Ethambutol active

The activity of rifampicin against mycobacteria has been intensively studied [430—432] both in vivo and in vitro, as has its activity in combination with other drugs such as isoniazid [433] and ethambutol [434]. 

Pharmacology Ethambutol diffuses into actively growing mycobacterium cells such as tubercle bacilli. It inhibits the synthesis of at least 1 metabolite, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross-resistance with other agents has been demonstrated. 

Ethambutol (Myambutel) [Antitubercular Agent] Uses Pulm TB other mycobacterial Infxns, MAC Action i RNA synth Dose Adults Feds >12 y. 15-25 mg/kg/d PO single dose X in renal impair, take w/ food, avoid antacids Caution [B, +] Contra Unconscious pts, optic neuritis Disp Tabs SE HA, hyperuricemia, acute gout, abd pain, T LFTs, optic neuritis, GI upset Interactions T Neurotox W/ neurotoxic drugs X effects W/ A1 salts EMS May affect glucose (hypoglycemia) may cause vision problems OD Sxs unknown activated charcoal may be effective symptomatic and supportive... 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

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. 

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... 

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... 

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 synthetic application of the a-chloro aldehydes has been demonstrated by the preparation of a variety of important chiral building blocks (Scheme 2.35) [26b]. The a-chloro aldehydes could be reduced to the corresponding optically active a-chloro alcohols in more than 90% yield, maintaining the enantiomeric excess by using NaBFU. It was also shown that optically active 2-aminobutanol - a key intermediate in the synthesis of the tuberculostatic, ethambutol - could be obtained in high yields by standard transformations from 2-chlorobutanol. Furthermore, the synthesis of an optically active terminal epoxide was demonstrated. The 2-chloro aldehydes could also be oxidized to a-chloro carboxylic acids in high yields without loss of optical purity, and further transformations were also presented. 

In the treatment of tuberculosis, resistant strains of M. tuberculosis (multidrug-resistant tuberculosis, MDRTB) present a growing problem, so that new antituber-culotic agents are required which act according to a different mechanism to that of standard agents such as isoniazid, rifampicin, pyrazinamide, and ethambutol. The more modern fluoroquinolones are of particular interest, and in particular moxifloxacin, which has powerful in vitro and in vivo activity and, in contrast to sparfloxacin and clinafloxacin, is not photo toxic [191]. 

Moxifloxacin s MIC90 value of 1 mg L"1 means that it has the same in vitro activity against M. tuberculosis as levofloxacin, and is more effective than ofloxacin (MIC90 = 2 mg L"1) and ciprofloxacin (MIC90 = 4 mg IT1) [192-194]. A combination of moxifloxacin and isoniazid proved to be more effective in vivo than the individual compounds [195,196], whereas a combination with ethambutol was less effective [196]. Based on the mutant prevention concentration (MPC), which is a parameter for the selection of resistant pathogens during antibiotic treatment, moxifloxacin was found to be the most effective fluoroquinolone against M. tuberculosis [197]. 

With both the above regimens, ethambutol by mouth or streptomycin i.m. should be added for the first 2 months if there is a likelihood of drug-resistant organisms, or if the patient is severely ill with extensive active lesions. 

Dickinson JM, Aber VR, Mitchison DA. Bactericidal activity of streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide alone and in combination against Mycobacterium tuberculosis. Am Rev Respir Dis 1977 116(4) 627-35. 

The agents most commonly used for the treatment of active MTB are isoniazid, rifampin, pyrazinamide, and ethambutol. Usually a four-drug regimen consisting of these first-line agents is preferred for the initial empiric treatment of MTB. When drug susceptibilities are known, the regimen should... 

Ethambutol is active only again.st dividing mycobacteria. It has no effect on encapsulated or other nonproliferating forms. The in vitro effect may be bacteriostatic or bactericidal, depending on the conditions. Its selective toxicity toward mycobacteria appears to be related to the inhibition of the incorporation of myeoiic acids into the cell walls of these organisms. 

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... 

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... 

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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