Ethambutol: first-line anti-tuberculosis drug (EMB)
Ethambutol (EMB, brand name Myambutol, generic) is a first-line anti-tuberculosis drug and has been part of the standard armamentarium since 1961. In the modern four-drug initial regimen ethambutol is given alongside isoniazid, rifampicin and pyrazinamide for the first two months. Its main role is to prevent resistance, especially when the resistance profile is unknown or when there is a high resistance risk.
The substance is bacteriostatic and is also active against atypical mycobacteria such as Mycobacterium avium complex (MAC) and Mycobacterium kansasii. Limiting factors are the typical ocular toxicity in the form of optic neuritis and the need for dose adjustment in renal impairment.
Mechanism of action
Ethambutol inhibits arabinosyl transferase, an enzyme required for building the mycobacterial cell wall. The mycobacterial cell wall contains large amounts of arabinogalactan and lipoarabinomannan, which are essential for structural integrity. Without functional arabinosyl transferase, the wall cannot be replenished and growth halts.
This bacteriostatic action also enhances the uptake of other anti-tuberculosis drugs into the bacterial cell. Clinically this is important: ethambutol alone is not sufficiently effective but contributes therapeutic value as a resistance partner and synergist within the combination regimen.
The action is restricted to dividing bacteria; quiescent persisters are not reached. Therefore tuberculosis therapy always requires several months.
Indications
- Standard initial therapy of pulmonary and extrapulmonary tuberculosis: in combination with isoniazid, rifampicin and pyrazinamide for 2 months (standard 6-month regimen)
- Tuberculosis with prior treatment or known resistance: prolonged use in tailored regimens
- Mycobacterium avium complex (MAC) infection: part of the standard therapy with clarithromycin or azithromycin and rifabutin
- Mycobacterium kansasii infection: part of combination therapy
- Atypical mycobacterioses (e.g. M. abscessus): off-label in specialised regimens
Dosing and administration
Adults: 15 to 20 mg per kg body weight once daily, usually 1,200 to 1,600 mg. Maximum dose: 25 mg per kg in exceptional cases for short periods only.
Children: 15 mg per kg daily. Older recommendations were cautious about ethambutol in young children because of difficulty detecting optic neuritis; current WHO guidance accepts use in standard therapy if vision testing is normal.
Renal impairment: ethambutol is 80 % renally eliminated; dose adjustment or peak monitoring (peak 2 to 5 mg/L) in impaired function. In haemodialysis patients give after dialysis.
Take fasting with water, at least 1 hour before or 2 hours after meals. Aluminium- and magnesium-containing antacids must be 2 hours apart.
Side effects
Common: hyperuricaemia (often asymptomatic), gastrointestinal complaints (nausea, vomiting, abdominal pain), headache, fatigue, pruritus, rash.
Uncommon: optic neuritis (typical dose-dependent toxicity), peripheral neuropathy, dizziness, confusion, fever, arthralgia.
Rare and very rare: acute gout, hepatitis, thrombocytopenia, leukopenia, anaphylaxis, Stevens Johnson syndrome, interstitial nephritis.
Optic neuritis:
- The most relevant adverse effect, mainly dose-dependent (above 25 mg per kg distinctly more frequent)
- Symptoms: visual deterioration, colour vision disturbance (especially red-green), central scotoma, restricted visual field
- Bilateral or unilateral
- Usually reversible after immediate stopping, but in severe cases persistent
- Ophthalmological assessment before therapy (visus, colour vision, visual field), monthly during higher dose or in at-risk patients
- Any visual deterioration triggers immediate discontinuation and ophthalmological evaluation
Interactions
- Aluminium- and magnesium-containing antacids: reduced absorption, minimum 2 hours apart
- Other ophthalmotoxic substances (hydroxychloroquine, tamoxifen): additive risks
- Other neurotoxic substances (linezolid, vincristine): additive polyneuropathy
- Renally eliminated co-medication: joint level monitoring in impaired function
- Allopurinol: caution with hyperuricaemia and gout history
Special considerations
Pregnancy: ethambutol is the most thoroughly documented anti-tuberculosis drug in pregnancy and is acceptable in standard therapy.
Breastfeeding: small amounts pass into milk, clinically unproblematic.
Pre-existing visual impairment: with pre-existing optic disease (glaucoma, macular degeneration, diabetic retinopathy) symptom interpretation is harder. More intense surveillance is sensible; alternative agents may be considered.
Hyperuricaemia and gout: ethambutol raises uric acid levels. With symptomatic gout or hyperuricaemia, close monitoring; possibly additional uricostatic therapy.
Adherence: tuberculosis therapy works only with full and consistent intake. DOT (directly observed therapy) is recommended for at-risk patients to avoid resistance.
Dark urine: rifampicin in the same regimen turns urine orange-red. This is part of normal therapy and not caused by ethambutol.
Related substances
- Isoniazid, INH as the cornerstone of TB therapy
- Rifampicin, another standard agent
- Oxytetracyclin, alternative tetracycline antibiotic
- Azithromycin, often part of MAC therapy
Frequently asked questions
Why do I need ethambutol if three other TB drugs are already prescribed?
Ethambutol mainly prevents resistance to the other agents. With an unknown resistance profile at the start of therapy it protects the overall regimen. Once susceptibility is documented, it can usually be stopped after 2 months.
How do I recognise optic neuritis early?
First hints are subjective deterioration of vision, problems with colour vision (especially red-green), unclear spots in the visual field or blurred vision. With any suspicious symptom: pause therapy and see an eye doctor without delay.
Can I become pregnant during TB therapy?
Pregnancy during active TB treatment is not ideal but is no absolute reason to stop. Ethambutol, isoniazid and rifampicin are acceptable in pregnancy. Pyrazinamide is debated but allowed in many guidelines. Close counselling is needed.
How long do I have to take ethambutol?
In standard therapy of drug-susceptible TB 2 months as part of the initial phase. With resistance, atypical mycobacteria or MAC therapy can be much longer, often 6 to 18 months.
Sources
- BfArM Federal Institute for Drugs and Medical Devices
- EMA European Medicines Agency
- AWMF tuberculosis guideline
- Gelbe Liste ethambutol monograph
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