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Ethambutol
See also Antituberculosis drugs
General information
Ethambutol is tuberculostatic and acts against Mycobacterium tuberculosis and Mycobacterium kansasii as well as some strains of Mycobacterium avium complex. It has no effect on other bacteria. The sensitivities of non-tuberculous mycobacteria are variable. Ethambutol suppresses the growth of most isoniazid-resistant and streptomycin-resistant tubercle bacilli [ ].
Adverse reactions to ethambutol are mainly seen in patients taking very high doses, that is over 25 mg/kg/day. Dosages over 25 mg/kg/day should be administered for only about 2 weeks at the beginning of therapy. Treatment can then be continued with 15 mg/kg/day. If initial problems arise and ethambutol is essential, the daily dose should not exceed 10 mg/kg.
About 80% of an oral dose of ethambutol is absorbed from the gastrointestinal tract. Peak plasma concentrations are reached in 2–4 hours and the half-life is 3–4 hours. Within 24 hours, about 60% is excreted unchanged in the urine. In patients with renal insufficiency, the dose has to be altered [ ]. There is no indication for ethambutol monotherapy.
General adverse effects and adverse reactions
Visual disturbances are the most common adverse reactions and also the most important. These include diminished visual acuity, retrobulbar neuritis, retinal pigment displacement, and (rarely) hemorrhages. Gastrointestinal symptoms (abdominal pain or vomiting), and headache, dizziness, mental confusion, and hallucinations are all rarely seen. Adverse effects are more frequent in elderly patients and patients with alcoholism, diabetes, or renal insufficiency. Stevens–Johnson syndrome, toxic epidermal necrolysis [ ], purpura-like vasculitis, acute thrombogenic purpura, joint pain, drug fever, tachycardia, and leukopenia have been attributed to allergy. As these reactions often arise during combined treatment with other tuberculostatic drugs, it is difficult or impossible to determine which drug is responsible. Tumor-inducing and teratogenic effects have not been described.
Organs and systems
Respiratory
Acute lung injury has been attributed to ethambutol [ ].
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A 78 year old woman with active pulmonary tuberculosis was given isoniazid, rifampicin, ethambutol, and pyrazinamide. After 10 days she developed a fever, dyspnea, left-sided pleuritic chest pain, and hypoxemia. A chest CT scan showed bilateral pleural effusions. A biopsy specimen from the anterior basal segment of the right lower lobe showed diffuse alveolar epithelial damage, focal hemorrhage, and alveolar wall thickening, with moderate infiltration of inflammatory cells. Drug-induced acute lung injury was suspected and the antituberculosis drugs were withdrawn after 34 days. The fever subsided and the dyspnea and general weakness improved. The chest X-ray showed significant clearing of the infiltration with reduced pleural effusions but persistent atelectasis of the middle lobe in the right lung 1 month later. Isoniazid, rifampicin, and pyrazinamide were restarted 14, 19, and 30 days later respectively and there was no recurrence. Rechallenge was not undertaken.
The authors concluded that the lung injury was due to ethambutol.
Nervous system
Peripheral neuropathy can precede or accompany ocular damage from ethambutol. These symptoms can serve as warning of impending eye damage [ ]. Loss of sensitivity, with numbness and tingling of the fingers, are relatively rare adverse effects [ ]. Electroneuromyography in ethambutol-induced neuropathy has confirmed that elderly patients are at increased risk [ ]. Sensory changes are more severe than motor dysfunction [ ].
Sensory systems
Optic neuropathy
Optic neuropathy, which is primarily retrobulbar, is the most important adverse effect of ethambutol and takes two forms central and peripheral. The commoner is axial neuritis (central type), which involves the papillomacular bundle and results in reduced visual acuity, cecocentral scotoma, and blue-yellow color vision impairment. In periaxial neuritis (peripheral type) there is peripheral visual field loss, especially bitemporal defects, with sparing of visual acuity and red-green color vision impairment [ ]. Rarely damage to the retina and macula has also been reported [ , ]. The EIDOS and DoTS descriptions of this adverse reaction are shown in Figure 1 .
A review of 101 patients with clinical and electrophysiological findings suggestive of ethambutol retinopathy has been reported [ ]. The retinal findings included retinal pigment epithelial changes, macular edema, and flame-shaped hemorrhages. Electroretinography showed reduced wave amplitude and an abnormal wave pattern electro-oculography showed an abnormal Arden ratio.
The degree of optic nerve damage in patients with ethambutol-induced optic neuropathy, when the optic disc typically looks normal, is hard to assess. In a retrospective study in eight patients with a history of ethambutol-induced optic neuropathy, changes in retinal nerve fiber layer thickness (RNFLT) were measured using optical coherence tomography within 3 months after withdrawal of ethambutol [ ]. All had visual deficits characteristic of ethambutol-induced optic neuropathy at their initial visit, and the follow-up examination was performed within 12 months. Compared with the initial measurement, there was a statistically significant reduction in mean RNFLT in the temporal, superior, and nasal quadrants, the greatest reduction being in the temporal quadrant. During follow-up periods of 2–12 months, there was improved vision in both eyes in six patients, but either further impairment of RNFLT or no change. The authors concluded that impaired RNFLT in all quadrants of the optic disc was associated with ethambutol-induced optic neuropathy. Selective loss of fibers in the papillomacular bundle could explain the more prominent reduction on the temporal side. Recovery is often not complete, even in patients who report visual improvement after withdrawal of ethambutol.
Optical coherence tomography has been used to document reversible changes in the nerve-fiber layer secondary to ethambutol-induced optic neuropathy [ ].
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A 70-year-old man with Mycobacterium avium intracellulare complex pneumonia was given a combination of drugs that included ethambutol 2 g/day (29 mg/kg/day). He developed gradual painless loss of vision over 3 months after 7 months of treatment. There was marked thickening of the inferior quadrant nerve fibers corresponding to the visual field defects in the superior quadrant. As the thickness of the inferior quadrant nerve-fiber layer abated the visual fields improved in the superior quadrant.
These changes were attributed to retinal ganglion cell axonal swelling that resolved over time after withdrawal of ethambutol.
Presentation
Ocular symptoms begin with bilateral progressive blurred vision or defects in color vision. However, some individuals are asymptomatic and abnormalities are detected only by tests of vision. A central scotoma is the most common visual field defect. Dyschromatopsia in the form of red-green color changes may be the earliest sign. Fundoscopy is usually normal.
Ethambutol can reportedly precipitate symptoms in Leber′s hereditary optic neuropathy [ ].
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A 70-year-old woman with tuberculosis took ethambutol, rifampicin, isoniazid, and pyrazinamide. She had marked reduction in visual acuity in both eyes after 3 months of treatment and ethambutol was withdrawn. Her corrected visual acuity was 0.03 in both eyes. There was no hyperemia, swelling of the optic disc, or capillary dilatation in either eye. Centrocecal scotomas were found bilaterally. After 1 month her visual acuity had further reduced to 0.01 and the scotomas had enlarged. Genetic analysis revealed a point mutation in mitochondrial DNA 11778.
The authors concluded that ethambutol could be a risk factor for Leber′s hereditary optic neuropathy and found three similar cases in a literature reviews.
Mechanism
The exact mechanism of ethambutol-induced ocular toxicity is not known.
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The earliest onset of visual disturbance occurred in a 26-year-old man 3 days after beginning combined treatment including 15 mg/kg/day ethambutol, suggesting an idiosyncratic reaction [ ].
However, there is an association with low serum zinc concentrations and reduced renal function [ , ]. Biochemical research has shown the importance of zinc metabolism in the retina [ ]. Zinc is found in high concentrations in the choroid, the retina, and especially the ganglion cells. Retinol dehydrogenase, a zinc-containing enzyme, interferes with the transformation of retinol (vitamin A1), which is essential for color sensation and conal vision. Furthermore, zinc is involved in the biosynthesis of the specific transport of retinol from the liver to the effector cells. Ethambutol is a chelating agent and makes zinc unavailable for axoplasmic transport, provoking optic or retrobulbar neuritis [ ]. Patients with zinc blood concentrations below 0.7 μg/ml (reference range 0.9–1.0 μg/ml) before the use of ethambutol are at high risk of ocular disturbances [ ].
Dose relation
Ocular toxicity due to ethambutol is dose-related in the therapeutic range. At doses of over 50 mg/kg/day, over 40% of adults develop toxicity, compared with 0–3% at a dose of 15 mg/kg/day [ ].
Dosages not over 25 mg/kg/day during the first 2 months of treatment and 15 mg/kg/day thereafter are generally accepted as adequate [ ]. At a dosage of 15 mg/kg/day, which should be regarded as a maximum for maintenance therapy, ocular toxicity developed in only 1.6% of patients [ ]. Advanced age [ ], renal insufficiency, and diabetes can enhance ocular damage.
Time-course
The mean interval between the onset of therapy and the adverse reactions is as short as 1.5 months or as long as 12 months after the start of therapy [ ].
The onset of visual loss can be sudden and dramatic, with color vision defects in the red-green or blue";-yellow spectra, as well as variable field defects. In acute cases, disc edema is accompanied by splinter hemorrhages. Retrobulbar neuritis with ethambutol can be predominantly axial, presenting with reduced visual acuity and central scotoma, or periaxial, with peripheral field defects. In non-acute types the fundi and discs appear normal [ ]. Visual defects can be unilateral or bilateral.
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