Continuing Education Activity

Ethambutol is a medication used in the management and treatment of tuberculosis. It is a bacteriostatic drug that inhibits cell wall synthesis. This activity outlines the indications, actions, and contraindications for ethambutol as a valuable agent in the treatment of tuberculosis. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, monitoring) pertinent for healthcare team members in treating patients with tuberculosis and related conditions.

Objectives:

• Identify the mechanism of action of ethambutol.
• Describe the potential adverse effects of ethambutol.
• Review the appropriate monitoring for patients receiving therapy with ethambutol.
• Outline some interprofessional team strategies for improving care coordination and communication to advance ethambutol and improve outcomes.

Indications

Ethambutol(EMB) has been available to treat tuberculosis (TB) since the 1960s. The original formulation of EMB was a racemic mixture of its L and D forms. The D form of ethambutol was known for its therapeutic effect; however, the L form was known for its toxicity and hence, discontinued.[1] Ethambutol is used for the treatment of pulmonary tuberculosis. It should not be used alone but rather in tandem with at least one other antituberculosis drug such as isoniazid. EMB shows effectiveness against strains of Mycobacterium tuberculosis but not so much against viruses, fungi, or other bacteria. Antituberculosis medications used in conjunction with EMB include cycloserine, ethionamide, pyrazinamide, viomycin, isoniazid, aminosalicylic acid, and streptomycin.  

Mechanism of Action

Ethambutol is one of the first lines of treatment for tuberculosis (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.[2] However, the underlying molecular mechanisms remain unclear.[3]

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. A study indicates that ethambutol binds to a TetR transcriptional regulator that enhances the INH sensitivity of the inhA gene. As a result, this increases the killing effect of INH.[4]

Administration

Standard dosing for adults is 100 mg or 400 mg oral tablets. However, in children, it varies between 15-20mg/kg of their body weight.[5]

Ethambutol should not be used stand-alone in initial treatment or re-treatment. It should be used in conjunction with another antituberculosis drug. Current first-line therapy for tuberculosis is a quadruple therapy of isoniazid(INH), rifampicin(RMP), pyrazinamide(PZA), and ethambutol(EMB) for two months, followed by a 4-month continuation of isoniazid and rifampicin and/or ethambutol.[6] 

Initial Treatment

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

Re-treatment

Recurrent tuberculosis is still a global issue. There has only been one reported re-treatment with ethambutol in a patient who previously recovered from ethambutol-induced optic neuropathy. The patient's initial treatment consisted of 22 mg/kg/day of ethambutol along with rifampicin, clarithromycin, and ciprofloxacin that eventually developed into ethambutol induced optic neuropathy. After she discontinued ethambutol, her visual acuity recovered while she continued to finish her regimen. However, ten years later, the patient was diagnosed with tuberculosis again. The patient was treated with rifampicin, clarithromycin, and ethambutol at 25 mg/kg/day three days a week. With the supplementation of copper at 2mg daily, the patient did not show significant signs of visual change after a 14-month course regimen.[7]

There have been recent studies to assess the administration of a dry powder inhaler (DPI) using EMB-loaded solid lipid nanoparticles(SLNs). The DPI formulations consisted of spray drying EMB-loaded SLNS with and without mannitol. The encapsulation efficiency was higher than 98%, and the particle size was sub-100 nm. Results have shown that EMB-loaded SLN DPI has high potential in the future direct treatment of TB.[8]

Adverse Effects

Loss of Visual Acuity

• Optic neuropathy/optic neuritis/retrobulbar neuritis
  • Decreased visual acuity
  • Scotoma
  • Color blindness
  • Visual defect (e.g., blurred vision)
• Peripheral neuropathy[9]                              
• Hepatotoxicity
• Numbness and tingling of extremities due to peripheral neuritis
• Mental confusion, disorientation, and possible hallucinations
• Psychosis[10]

There does not seem to be a teratogenic effect from EMB for pregnant women.[11]

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

Contraindications

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

Monitoring

A dosing regimen of an oral 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.[12] Serum levels of EMB decrease to undetectable levels by 24 hours since the last dose 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, it requires immediate discontinuation of the drug. However, there are reports of cases of irreversible blindness. Due to the adverse effect of ethambutol associated optic neuropathy, visual acuity testings such as baseline visual acuity, color vision, and a Humphrey visual field (HVF) should be performed periodically when administering EMB treatment during the regimen.[1]

Hepatotoxicity is a common adverse effect with antituberculosis treatments. Hence, both baseline and periodic hepatic function require assessment.

Patients receiving iron overload may need prolonged treatment or add an additional bactericidal drug to their regimen. One study showed that iron loading negatively affected the bactericidal properties of isoniazid (INH) and ethambutol (EMB). The excess iron has a limiting effect on the bactericidal effects of INH and completely inhibits that of EMB. Although this study focused on murine tuberculosis, it may have clinical implications for HIV-positive patients with lower CD4+ cells 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 an additional bactericidal drug to their regimen against tuberculosis.[13]

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.[5] There are currently unknown protocols to detect subclinical ethambutol-induced ocular toxicity. A study in Korea conducted various visual tests such as color vision tests, retinal nerve fiber layer optical coherence tomography tests (RNFL OCT), and pattern visual evoked potential tests (pattern VEP). The study showed that RNFL OCT and pattern VEP showed promising results as they could detect changes in visual patterns after six months, while other tests in visual acuity, color vision, or visual fields showed no significant changes.[14]

The manifestation of EMB-induced optic neuropathy appears to be from EMB’s 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 by EMB.[15] An in-vitro study suggests that therapeutic copper can be a potential treatment to prevent EMB-induced optic neuropathy while not compromising EMB’s bacteriostatic properties.[16]

Patients that experience any visual symptoms should discontinue the drug immediately and consult their doctor.

Enhancing Healthcare Team Outcomes

Ethambutol-induced optic neuropathy (ION) 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 EON, between 0.7 and 1.29% of patients on EMB showed a prevalence of EON when taking the World Health Organization (WHO) recommended dosages. Optical coherence tomography (OCT) showed a decrease in the thickness of the retinal nerve fiber layer (RNFL) that was clinically significant.[17] Ethambutol induced optic neuropathy s a well-known adverse effect of EMB treatment; all patients on ethambutol should be screened regularly by ophthalmologists 

Although EMB is a bacteriostatic agent used to prevent the emergence of drug resistance to other first-line drugs, there is beginning to be an acknowledgment for ethambutol resistant strains.[2] With the rise of drug-resistant strains of TB and the current six-month regimen of four drugs that can potentially expand to 18 to 24 months leading to inadequate compliance and poor outcomes, there is a search for different treatments. Completion of and compliance to the anti-tuberculosis regimen are of paramount importance in an effort to treat TB patients and control TB globally.[18] The development of new drugs such as benzothiazinones, compound SQ-109, PA-824 (a bicyclic derivative of nitroimidazole), delamanid, and bedaquiline to combat these challenges can have significant impacts on the way tuberculosis is treated and transmitted.[2] 

Given the toxicity profile of ethambutol, the decision to use it in treating tuberculosis cases should involve an entire interprofessional team, including infectious disease specialists, other clinicians (including mid-level practitioners), nurses, and pharmacists also specializing in infectious disease. Close monitoring of the patient, careful assessment of the medication profile, and determining the susceptibility of the infection are all key factors in chatting the therapeutic course. With an interprofessional approach, the likelihood of a positive outcome with fewer adverse effects is more likely. [Level 5]