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PubMed1997

Optic neuropathy associated with ethambutol in Koreans.

Ethambutol is a useful first line antituberculous drug, but can cause significant visual impairment. In order to determine the clinical manifestations of optic neuropathy associated with ethambutol, and the margin of drug safety in Koreans, we investigated ten men and four women, diagnosed between 1995 and 1997 at Seoul Municipal Boramae Hospital as suffering from ethambutol toxicity. After determining their history, including the period during which ethambutol had been administered, and its dose, a complete eye examination was performed, including measurement of best-corrected visual acuity, pupillary examination, color vision, fundus examination and a test of visual field. Ocular ethambutol toxicity was observed at a dose as low as 12.3 mg/kg. Abnormal ophthalmic findings include decreased visual acuity and abnormal visual field, especially in the central scotoma, and abnormal color perception. In conclusion, ethambutol at a low dose can cause optic neuropathy, and for the early detection of this, a color vision test is important.

Antitubercular Agents↗
PubMed2003

Evaluation of visual functions in patients on ethambutol therapy for tuberculosis: a prospective study.

UNLABELLED: To study the incidence of clinical and subclinical optic nerve toxicity with ethambutol therapy in patients with tuberculosis and to evaluate the reversibility of its side effects after cessation of therapy. This prospective randomized controlled study included 60 newly diagnosed adult cases of tuberculosis, who were randomly assigned into two groups. The study group included 30 patients (60eyes) who received ethambutol as a part of their anti-tubercular treatment and the control group included 30 patients (60eyes) who did not receive ethambutol. The patients were examined on monthly basis. The visual parameters studied were best corrected visual acuity, pupillary reactions, optic disc changes, color vision, contrast sensitivity, pupil cycle time, visual field charting and visual evoked potential. Ethambutol was stopped in those patients in whom toxicity was detected and they were followed more frequently. Only one patient (3.3%) showed decrease in visual acuity, three patients (10%) developed visual field defects, two patients (6.7%) showed deterioration of contrast sensitivity, the pupil cycle time was prolonged in one eye and two patients (6.7%) showed abnormal visual evoked potential. During the therapy, all patients in the study group had normal pupillary reactions, fundus picture and color vision. CONCLUSIONS: Ethambutol induced ocular toxicity was seen in three patients (10%) in our study. The maximum visual recovery occurred in first six to eight weeks after stopping ethambutol. The visual recovery was complete in only one patient, but it was partial in two patients i.e. visual fields, contrast sensitivity and visual evoked potential remained abnormal.

Adult↗
PubMed2006

Ocular toxicity of ethambutol.

OBJECTIVE: To review the literature on ocular toxicity of ethambutol--its background, clinical presentation, toxicity characteristics, management, monitoring, and preventive measures. DATA SOURCES: Literature search of Medline from 1962 to May 2005. STUDY SELECTION: All related literature in English using the search formula: (ethambutol OR myambutol) AND (eye* OR ophthal* OR ocular) AND (adverse OR toxic). DATA EXTRACTION: All information was collected and analysed by authors. DATA SYNTHESIS: Ethambutol hydrochloride is a commonly used first-line anti-tuberculous agent. Although rare, ocular toxicity in the form of optic neuritis (most commonly retrobulbar neuritis) has been well documented since its first use in the 1960s. Classically described as dose- and duration-related and reversible on therapy discontinuation, reversibility of optic neuritis remains controversial. International guidelines on prevention and early detection of ethambutol-induced ocular toxicity have been published. Nonetheless, opinion of the clinical effectiveness of regular vision tests to enable early detection of toxicity is divided. CONCLUSIONS: The course of ethambutol-induced ocular toxicity is unpredictable. Measures to ensure a high level of awareness in medical staff and patients of this potential adverse effect appear to be the best current preventive method. Classified by the World Health Organization as a place with an intermediate tuberculosis burden and good health infrastructure, Hong Kong is in a good position to examine the unanswered questions about ethambutol-induced ocular toxicity.

Antitubercular Agents↗
PubMed2006

Ethambutol-associated optic neuropathy.

INTRODUCTION: Ethambutol is used in the treatment of tuberculosis, which is still prevalent in Southeast Asia, and can be associated with permanent visual loss. We report 3 cases which presented with bitemporal hemianopia. CLINICAL PICTURE: Three patients with ethambutol-associated toxic optic neuropathy are described. All 3 patients had loss of central visual acuity, colour vision (Ishihara) and visual field. The visual field loss had a bitemporal flavour, suggesting involvement of the optic chiasm. TREATMENT: Despite stopping ethambutol on diagnosis, visual function continued to deteriorate for a few months. Subsequent improvement was mild in 2 cases. In the third case, visual acuity and colour vision normalised but the optic discs were pale. OUTCOME: All 3 patients had some permanent loss of visual function. CONCLUSIONS: Ethambutol usage is associated with permanent visual loss and should be avoided if possible or used with caution and proper ophthalmological follow-up. The author postulates that in cases of ethambutol associated chiasmopathy, ethambutol may initially affect the optic nerves and subsequently progress to involve the optic chiasm.

Aged↗
PubMed1987

Optic neuropathy in ethambutol-treated renal tuberculosis.

Ethambutol is frequently used in the treatment of tuberculosis, and, although optic neuropathies have been reported with the use of ethambutol, this adverse side effect has been considered to be rare and generally reversible with discontinuation of the medication. However, we recently saw two patients with renal tuberculosis treated with ethambutol in whom visual loss from toxic optic neuropathies was severe and irreversible despite careful ophthalmological monitoring and prompt discontinuation of the agent at the first sign of impaired visual function. While ethambutol treatment is most commonly instituted for pulmonary tuberculosis, it is interesting to note that both of these patients had renal tuberculosis. Since ethambutol is actively excreted via the renal system, compromise of renal function such as due to renal tuberculosis may lead to serum concentration elevations of ethambutol sufficient to produce optic neuropathy.

Adult↗
PubMed1979

[A pilot and a controlled study of the influence of ethambutol on serum urate concentration and uric acid clearance (author's transl)].

Ethambutol is said to be capable of elevating serum urate concentration. This statement was reconsidered in three investigations using strictly supervised administration of ethambutol in a single daily dose of 25 mg. per kg. of body weight: (1) In short term administration 10 healthy subjects received ethambutol for eight days. (2) In a pilot study 13 patients suffering from pulmonary tuberculosis were treated with a triple combination including thambutol for six months. (3) In a controlled trial 23 patients were randomly allocated to one of the following regiments: In the first group patients received ethambutol plus isoniazid plus rifampicin for six months. In the second group patients received streptomycin plus isoniazid plus PAS for three months and thereafter streptomycin plus isoniazid plus ethambutol for another three months. Serum urate concentrations and clearances of uric acid and of creatinine were determined periodically in all subjects. A slight increase in serum urate concentration occurring in long term therapy showed no relation to ethambutol administration, but was obviously dependant on parameters related to the course of the disease in form of increase in body weight and physical activity, or related to the well known syntropy of chronic alcoholism and tuberculosis.

Alcoholism↗
PubMed1983

Hyperuricaemia induced by ethambutol.

Seventy patients with pulmonary tuberculosis and 12 healthy controls were included in a study to observe the effect of ethambutol on serum uric acid level. In ethambutol-treated cases a statistically significant increase in mean serum uric acid levels was observed in the second, third and fourth week of treatment. This increase was independent of dosage of ethambutol. However, 22 of the 52 (42%) ethambutol-treated cases showed no increase. Streptomycin was found not to potentiate the hyperuricaemic action of ethambutol. Hyperuricaemia due to ethambutol was reversed with probenicid but not by salicylates. No patient developed acute gouty arthritis although two developed arthralgia.

Adolescent↗
PubMed1999

Effect of rifabutin on ethambutol pharmacokinetics in healthy volunteers.

The effect of repeated administration of rifabutin on the pharmacokinetics and metabolism of ethambutol was evaluated in ten healthy volunteers. The subjects received a single oral administration of 1200 mg ethambutol on days 1 and 10 and a single daily oral dose of 300 mg rifabutin from days 3 to 9. No statistically significant difference was found in plasma pharmacokinetics (C(max), t(max), AUC, half-life and MRT) and in the renal clearance, whereas a significant decrease in the amount of unchanged ethambutol excreted in urine was observed. The decrease observed in ethambutol urinary excretion may be accounted for by taking into consideration the variability of the urinary excretion of ethambutol reported in the literature. However, a slight, likely not clinically relevant, induction or activation of kidney alcohol and/or aldehyde dehydrogenase isoenzymes by rifabutin cannot be ruled out at present. Evidence exists in the present study for autoinduction of rifabutin metabolism; this is shown by the lower plasma concentrations obtained 24 h after the seventh dose as compared to the theoretical concentrations.

Adult↗
PubMed2003

Leber's hereditary optic neuropathy mutations in ethambutol-induced optic neuropathy.

Primary mitochondrial DNA (mtDNA) mutation at the nt 11778 site in Leber's hereditary optic neuropathy (LHON) has been reported to be present in patients with ethambutol-induced optic neuropathy. To study further this association between LHON and ethambutol-induced optic neuropathy, we tested ethambutol-induced optic neuropathy patients for the presence of the mtDNA mutations at nucleotides (nt)-11778, nt-14484, nt-3460, nt-15257, nt-9438, nt-9804, nt-13730, and nt-14459 in 24, 15, 8, 6, 5, 5, 5, and 5 patients respectively. However, none of the ethambutol-induced optic neuropathy patients was found to exhibit any pathogenic LHON mtDNA mutation. In conclusion, we found no evidence of any association between ethambutol-induced optic neuropathy and the LHON mutations.

Adult↗
PubMed2004

Optical coherence tomography can measure axonal loss in patients with ethambutol-induced optic neuropathy.

PURPOSE: To map and identify the pattern, in vivo, of axonal degeneration in ethambutol-induced optic neuropathy using optical coherence tomography (OCT). Ethambutol is an antimycobacterial agent often used to treat tuberculosis. A serious complication of ethambutol is an optic neuropathy that impairs visual acuity, contrast sensitivity, and color vision. However, early on, when the toxic optic neuropathy is mild and partly reversible, the funduscopic findings are often subtle and easy to miss. METHODS: Three subjects with a history of ethambutol (EMB)-induced optic neuropathy of short-, intermediate-, and long-term visual deficits were administered a full neuro-ophthalmologic examination including visual acuity, color vision, contrast sensitivity, and fundus examination. In addition, OCT (OCT 3000, Humphrey-Zeiss, Dublin, CA) was performed on both eyes of each subject using the retinal nerve fiber layer (RNFL) analysis protocol. OCT interpolates data from 100 points around the optic nerve to effectively map out the RNFL. RESULTS: The results were compared to the calculated average RNFL of normal eyes accumulated from four prior studies using OCT, n=661. In all subjects with history of EMB-induced optic neuropathy, there was a mean loss of 72% nerve fiber layer thickness in the temporal quadrant (patient A, with eventual recovery of visual acuity and fields, 58% loss; patient B, with intermediate visual deficits, 68% loss; patient C, with chronic visual deficits, 90% loss), with an average mean optic nerve thickness of 26+/-16 microm. There was a combined mean loss of 46% of fibers from the superior, inferior, and nasal quadrants in the (six) eyes of all three subjects (mean average thickness of 55+/-29 microm). In both sets (four) of eyes of the subjects with persistent visual deficits (patients B and C), there was an average loss of 79% of nerve fiber thickness in the temporal quadrant. CONCLUSIONS: The OCT results in these patients with EMB-induced optic neuropathy show considerable loss especially of the temporal fibers. This is consistent with prior histopathological studies that show predominant loss of parvo-cellular axons (or small-caliber axons) within the papillo-macular bundle in toxic or hereditary optic neuropathies. OCT can be a valuable tool in the quantitative analysis of optic neuropathies. Additionally, in terms of management of EMB-induced optic neuropathy, it is important to properly manage ethambutol dosing in patients with renal impairment and to achieve proper transition to a maintenance dose once an appropriate loading dose has been reached.

Aged↗
PubMed1978

Comparison of various measures of sensitivity of M. tuberculosis to ethambutol.

A sensitivity test for ethambutol was standardised, and performed on cultures isolated from patients before and after the start of chemotherapy with ethambutol and isoniazid. A discrimination type of approach was employed and three criteria of resistance were evolved: (a) growth of 20 colonies or more on ethambutol 4 microgram/ml, using a standard inoculum; (b) a proportion of 25% or more on ethambutol 1.4 microgram/ml; (c) a proportion of 5% or more on ethambutol 2 microgram/ml. The MIC definition appears to be the best in view of its simplicity and insensitivity of the classification (as sensitive or resistant) to variations in inoculum size.

Drug Resistance, Microbial↗
PubMed1981

Ethambutol plus isoniazid for the treatment of pulmonary tuberculosis--a controlled trial of our regimens.

A controlled clinical trial of 4 regimens was undertaken in patients with bacteriologically positive, newly-diagnosed pulmonary tuberculosis. The regimens were: ethambutol 15 mg/kg plus isoniazid 400 mg, daily (E7H7); ethambutol 45 mg/kg plus isoniazid 15 mg/kg, twice a week (E2H2); ethambutol 90 mg/kg plus isoniazid 15 mg/kg, once a week plus isoniazid 15 mg/kg, mid-way between the weekly doses (E1H2); and ethambutol 90 mg/kg plus isoniazid 15 mg/kg, once a week (E1H1). All patients received streptomycin 1 g plus ethambutol 25 mg/kg body-weight plus isoniazid 400 mg daily for the first 2 weeks. The total duration of treatment was 12 months for all patients. There were 484 patients admitted to the study. After excluding 60 (41 with initial drug resistance to isoniazid), there remain 424 patients (107 E7H7, 101 E2H2, 107 E1H2, 109 E1H1) in the main analyses. The pretreatment characteristics of the 4 groups were broadly similar. A favourable response at 12 months was observed in 96%, 88%, 93% and 75% of patients respectively: the differences between the E1H1 regimen and the other 3 regimens were all significant (P less than or equal to 0.03) as was that between the E7H7 and E2H2 regimens (P = 0.05). Among the slow inactivators of isoniazid, the proportions with a favourable response at one year were similar in the 4 groups (range 95--91%). However, among the rapid inactivators, the proportion with a favourable response in the E1H1 group was only 57%. There was suggestive evidence that the E1H2 regimen was superior to the E2H2 regimen. Of the patients with bacteriologically quiescent disease at 1 year, approximately a half, at random, had no further chemotherapy and were followed up for a 4-year period. Bacteriological relapse requiring retreatment occurred in 15% of 54 E7H7 patients, 26% of 38 E2H2, 33% of 43 E1H2 and 54% of 37 E1H1 patients, a significant difference (P less than 0.001). A final evaluation of long-term (5-year) favourable response achieved by the 12-month regimens was 83% for the E7H7, 63% for the E2H2, 63% for the E1H2 and 33% for the E1H1 regimens. In general, the regimens were well tolerated and the incidence of adverse reactions to the drugs was low. Of the 424 patients, 6 (1.4%) developed a visual disturbance during the year of chemotherapy.

Adolescent↗
PubMed1996

Modulating wavelength discrimination in goldfish with ethambutol and stimulus intensity.

Wavelength discrimination in goldfish was measured behaviourally. Both acute application of ethambutol injected into the eye and chronic application by feeding the animals daily 25 mg ethambutol for 1 month had the same effect on wavelength discrimination in the range of 560-640 nm. This means that: (1) electrophysiological experiments, in which drug application is primarily acute, reflect the same disturbance as behavioural experiments, in which drug application is chronic; and that (2) the origin of the color vision defect must be retinal. Furthermore reduction in stimulus intensity by 2 log units caused, in control fish, a similar disturbance in wavelength discrimination as induced by ethambutol, whereas an increase of stimulus intensity by 2 log units abolished in ethambutol-fed fish the discrimination disturbance. These results indicate that ethambutol shifts the threshold for wavelength discrimination without changing the absolute sensitivity of the cone systems.

Animals↗
PubMed2005

Mechanistic explanation to the catalysis by pyrazinamide and ethambutol of reaction between rifampicin and isoniazid in anti-TB FDCs.

Rifampicin and isoniazid are known to interact with each other in solid formulation environment to yield isonicotinyl hydrazone (HYD). In earlier studies, this reaction was indicated to be catalyzed by pyrazinamide and ethambutol hydrochloride, the two other co-drugs present in oral anti-tuberculosis fixed-dose combination (FDC) formulations. Accordingly, the present study was carried out to understand the catalytic role of pyrazinamide and ethambutol hydrochloride on the reaction between rifampicin and isoniazid. For the purpose, organic bases and amides similar in structure to pyrazinamide and ethambutol hydrochloride were combined individually with rifampicin and isoniazid. The compounds employed were pyrazine, piperdine, pyrollidine, pyridine, triethylamine, diisopropylethylamine, picolinamide, benzamide, ethylenediamine, ethanolamine, diethanolamine, and triethanolamine. An additional study was also carried out in the presence of free base of ethambutol. The mixtures were exposed to accelerated stability test condition of 40 degrees C/75% RH for 15 d. The nature of the products formed and the changes in relative concentrations of the drugs and products were followed by HPLC. The drugs showed different extent of degradation, yielding HYD, and in some cases degradation products of rifampicin. The results confirmed the catalytic role of pyrazinamide and ethambutol hydrochloride. The catalysis is postulated to involve intra-molecular proton transfer during transhydrazone formation process, entailing a tetrahedral mechanism.

Amides↗
PubMed1999

Ethambutol-sugar hybrids as potential inhibitors of mycobacterial cell-wall biosynthesis.

Ethambutol is an established front-line agent for the treatment of tuberculosis, and is also active against Mycobacterium avium infection. However, this agent exhibits toxicity, and is considered to have low potency. The action of ethambutol on the mycobacterial cell wall, particularly the arabinan, and comparison of the structure of ethambutol with several of the cell-wall saccharides, suggested that ethambutol-saccharide hybrids might lead to agents with a more selective mechanism of action. To this end, eight ethambutol-saccharide hybrids were synthesized and screened against M. tuberculosis and several clinical isolates of M. avium.

Antitubercular Agents↗
PubMed1994

The individual microbiologic effect of three antimycobacterial agents, clofazimine, ethambutol, and rifampin, on Mycobacterium avium complex bacteremia in patients with AIDS.

The individual antibacterial activities of clofazimine, ethambutol, and rifampin in the treatment of Mycobacterium avium complex bacteremia in patients with AIDS were determined. Sixty human immunodeficiency virus 1-infected patients who had at least one blood culture positive for M. avium complex were randomized to receive either clofazimine (200 mg), ethambutol (15 mg/kg), or rifampin (600 mg) once daily for 4 weeks. Only ethambutol resulted in a statistically significant reduction in the level of mycobacteremia. The median change in individual baseline colony counts was -0.60 log10 cfu/mL after 4 weeks of ethambutol (P = .046). In contrast, median changes in individual baseline colony counts were -0.2 log10 cfu/mL and +0.2 log10 cfu/mL for clofazimine and rifampin, respectively (both, P > .4). Ethambutol had greater antibacterial activity, as determined by changes in the level of mycobacteremia, than either rifampin or clofazimine, supporting its continued use in combination with other agents in the treatment of M. avium infection.

AIDS-Related Opportunistic Infections↗
PubMed1980

Peripheral nerve conduction function in patients treated with antituberculotic agents, with special reference to ethambutol and isoniazid.

The electrophysiological examination was made to clarify the effect of ethambutol on the peripheral nervous system in 39 patients at tuberculous sanatorium. Abnormalities in the sensory nerve action potential (toe-ankle) were observed in about 10 percent of the patients treated with ethambutol, and these patients were mostly elderly and/or received the high dose of ethambutol. The mixed nerve conduction velocity (ankle-knee) showed a significant decrease compared with healthy subjects. The conduction velocity tended to decrease in the high ethambutol dosage (200 gm or more) group compared with the low dosage (200 gm or less) group. The tendency for the conduction velocity to decrease was also observed in the 18 patients treated with isoniazid but the abnormalities were mild compared with the ethambutol.

Action Potentials↗
PubMed1992

Sparfloxacin, ethambutol, and cortisol receptor inhibitor RU-40 555 treatment for disseminated Mycobacterium avium complex infection of normal C57BL/6 mice.

Sparfloxacin (50 mg/kg of body weight given subcutaneously each day), alone or in combination with ethambutol (50 mg/kg given subcutaneously each day), was examined for its therapeutic efficacy against experimental infection induced with the Mycobacterium avium complex in normal C57BL/6 mice. In addition, the potential anti-infective role of RU-40 555 (100 mg/kg given intraperitoneally each day), a drug that inhibits the cortisol receptors, was examined in the same model. Treatments were started 24 h after intravenous bacterial challenge and were continued for 21 days. Compared with controls, sparfloxacin or ethambutol decreased the CFU counts in spleens and lungs (P < 0.001). The sparfloxacin plus ethambutol combination was more effective than sparfloxacin alone in spleens (P < 0.001) but not in lungs. The sparfloxacin plus ethambutol plus RU-40 555 combination was more effective than the sparfloxacin plus ethambutol combination in spleens and lungs (P < 0.001). Thus, in this model, RU-40 555 enhanced the antibacterial activities of the antibiotics tested. Results of the study showed that normal C57BL/6 mice infected with the M. avium complex can be used for the evaluation of antimicrobial agents.

Animals↗