Resistance to ethambutol

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. 

It suppresses the growth of most isoniazid- and streptomycin-resistant tubercle bacilli. Resistance to ethambutol develops very slowly in vitro. 

Nearly all strains ofM. tuberculosis and M. kansasii and many strains of MAC are sensitive to ethambutol. Sensitivities of other mycobacteria are variable. Ethambutol has no effect on other bacteria. Growth inhibition by ethambutol requires 24 hours and is mediated by inhibition ofara-binosyl transferases involved in cell wall biosynthesis. Resistance to ethambutol develops very slowly in vitro, but can result from single amino acid mutations when given alone. 

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. 

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. 

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. 

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... 

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. 

Pneumococci resistant to penicillins, certain cephalosporins, and macrolides are increasingly common. These organisms generally are susceptible to vancomycin, the new fluoroquinolones, and cefotaxime or ceftriaxone. M. tuberculosis resistant to one or more first-hue anti-tubercular agents (e.g., isoniazid, rifampin, ethambutol, streptomycin, and pyrazinamide) have increased in frequency as well. This has been... 

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... 

Ethambutol inhibits synthesis of one or more metabolites, causing impairment of cell metabolism, arrest of multiplication, and cell death. It is indicated in the treatment of tuberculosis, in combination with other agents in patients with Mycobacterium tuberculosis resistant to isoniazid or rifampin, or when there is intolerance to other antituberculous agents. 

A combination of rifampin and ethambutol is probably effective minocycline or tetracycline is active in vitro and is used by some physicians. M. scrofulaceum is an uncommon cause of cervical lymphadenitis that is treated with surgical excision. Microbes of the M. fortuitum complex (including Mycobacterium chelonae) may cause chronic lung disease and infections of skin and soft tissues. The microorganisms are highly resistant to most drugs, but amikacin, cefoxitin, and tetracyclines are active in vitro. 

For known resistance to isoniazid (or if the patient cannot tolerate the drug), the currently recommended regimen involves directly observed therapy (EXDT) with rifampin plus ethambutol plus pyrazinamide for 18 months (< 12 months after a negative sputum culture is reported). 

In the case of resistance to both INH and rifampin, initial regimens still include both drugs plus ethambutol, pyrazinamide, streptomycin (or other aminoglycoside), and a fluoroquinolone. Continuation therapy should include at least three drugs shown to be active in vitro against the infecting strain. The appropriate duration of therapy has not been established. 

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