Continuing Education Activity

Ethambutol is a bacteriostatic drug that inhibits cell wall synthesis and is used to manage and treat tuberculosis (TB). The mechanism of action, dosing considerations, pharmacokinetics, adverse event profiles, contraindications, boxed warnings, and monitoring strategies are highlighted within a multi-drug treatment. In particular, the severe adverse drug reaction relating to optic neuropathy is discussed, with relevant interventions mentioned. New drugs like bedaquiline offer promise in improving TB outcomes, but addressing pharmacy challenges and ensuring interprofessional collaboration remains crucial for effective patient management with ethambutol therapy. Given the emergence of ethambutol-resistant TB strains, the emphasis on contraindicated single regimen use is important.

This activity will highlight other key factors, such as off-label uses, dosing, and monitoring, pertinent to healthcare team members treating patients with tuberculosis and related conditions. The interprofessional team, including infectious disease specialists or ophthalmologists in complicated cases, is equipped with comprehensive knowledge to enhance patient care during therapy with ethambutol.

Objectives:

• Identify the mechanism of action of ethambutol in comparison to other medications for tuberculosis.

• Evaluate the potential adverse effects of ethambutol with emphasis on optic neuropathy.

• Determine the appropriate monitoring for patients undergoing therapy with ethambutol.

• Implement effective collaboration among interprofessional team members to improve treatment efficacy for patients who benefit from treatment with ethambutol.

Indications

Ethambutol has been utilized to treat tuberculosis (TB) since the 1960s. The original formulation of ethambutol was a racemic mixture of the L and D forms. The D form of ethambutol was known for therapeutic effect; however, the L form was known for toxicity and, hence, discontinued.[1]

FDA-Approved Indications

Ethambutol is used for the treatment of pulmonary tuberculosis. The medication should not be used as a single regimen but rather in tandem with at least 1 antitubercular drug, such as isoniazid. Ethambutol is effective against Mycobacterium tuberculosis strains but less effective against viruses, fungi, or other bacteria. Antitubercular medications used with ethambutol include cycloserine, ethionamide, pyrazinamide, viomycin, isoniazid, aminosalicylic acid, and streptomycin.[2]

Off-Label Uses

The American Thoracic Society/European Society of Clinical Microbiology and Infectious Diseases/European Respiratory Society/Infectious Diseases Society of America guideline for nontuberculous mycobacterial pulmonary disease endorses ethambutol for Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi.[3] Few imaging techniques can directly visualize tuberculosis in the body. Although not widely documented, technetium-99m ethambutol scintigraphy is emerging as a promising method. In a recent case, a patient with an iliopsoas abscess demonstrated increased uptake on Tc-99m ethambutol scintigraphy, later confirmed tubercular through pus analysis. This underscores the potential of Tc-99m ethambutol scintigraphy as a sensitive tool for detecting tubercular lesions, offering valuable insights for treatment and monitoring.[4]

Mechanism of Action

Ethambutol is one of the first lines of treatment for TB, along with rifampicin, isoniazid, and pyrazinamide. Ethambutol is considered a bacteriostatic drug, interfering with the biosynthesis of arabinogalactan in the cell wall, halting multiplying bacilli.[5] However, the underlying molecular mechanisms remain unclear.[6]

Researchers speculate that ethambutol has synergistic effects with isoniazid (INH) against Mycobacterium tuberculosis through a transcriptional repressor of the inhA gene, a targeted gene by INH that encodes for an enoyl-acyl carrier protein reductase which is necessary for bacterial cell wall integrity. The results of a study indicate that ethambutol binds to a TetR transcriptional regulator that enhances the INH sensitivity of the inhA gene. As a result, the bactericidal effect of INH is increased.[7]

Pharmacokinetics

Absorption: Ethambutol achieves peak serum concentrations within 2 to 4 hours post-administration. Upon daily administration at this dosage over prolonged periods, serum levels remain consistent.

Distribution: The drug's distribution is widespread, with erythrocyte concentrations approximately twice that of plasma. Ethambutol hydrochloride diffuses readily into actively growing mycobacterium cells, contributing to therapeutic efficacy.

Metabolism: The metabolism of ethambutol to an aldehyde intermediate and dicarboxylic acid is catalyzed by the alcohol dehydrogenase enzyme.

Excretion: Ethambutol is eliminated primarily via renal excretion, with a smaller fraction excreted in the feces. Patients with renal insufficiency may exhibit marked drug accumulation due to impaired clearance mechanisms.[8]

Administration

Available Dosage Forms and Strengths

Ethambutol can be administered orally and in tablet form in 400 and 100 mg doses. Ethambutol should not be used stand-alone in initial treatment or re-treatment. The medication should be used in conjunction with another antitubercular drug. Current first-line therapy for tuberculosis is a quadruple therapy of isoniazid (INH), rifampicin, pyrazinamide, and ethambutol for 2 months, followed by a 4-month continuation of isoniazid, rifampicin, and ethambutol. 

Adult Dosage

Initial treatment

Initial treatment for patients who have not received previous tuberculosis therapy should be administered with 15 mg/kg of body weight every 24 hours.

Re-treatment

Multidrug-resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB) is a global issue.[9] For patients with a history of previous tuberculosis treatment, the recommended dosage of ethambutol is 25 mg/kg administered orally daily. After 60 days of continuous therapy, the dosage should be reduced to 15 mg/kg administered orally once daily. The dosages for ethambutol, recommended by the American Thoracic Society (ATS)/Centers for Disease Control and Prevention (CDC) and Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for drug-susceptible tuberculosis, are outlined below.

Daily regimen

• For individuals weighing 40 to 55 kg: 800 mg (14.5 to 20 mg/kg)
• For individuals weighing 56 to 75 kg: 1200 mg (16 to 21.4 mg/kg)
• For individuals weighing 76 to 90 kg: 1600 mg (17.8 to 21.1 mg/kg)

Thrice weekly regimen

• For individuals weighing 40 to 55 kg: 1200 mg (21.8 to 30 mg/kg)
• For individuals weighing 56 to 75 kg: 2000 mg (26.7 to 35.7 mg/kg)
• For individuals weighing 76 to 90 kg: 2400 mg (26.7 to 31.6 mg/kg)

Twice weekly regimen

• For individuals weighing 40 to 55 kg: 2000 mg (36.4 to 50 mg/kg)
• For individuals weighing 56 to 75 kg: 2800 mg (37.3 to 50 mg/kg)
• For individuals weighing 76 to 90 kg: 4000 mg (44.4 to 52.6 mg/kg)

These dosages are calculated based on estimated lean body weight and are suitable for patients with normal renal function.[10] 

Only one reported re-treatment with ethambutol was documented in a patient who previously recovered from ethambutol-induced optic neuropathy. The patient's initial treatment consisted of 22 mg/kg/day of ethambutol with rifampicin, clarithromycin, and ciprofloxacin, which eventually developed into ethambutol-induced optic neuropathy. After clinicians discontinued ethambutol, her visual acuity recovered while she continued her regimen. However, 10 years later, the patient was diagnosed with tuberculosis again. The patient was treated with rifampicin, clarithromycin, and ethambutol at 25 mg/kg/day 3 days a week. With the supplementation of copper at 2 mg daily, the patient did not show significant signs of visual change after a 14-month course regimen.[11]

The results of recent studies have assessed the administration of a dry powder inhaler using ethambutol-loaded solid lipid nanoparticles. The dry powder inhaler formulations consisted of spray-drying ethambutol-loaded solid lipid nanoparticles with and without mannitol. The encapsulation efficiency was higher than 98%, and the particle size was sub-100 nm. Results have shown that dry powder inhalers using ethambutol-loaded solid lipid nanoparticles have a high potential for the direct treatment of TB.[12]

Specific Patient Populations

Hepatic impairment: Hepatotoxicity, including instances of liver damage leading to fatalities, has been reported with the use of ethambutol. Conducting baseline liver function assessments and monitoring hepatic function throughout treatment is necessary.

Renal impairment: To mitigate the risk of toxicity, the dosing regimen for ethambutol must be adjusted in patients with hemodialysis or creatinine clearance below 30 mL/min. Ethambutol should be administered 3 times a week instead of daily.

Pregnancy considerations: Ethambutol does not seem to have a teratogenic effect on pregnant women.[13]

Breastfeeding considerations: Limited evidence suggests that maternal intake of ethambutol of 15 mg/kg daily results in minimal levels in the breast milk, posing low risk to infants. The CDC advises against discouraging breastfeeding in women being treated with ethambutol.[14]

Pediatric patients: Ethambutol is not recommended for use in children aged under 13 due to the lack of established safety parameters. Per IDSA/CDC/ATS guidelines, the pediatric dose for ethambutol ranges from 15 to 25 mg/kg.[2]

Older patients: Limited data on the use of ethambutol in older patients suggests comparable safety and tolerability to adults. Assessing renal and hepatic function in older patients is necessary due to age-related changes that can impact the metabolism and excretion of medications.

Adverse Effects

Loss of Visual Acuity

• Optic neuropathy/optic neuritis/retrobulbar neuritis
  • Decreased visual acuity
  • Scotoma
  • Color blindness
  • Visual field defect
  • Blurred vision
• Peripheral neuropathy                              
• Hepatotoxicity
• Numbness and tingling of extremities due to peripheral neuritis
• Mental confusion, disorientation, and possible hallucinations
• Psychosis [15][16]

Patients with impaired renal function from renal tuberculosis may be more susceptible to ethambutol-induced optic neuropathy; this may be due to dependency on the kidney for excretion.[1]

Drug-Drug Interactions

Coadministration of ethambutol with aluminum hydroxide-containing antacids in patients with tuberculosis reduced mean serum concentrations and urinary excretion of ethambutol.[17] Avoid concurrent use of ethambutol with these antacids for at least 4 hours after administration. The results of a recent study found that the effectiveness of ethambutol against tuberculosis was negatively affected by metformin and rosiglitazone. Combining these drugs could harm tuberculosis treatment, especially during the initial phase, as ethambutol is crucial. Therefore, combined use is not advised in patients with tuberculosis receiving Directly Observed Therapy (DOT). Further research is needed to validate these findings.[18]

Contraindications

Patients need screening for contraindications to ethambutol. These contraindications would include patients incapable of noting visual symptoms, such as those with dementia, mental retardation, and children due to ethambutol-induced optic neuropathy. Other contraindications are patients with pre-existing ophthalmological diseases due to the ocular toxicity of ethambutol.[1] Contraindications also include hypersensitivity to ethambutol in patients.

Monitoring

A dosing regimen of a daily dose of 25 mg/kg of body weight of ethambutol reaches a therapeutic range of 2 to 6 mcg/mL in serum 2 hours after administration.[19] Serum levels of ethambutol decrease to undetectable levels by 24 hours, except for some patients with impaired renal function.

Ethambutol may cause ocular toxicity, which may be related to the dose and duration of the treatment. If signs indicate such an effect, immediate discontinuation of the drug is required. However, reports of cases of irreversible blindness exist. Due to the adverse effect of ethambutol-associated optic neuropathy, visual acuity tests such as baseline visual acuity, color vision, and a Humphrey visual field should be performed periodically when administering the treatment during the regimen.[1] Hepatotoxicity is a common adverse effect of antitubercular treatments. Hence, both baseline and periodic hepatic function require assessment.

Patients receiving iron overload may need prolonged treatment or added bactericidal drugs to their regimen. One study showed that iron loading negatively affected the bactericidal properties of isoniazid (INH) and ethambutol. The excess iron limits the bactericidal effects of INH and completely inhibits that of ethambutol. Although this study focused on murine tuberculosis, clinical implications for HIV-positive patients with lower CD4+ cells may exist but may also have certain degrees of iron loading or patients with haptoglobin 2-2 genotype. Due to the adverse effects of excess iron, patients who have these conditions may need to consider a more prolonged treatment and/or add bactericidal drugs to their regimen against tuberculosis.[20]

Toxicity

Signs and Symptoms of Toxicity

One of the most well-known adverse effects is optic neuritis. The effect of neuritis is dose-related, with greater than 40% of adults developing toxicity at doses greater than 50 mg/kg and around 0% to 3% of adults developing toxicity at 15 mg/kg/daily.[21] Currently, unknown protocols detect subclinical ethambutol-induced ocular toxicity. The results of a study in Korea conducted various visual tests such as color vision tests, retinal nerve fiber layer optical coherence tomography tests, and pattern visual evoked potential tests. The results showed that retinal nerve fiber layer optical coherence tomography tests and pattern visual evoked potential tests were promising as they could detect changes in visual patterns after 6 months, while other tests in visual acuity, color vision, or visual fields showed no significant changes.[22]

Management of Toxicity

The manifestation of ethambutol-induced optic neuropathy appears to be from the chelation of copper. A study with 60 patients undergoing treatment with ethambutol monitored their serum copper levels. Statistical analysis confirmed a significant change in copper concentration, supporting the copper chelation effect.[23] An in-vitro study suggests that therapeutic copper can potentially prevent ethambutol-induced optic neuropathy while not compromising the bacteriostatic properties.[24] Patients who experience any visual symptoms should discontinue the drug immediately and consult their doctor.[25]

Enhancing Healthcare Team Outcomes

Ethambutol-induced optic neuropathy is a well-known disease that can be irreversible but is preventable. Timely and appropriate screenings are important in determining the outcome of the patient. According to epidemiologic studies investigating this neuropathy, between 0.7% and 1.29% of patients showed a prevalence of optic neuropathy when taking the World Health Organization (WHO) recommended dosages. Optical coherence tomography demonstrated a clinically significant decrease in the thickness of the retinal nerve fiber layer.[26] Ethambutol-induced optic neuropathy is a well-known adverse effect of treatment; all patients on ethambutol should be screened regularly by ophthalmologists.[25]

Although ethambutol is a bacteriostatic agent used to prevent the emergence of drug resistance to other first-line drugs, ethambutol-resistant strains are recognized. With the rise of drug-resistant strains of TB and the current 6-month regimen of 4 drugs that can potentially expand to 18 to 24 months, leading to inadequate compliance and poor outcomes, a search for different treatments persists. Completion of and compliance with the anti-tuberculosis regimen are of paramount importance to treating patients with TB and controlling TB globally.[27] The development of new drugs such as bedaquiline, pretomanid, delamanid, and bedaquiline to combat these challenges can have significant impacts on the way tuberculosis is treated and transmitted.[5][28] 

Pharmacies are crucial in TB control, especially in high-burden countries. However, they often face challenges in providing quality care, including the availability of anti-TB drugs and patient management. Interventions, such as public-private mix initiatives, aim to improve case detection by training pharmacists to refer symptomatic patients for testing. Ethambutol, a key anti-TB drug, is often stocked, but quality assurance is essential. Future efforts should focus on expanding interventions to improve patient counseling and address inappropriate medication sales while establishing global pharmacy-specific guidelines and enhancing regulatory environments.[29]

Given ethambutol's toxicity profile, the decision to treat tuberculosis cases should involve an interprofessional team, including infectious disease specialists. Close monitoring of the patient, careful assessment of the medication profile, and determining the susceptibility of the infection are all key factors in charting the therapeutic course. An interprofessional team approach and open communication between infectious disease specialists, nurse practitioners, physician assistants, pharmacists, and ophthalmologists are necessary to optimize patient outcomes with ethambutol therapy.