland D, Kauffman C, Huycke M, Evans TG, Heifets L. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium. Clin Infect Dis 1998 27(5) 1278-85. 

Arguments have been advanced for the abandonment of thiacetazone as an antituberculosis drug (11,12), despite its cheapness, on the grounds that it often causes severe skin reactions, some rapidly fatal, in patients infected with HIV-1 (13). The WHO and lUATLD has recommended careful information and surveillance of possible adverse reactions, particularly cutaneous, in patients treated for tuberculosis in such countries and immediate replacement with ethambutol if there are any prodromal signs of toxicity. 

The WHO and the World Bank agree that the control of TB is one of the most cost-effective health interventions any nation can pursue. Early identification of TB cases and the effective use of isoniazid, rifampin, and pyrazinamide (plus ethambutol) while the isolate is still drug-susceptible always should be the primary goals of public health departments. Contact investigation and treatment of those infected but without disease are important secondary goals to reduce the number of future cases. 

Treatment regimens for Mycobacterium avium complex infection should contain at least two antimycobacterial agents. Every regimen should contain either clarithromycin or azithromycin plus a second agent such as ethambutol. 

Benson CA, Williams PL, Currier IS, et al. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome. CUn Infect Dis 2003 37 1234-1243. 

From the discussion above is it clear that both AG and LAM play paramount roles in the infection and smvival of mycobacteria in the host. Drugs that act by inhibiting the biosynthesis of these polysaccharides are expected to show antimycobacterial action. One of the commonly used antimberculosis agents, ethambutol [(S,S )-2,2 -(ethylenediimino)di-l-butanol, 22] (Fig. 7), has been used for the treatment of tuberculosis since 1961, when it was first reported to have antimycobacterial activity... 

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. 

Clarithromycin or azithromycin is recommended as first-line therapy for prophylaxis and treatment of disseminated infection caused by M. avium-intracellulare in AIDS patients and for treatment of pulmonary disease in non-HIV-infected patients. Azithromycin (1.2 g once weekly) or clarithromycin (500 mg twice daily) is recommended for primary prevention for AIDS patients with fewer than 50 CD cells per mm. Single-agent therapy should not be used for treatment of active disease or for secondary prevention in AIDS patients. Clarithromycin (500 mg twice daily) plus ethambutol (15 mg/kg once daily) with or without rifabutin is an effective combination regimen. Azithromycin (500 mg once daily) may be used instead of clarithromycin, but clarithromycin appears to be slightly more efficacious. Clarithromycin also has been used with minocychne for the treatment of Mycobacterium leprae in lepromatous leprosy. 

Rifabutin is effective for the prevention of MAC infection in HIV-infected individuals. At a dose of 3(X) mg per day, rifabutin decreased the frequency of MAC bacteremia (2%). However, azithromycin or clarithromycin are more effective and less likely to interact with highly active antiretroviral therapy (HAART) drugs. Rifabutin also is commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients, as it has a less profound CYP-dependent interaction with indinavir and nelfinavir. Rifabutin also is used in combination with clarithromycin and ethambutol for the therapy of MAC disease. 

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