Ethambutol resistance

Mutations resulting in ethambutol resistance can arise spontaneously. The exact changes are unknown but may involve enzymes in carbohydrate synthesis pathways. 

The answer is c. (Hardman, pp 1161-1162.) An important problem in the chemotherapy of TB is bacterial drug resistance For this reason, concurrent administration of two or more drugs should be employed to delay the development of drug resistance. Isoniazid is often combined with ethambutol for this purpose. Streptomycin or rifampin may also be added to the regimen to delay even further the development of drug resistance. 

The drug can likely be used safely in older children but should be used with caution in children less than 5 years of age, in whom visual acuity cannot be monitored. In younger children, ethambutol at the dose of 15 mg/kg per day can be used if there is suspected or proven resistance to isoniazid or rifampin. 

The initial phase of the regimen must contain at least 3 of the following drugs Isoniazid, rifampin, and pyrazinamide, along with either ethambutol or streptomycin if the local resistance pattern to isoniazid is not documented or is greater than 4%. 

The 6-month regimen Ordinarily this consists of an initial 2-month phase of rifampin, isoniazid, and pyrazinamide and, if clinically indicated, streptomycin or ethambutol, followed by 4 months of rifampin and isoniazid. Reassess the need for a fourth drug when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than 4 P.1008... 

In patients who have received previous therapy, mycobacterial resistance to other drugs used in initial therapy is frequent. In retreatment patients, combine ethambutol with at least 1 of the second-line drug(s) not previously administered to the patient, and to which bacterial susceptibility has been indicated. 

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. 

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. 

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. 

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. 

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. 

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... 

Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol, 1-5 mcg/mL. Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB operon. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene. 

As with all antituberculous drugs, resistance to ethambutol emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in combination with other antituberculous drugs. 

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. 

Ethambutol suppresses the growth of isoniazid- and streptomycin-resistant tubercle bacilli. The most important but not common side effects are optic neuritis, decreased visual acuity, and inability to perceive the color green. 

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. 

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... 

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]. 

The drugs used to treat TB include capreomycin, cycloserine, ethambutol, isoniazid, pyrazinamide, rifabutin, rifampicin and streptomycin. Resistance is most likely with long courses of treatment of antimicrobial agents and treatment courses are six (or even nine) months long. 

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. 

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. 

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