Ethambutol: An overview

INTRODUCTION — 

Ethambutol is an antimycobacterial agent that is most commonly used in combination with other drugs in the treatment of tuberculosis (TB) [1]. It is also used as part of a combination regimen in the therapy of nontuberculous mycobacterial infections [1,2].

Guidelines on treatment of TB published by the American Thoracic Society (ATS), United States Centers for Disease Control and Prevention (CDC), and Infectious Disease Society of America (IDSA) may be accessed through the ATS website.

Guidelines on treatment of nontuberculous mycobacterial infections published by the ATS, European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and IDSA may be accessed through the IDSA website.

MECHANISM OF ACTION — 

The mechanism of action of ethambutol is not completely known. There is evidence that the drug exerts its bacteriostatic activity by virtue of inhibition of arabinosyl transferase, an enzyme that polymerizes arabinose into arabinan and then arabinogalactan, a mycobacterial cell wall constituent.

SPECTRUM OF ACTIVITY — 

The antimicrobial activity of ethambutol is limited to mycobacteria. Most data regarding the clinical and in vitro activity of ethambutol derive from experience in patients with tuberculosis (TB). Synergy of ethambutol against Mycobacterium tuberculosis has been demonstrated in some in vitro models with other antimycobacterial drugs, such as isoniazid, rifampin, and fluoroquinolones. However, its primary role for treatment of Mycobacterium avium complex in combination with macrolides is to delay macrolide resistance in these patients [3].

RESISTANCE

●M. tuberculosis – The breakpoint for M. tuberculosis complex ethambutol susceptibility is ≤5 mcg/mL; the breakpoint for ethambutol resistance is >5 mcg/mL [4].

M. tuberculosis resistance to ethambutol is due to random spontaneous genetic mutations, occurring at a rate of approximately 1 in 10⁷ organisms. Mutations mediated primarily via mutations in the embB gene most commonly result in increased production of the enzyme arabinosyl transferase, which overwhelms the inhibitory effects of ethambutol [5-7]. (See "Epidemiology and molecular mechanisms of drug-resistant tuberculosis".)

Primary (pretreatment) resistance rates of M. tuberculosis to ethambutol vary widely, depending largely on the population sampled and method used to detect resistance. In one report, resistance to ethambutol in the United States ranged from 0.9 to 4.2 percent (depending on the region of birth) [8]. The rate of ethambutol resistance in the United States increases in foreign-born individuals and, in general, is seen most frequently in isolates resistant to other first-line antituberculous agents.

The sensitivity of whole genome sequencing for detection of ethambutol resistance in clinical M. tuberculosis complex isolates is limited (60 to 65 percent) [9,10].

●Nontuberculous mycobacteria – Routine susceptibility testing is not recommended for clinical decision making; minimum inhibitory concentration (MIC) ≤4 mcg/mL may be considered as a susceptible threshold. For Mycobacterium kansasii, MICs ≤4 mcg/mL and ≥8 mcg/mL would be considered susceptible and resistant, respectively [11].

In vitro resistance to ethambutol was reported in approximately 50 percent of nontuberculous mycobacterium (NTM) pulmonary isolates, most of which were M. avium complex (MAC) [12]. Despite a report of favorable treatment outcomes in patients with MAC lung disease with ethambutol MICs <8 mcg/mL [13] (see "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Treatment of Mycobacterium avium complex pulmonary infection in adults"), there is generally a lack of correlation of susceptibility and outcome in the treatment of this infection [14,15].

Resistance rates are variable against other species of NTM. For example:

•Mycobacterium bovis and Mycobacterium kansasii are usually inhibited by ethambutol concentrations that are achievable in the blood. However, in vitro standards for NTM are unavailable for M. kansasii [16]. Although Mycobacterium marinum is also commonly treated with ethambutol, routine susceptibility testing for this pathogen is not recommended [17].

•MAC is also generally susceptible but may require higher concentrations (up to 10 microgram/mL). However, isolate susceptibility varies widely, ranging from 2 to 32 mcg/mL by broth microdilution [13].

•Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium haemophilum, and Mycobacterium chelonae are often highly resistant to ethambutol [17].

PHARMACOKINETICS — 

Approximately 80 percent of an ethambutol dose is absorbed after oral administration. Absorption is proportional to dose and is not significantly altered by food but is reduced by concomitant ingestion of aluminum hydroxide. Peak serum concentrations after repeated doses of 25 mg/kg are approximately 4 to 5 microgram/mL and occur between two and four hours after administration.

Because of its low degree of protein binding (6 to 30 percent), ethambutol undergoes wide distribution. However, cerebrospinal concentrations are low (1 to 2 microgram/mL) even in the presence of inflamed meninges [18] suggesting that an alternative drug be used in treatment of central nervous system TB. Higher concentrations have been reported in both epithelial lining fluid and alveolar cells than plasma with highest in alveolar cells (15-fold that of plasma) [19].

Ethambutol is partially metabolized in the liver, with 50 to 80 percent of the drug excreted unchanged in the urine and 20 percent in the feces. The serum half-life of 2.5 to 3.6 hours may be prolonged to up to 10 hours in patients with end-stage kidney disease (table 1) [20].

PHARMACODYNAMICS — 

The target parameter which best describes optimal pharmacodynamic targets for ethambutol varies with study model and endpoint. Ratios of AUC/MIC have been described as the optimal target to describe microbiologic killing, while optimal resistance prevention has been correlated with time above the organism's MIC [21,22].

DOSING AND ADMINISTRATION — 

Ethambutol tablets are available in strengths of 100 and 400 mg. All regimens described below are used as part of combination therapy. For the treatment of tuberculosis (TB), regimens other than daily should utilize directly observed therapy.

For the treatment of TB in adults, the recommended dose is rounded based on tablet strength, body weight, and desired frequency of administration (table 1).

The frequency (daily versus intermittent) of ethambutol for the treatment of drug-susceptible TB is dependent on the phase of therapy (intense versus continuation), patient population, and the need/ability to employ intermittent therapy [23]. Daily doses approximate 15 mg/kg, while twice and three-times weekly dosing approximate 35 to 50 mg/kg and 25 mg/kg, respectively.

For treatment of M. avium complex (MAC) pulmonary disease, recommended dosing is based on severity and/or response to prior therapy. Regimens are 15 mg/kg daily or 25 mg/kg three times weekly. Patients with nonsevere, nodular bronchiectatic disease may receive three-times weekly therapy and those with severe, cavitary disease or refractory to prior therapy should receive daily therapy [24,25]. Daily therapy is also recommended in human immunodeficiency virus (HIV)-coinfected patients with disseminated disease [26].

Optimal dosing for nontuberculous mycobacterium other than MAC has not been determined. Despite the lack of correlation of treatment outcomes to susceptibility results, 15 mg/kg/day is generally recommended for M. kansasii pulmonary infections [25,27,28]. Similar lack of in vitro correlations and daily dosing recommendations apply to infections due to Mycobacterium xenopi and Mycobacterium malmoense. (See "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Treatment of Mycobacterium avium complex pulmonary infection in adults".)

SPECIAL POPULATIONS

Liver failure — No adjustment of the ethambutol dose is necessary in patients with hepatic failure.

Kidney disease — Approximately 50 to 80 percent of ethambutol is eliminated as unchanged drug via the kidneys. Therefore, dose adjustment is required in patients with severe kidney impairment to reduce the risk of toxicity (primarily ocular) [29,30].

●Patients with creatinine clearance ≥30 mL/minute − For these patients, no dose adjustment is required.

●Nonobese patients with creatinine clearance <30 mL/minute or receiving intermittent hemodialysis − For these patients, a standard dose (ie, 15 to 25 mg/kg of actual body weight ["dry weight"] for adults) should be administered three times weekly by directly observed therapy (table 1) [20,31,32].

Patients requiring intermittent hemodialysis should receive the dose after dialysis. In one report of a patient undergoing high-flux hemodialysis, a mean 41 percent decrease in serum ethambutol concentration during dialysis was observed [33].

●Patients on peritoneal dialysis − Data to guide dosing for these patients are limited. Therefore, the initial dosing for such patients is the same as for those on intermittent hemodialysis. Adjustments should be based on serum concentration monitoring.

●Patients on continuous venovenous hemofiltration − Data to guide dosing for these patients are limited. Therefore, the initial dosing for such patients is the same as for those on intermittent hemodialysis. In one case report, adequate ethambutol concentrations were maintained [34]. Adjustments should be based on serum concentration monitoring.

Issues related to serum concentration monitoring are discussed below. (See 'Serum concentration monitoring' below.)

Additional details are provided separately in the ethambutol drug monograph, available within UpToDate.

Children — In general, serum concentrations observed in children are lower than adults when receiving comparable weight-based doses [35,36]. This may be due to enhanced drug clearance relative to adult patients [37]. Therefore, dosing of ethambutol (given in combination with other antimycobacterial agents) in infants, children, and adolescents <15 years of age, weighing <40 kg is 20 mg/kg (range 15 to 25) mg/kg daily or 50 mg/kg twice weekly [23]. However, some data suggest that even compliance with standard WHO ethambutol dosing may result in exposures exceeding recommended reference ranges in a majority of children with tuberculosis (TB) [38].

Since visual acuity and color perception changes are difficult to assess in young patients, ethambutol may be avoided in children without cavitating lesions whose visual acuity cannot be accurately assessed and/or at low risk of resistance to alternate primary treatments. However, the magnitude of risk posed by ethambutol to children in this setting is debated [39]. Therefore, the American Academy of Pediatrics recommends ethambutol as part of the intensive-phase regimen for children with TB even in the absence of risk factors for resistance [23,40].

Pregnant and lactating patients — Ethambutol is generally considered safe during pregnancy. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)

While limited data are available, maternal daily doses of up to 15 mg/kg have resulted in low concentrations in breast milk unlikely to cause harm in infants >2 months of age [41]. Other studies utilizing simulated data reported concentrations in breastfed infants were not likely to be sufficient to cause concern [42].

Limited data regarding the pharmacokinetics of ethambutol in pregnant patients are available. In one report, ethambutol area under the time-concentration curve from 0 to 24 hours (AUC0-24) was reported to be 39 percent lower than in concentrations observed during the third trimester of pregnancy, but the data were limited by the lack of sample size in the post-partum group [43].

Older adults — Older adult patients may be more susceptible to the side effects of ethambutol, especially if they are receiving higher doses. Since renal function declines with age, careful attention should be paid to the need for potential dose adjustment based upon renal function in this patient population. The recommended maximum daily dose is 1.6 grams or 15 to 20 mg/kg ideal body weight. However, it is unknown whether higher doses in obese patients would be necessary and/or safe [44].

Patients with HIV infection — HIV patients receiving ethambutol in combination with rifampin frequently demonstrate low maximum serum concentrations (observed with a daily dose of 20 mg/kg or 50 mg/kg twice weekly or 30 mg/kg thrice weekly) [45,46]. In HIV-coinfected children, reductions in ethambutol have been reported regardless of antiretroviral therapy (ART) [47]. Therefore, reductions in exposure in HIV-coinfected patients are unlikely due to drug interactions related to their ART.

Patients with obesity — Data on optimal ethambutol dosing in individuals >90 kg or with BMI >30 are sparse; such patients may be a risk of inadequate drug exposure based on guidance for patients >75 kg in the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Disease Society of America (ATS/CDC/IDSA) guidelines (eg, ethambutol 1600 mg/day) [20,48,49].

Therefore, in such patients we initiate ethambutol therapy at 1600 mg/day, followed by serum drug concentration monitoring after three to five doses (within the first week of treatment and then as clinically indicated) to assess the need for dose adjustment. (See 'Serum concentration monitoring' below.)

ADVERSE EFFECTS — 

Ethambutol is generally well tolerated. Side effects are usually dose related and are more common when doses exceed 15 mg/kg.

Visual changes — Optic neuropathy (usually manifested as a change in visual acuity or red-green color blindness) is the most important ethambutol toxicity. It generally occurs after three to five months of therapy. Reports of ocular toxicity in children of all ages receiving ethambutol at doses of from 15 to 30 mg/kg documented are rare. In adults, the incidence of ocular toxicity occurred at >40 percent at doses of >50 mg/kg/day and 0 to 3 percent at a dose of 15 mg/kg/day [50]. In other reports, the incidence of optic neuropathy when ethambutol is taken for more than two months is 18 percent in subjects receiving more than 35 mg/kg per day, 5 to 6 percent with 25 mg/kg per day, and less than 1 percent with 15 mg/kg per day [51].

The increased incidence seen in patients with nontuberculous mycobacteria is most likely related to longer treatment durations [25]. Intermittent dosing has also been associated with a reduced incidence of reaction [52,53]. In a study of 229 patients treated with ethambutol for pulmonary M. avium complex (MAC) disease, the incidence of ocular toxicity, confirmed by an ophthalmologist, in those treated with daily ethambutol (25 mg/kg per day for two months, then 15 mg/kg per day) compared to intermittent therapy (25 mg/kg three days a week) was 6 versus 0 percent, respectively [50]. Ocular toxicity may be more common in patients with MAC when compared with those with tuberculosis (TB) due to longer durations of therapy.

Optic neuritis is reversible in most patients.

Guidelines to discuss the significance, prevention, detection, and management of ethambutol-induced optic neuropathy have recently been published [54].

Other reactions — Hematologic (neutropenia, thrombocytopenia), gastrointestinal (nausea, vomiting, abdominal pain, hepatotoxicity), central nervous system (headache, dizziness, confusion), and cutaneous reactions occur infrequently but may be more common in patients receiving concomitant ethionamide therapy.

Ethambutol, when used in combination with pyrazinamide for the treatment of latent TB in patients exposed to multidrug-resistant strains, has been associated with a high incidence of hepatotoxicity or gastrointestinal intolerance leading to discontinuation of therapy (approximately 60 percent of treated subjects in one report) [55].

Infrequently, ethambutol has been associated with eosinophilia and systemic symptoms [56]. In most of the existing reports, it was difficult to establish the unique contribution ethambutol played in such a reaction due to the concomitant administration of other first-line antituberculous agents.

MONITORING

Clinical monitoring — It is generally recommended that patients receiving ethambutol as part of combination therapy for treatment of a mycobacterial infection undergo baseline Snellen visual acuity and red-green color perception testing. All patients should be advised of the side effects associated with ethambutol, most notably those associated with the development of optic neuritis (such as reduction in visual acuity, altered color perception, or reduced brightness). The need for routine periodic visual acuity testing during therapy is controversial, especially if a dose of 15 mg/kg is chosen, but patients noting changes in their vision should be referred to an ophthalmologist for careful monitoring. In all patients receiving combination therapy for tuberculosis (TB) or M. avium complex (MAC) infections, baseline blood counts, serum chemistry, and liver function studies should be obtained and repeated in the event of suspected drug-related toxicity.

Serum concentration monitoring — In general, there are minimal data to correlating ethambutol serum concentrations and treatment outcome [57-59]. Therefore, there is no role for routine serum concentration monitoring.

Circumstances in which serum concentration monitoring may be useful to guide dosing include potential drug-drug interactions, suspected nonadherence, renal insufficiency or renal replacement therapy, obesity, HIV, suspected malabsorption, and/or either slow response or therapeutic failure.

For patients receiving 15 to 25 mg/kg daily, target peak (two hours post-dose) drug concentrations are 2 to 6 micrograms/mL. For patients receiving 50 mg/kg twice weekly, target peak (two hours post-dose) drug concentrations 4 to 12 mcg/mL. Peak concentrations below these ranges should prompt dose adjustment, with repeat serum concentration monitoring after three to five doses.

Since absorption may be delayed or impaired in some patients, some favor obtaining a second drug level (drawn six hours post-dose) to aid in characterizing the true peak concentration [30].

In situations when altered drug absorption is expected, obtaining both two-hour and six-hour concentration levels may be useful. In such settings, a six-hour concentration greater than or equal to the two-hour concentration (the expected time of peak concentration) would indicate delayed absorption. In contrast, in the setting of malabsorption, both the two-hour and six-hour concentrations would be below the expected range. Obtaining a six-hour sample also assists in determining drug clearance, after confirming expected absorption by two hours [58].

DRUG INTERACTIONS — 

Details about specific interactions may be obtained by using the drug interactions tool included within UpToDate.

SUMMARY AND RECOMMENDATIONS

●Clinical use – Ethambutol is an antimycobacterial agent that is most commonly used in combination with other drugs in the treatment of tuberculosis (TB). It is also used as part of a combination regimen in the therapy of Mycobacterium avium complex (MAC) infections in patients with or without concomitant infection with human immunodeficiency virus (HIV). (See 'Introduction' above.)

●Mechanism of action – The mechanism of action of ethambutol is not completely understood. There is evidence that ethambutol exerts its bacteriostatic activity through inhibition of arabinosyl transferase, an enzyme that plays an important role in mycobacterial cell wall formation. (See 'Mechanism of action' above.)

●Spectrum of activity – The antimicrobial activity of ethambutol is limited to mycobacteria. Synergy of ethambutol with other antimycobacterial drugs, such as rifampin and fluoroquinolones, has been demonstrated in vitro against M. tuberculosis. Ethambutol has variable activity against nontuberculous mycobacteria. (See 'Spectrum of activity' above.)

●Pharmacokinetics – Ethambutol is well absorbed after oral administration. Because of its low degree of protein binding, ethambutol undergoes wide distribution. However, cerebrospinal concentrations are low (even in the presence of inflamed meninges). (See 'Pharmacokinetics' above.)

●Dosing and administration – The dose of ethambutol is dependent upon body weight, frequency of administration, and indication. (See 'Dosing and administration' above.)

●Special populations

•Liver failure – No adjustment of the ethambutol dose is necessary in patients with hepatic failure. (See 'Liver failure' above.)

•Kidney disease – For patients with creatinine clearances <30 mL/min or receiving intermittent hemodialysis, the dosing interval for ethambutol should be extended from 24 to 36 hours. A small amount of ethambutol is removed by hemodialysis and doses should be administered after dialysis in these patients. (See 'Kidney disease' above.)

•Pregnancy – Ethambutol is generally considered safe during pregnancy. (See 'Pregnant and lactating patients' above.)

●Adverse effects – Optic neuropathy (usually manifested as a change in visual acuity or red-green color blindness) is the most important ethambutol toxicity. The reported incidence of optic neuropathy when ethambutol is taken for more than two months increases with higher dosing of the drug. Optic neuritis is reversible in most patients. (See 'Visual changes' above.)

●Monitoring – It is generally recommended that patients receiving ethambutol as part of combination therapy for treatment of a mycobacterial infection undergo baseline Snellen visual acuity and red-green color perception testing. (See 'Monitoring' above.)