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PubMed1978

Combined vs. single-drug studies of susceptibilities of Mycobacterium kansasii to isoniazid, streptomycin, and ethambutol.

The effects of combined drugs were compared uith the effects of single drugs in vitro against Mycobacterium kansasii. The single drugs isoniazid 1.0 microgram/ml, streptomycin 2.0 microgram/ml, and ethambutol 5.0 microgram/ml and the combinations of 1.0 microgram/ml isoniazid and 2.0 microgram/ml streptomycin, 1.0 microgram/ml isoniazid and 5.0 ethambutal and 1.0 microgram/ml isoniazid, 2.0 microgram/ml streptomycin and 5.0 microgram/ml ethambutol were evaluated as to their effects on M. kansasii organisms from 22 patients with pulmonary mycobacterial disease. These drugs were incorporated into Middlebrook 7H11 medium. Colonial growth was then observed and assigned numerical values for statistical analysis. The results showed that isoniazid was not significantly better than ethambutol. Streptomycin, however, was significantly better than both isoniazid and ethambutol alone. The double combinations were better than the single drugs, with isoniazid--streptomycin being better than isoniazid--ethambutol. The combination isoniazid--ethambutol was not significantly better than streptomycin alone. However, the triple combination of isoniazid--streptomycin--ethambutol was markedly better than all single drugs, better than isoniazid--ethambutol, but not better than isoniazid--streptomycin. Combined-drug testing thus showed a pattern of susceptibility not demonstrated by single-drug testing.

Ethambutol↗
PubMed2006

Evaluation of the nitrate-based colorimetric method for testing the susceptibility of Mycobacterium tuberculosis to streptomycin and ethambutol in liquid cultures.

OBJECTIVES: To evaluate the inexpensive colorimetric nitrate reductase-based antibiotic susceptibility (CONRAS) assay for testing the susceptibility of Mycobacterium tuberculosis to streptomycin and ethambutol in liquid cultures, and to compare the CONRAS test with the manual mycobacteria growth indicator tube (MGIT) test, using the radiometric BACTEC 460TB method as reference. METHODS: A total of 89 M. tuberculosis isolates were tested for susceptibility to streptomycin and ethambutol using the CONRAS and manual MGIT methods and the results were compared with BACTEC 460TB. Isolates with discrepant results between the CONRAS test and BACTEC 460TB were analysed using the agar proportion method, Etest and mutation analysis of genes involved in resistance to streptomycin and ethambutol. RESULTS: The agreement between the CONRAS test and BACTEC 460TB was 88% for streptomycin and 84% for ethambutol. The corresponding agreement of the manual MGIT test with BACTEC 460TB was 89 and 80%, respectively. There was good agreement for streptomycin and moderate agreement for ethambutol between the CONRAS and manual MGIT tests on one hand and BACTEC 460TB on the other (CONRAS test, kappa(streptomycin) 0.74 and kappa(ethambutol) 0.59, P < 0.001; manual MGIT test, kappa(streptomycin) 0.77 and kappa(ethambutol) 0.50, P < 0.001). CONCLUSIONS: There is good agreement for the two non-radiometric liquid culture methods (CONRAS and manual MGIT) compared with BACTEC 460TB for the detection of streptomycin resistance. Further standardization is needed for testing of ethambutol resistance using the CONRAS and manual MGIT assays.

Antitubercular Agents↗
PubMed1998

Ocular toxicity from ethambutol: a review of four cases and recommended precautions.

AIMS: To document the clinical and demographic features of cases of ethambutol ocular toxicity, to review the literature on this subject and to critically review current guidelines for ethambutol administration. METHODS: Cases of ocular toxicity from ethambutol were sought retrospectively at Green Lane and Wellington Hospitals between 1992 and 1995. The records of cases identified were examined. RESULTS: Four subjects with tuberculosis developed ocular toxicity 2 1/2, 7 1/2, 8 and 12 months after starting ethambutol. Normal visual acuity returned in three cases; one patient has severe, permanent visual impairment. Language difficulties were present in three subjects. CONCLUSIONS: Impaired communication was potentially very important in this series. Special care is needed in educating patients about ethambutol. We propose additional recommendations: 1. the usual daily dose of ethambutol should be 15 mg/kg/day, not 25 mg/kg/day; using 25 mg/kg/day (or lesser doses in the presence of renal impairment) should prompt regular formal ophthalmological evaluation (e.g. monthly) in cases with comprehension or communication difficulties; 3. both ethambutol and isoniazid should be stopped immediately if severe optic neuritis occurs. Isoniazid should be stopped if less severe optic neuritis does not improve within six weeks after stopping ethambutol.

Adult↗
PubMed2000

Ethambutol-induced vacuolar changes and neuronal loss in rat retinal cell culture: mediation by endogenous zinc.

Ethambutol is an efficacious antituberculosis agent. However, its use has been limited by the occurrence of ocular toxicity. To investigate characteristics and possible mechanisms of ethambutol ocular toxicity, we used primary rat retinal cultures as a model. Primary rat retinal cultures were obtained from newborn Sprague-Dawley rats and used for experiments after maturation (DIV > or = 10). Cytopathologic changes were examined under light and electron microscopes. Thy-1 (a membrane glycoprotein expressed by retinal ganglion neurons)-containing neurons and gamma-aminobutyric acid (GABA)-ergic neurons were identified immunocytochemically. Exposure of retinal cultures for 24-48 h to ethambutol induced cytoplasmic vacuolar changes and neuronal loss. Vacuolar changes were partially reversible with the termination of ethambutol exposure. Of neurons, Thy-1(+) ganglion neurons were more vulnerable than GABA(+) neurons. Glutamate antagonists, an antioxidant (trolox), or cycloheximide, did not attenuate either vacuolar changes or neuronal loss. A cell-permeant zinc chelator N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) markedly attenuated vacuolar degeneration and neuronal loss, while the addition of zinc augmented both. In rat retinal cultures, ethambutol induces reversible vacuolar degeneration as well as irreversible neuronal loss, more preferentially of Thy-1(+) ganglion neurons. Contrary to the current theories, ethambutol-induced retinal cytotoxicity in the present study is mediated not by excitotoxicity or zinc deficiency but by a mechanism requiring intracellular zinc. In addition, features of the ethambutol-induced cell death were not consistent with those of apoptosis.

Animals↗
PubMedDate not supplied

Leber's hereditary optic neuropathy precipitated by ethambutol.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) predominantly affects young men between 10 and 30 years of age. However, two cases of LHON during ethambutol administration have been reported in older men and one case in an older woman. We now report a second case of an older woman in whom administration of ethambutol triggered the development of LHON. CASE: A 70-year-old woman received ethambutol, rifampicin, isoniazid, and pyrazinamide for the treatment of tuberculosis. OBSERVATIONS: Three months after the beginning of this treatment, a marked decrease in visual acuity occurred in both eyes and ethambutol was discontinued. 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 decreased to 0.01, and the scotomas had enlarged. At this time, genetic analysis revealed a point mutation in mitochondrial DNA 11778. CONCLUSIONS: Ethambutol can be a risk factor for LHON because the number of reported ethambutol-related LHON cases has increased to four, including the present one. Ethambutol administration to patients with a family history of LHON should be avoided.

Aged↗
PubMed1976

Bactericidal activity in vitro and in the guinea-pig of isoniazid, rifampicin and ethambutol.

Serial viable counts on Mycobacterium tuberculosis exposed in vitro to isoniazid, rifampicin and ethambutol in Tween-albumin liquid medium showed no bactericidal synergism between isoniazid and rifampicin and no influence of ethambutol on the bactericidal activity of isoniazid or isoniazid plus rifampicin. Guinea-pigs with moderately advanced experimental tuberculosis were treated fro 11 weeks with either (1) ethambutol, (2) isoniazid, (3) isoniazid plus ethambutol, (4) isoniazid plus rifampicin, (5) isonaiazid plus rifampic in plus ethambutol, or (6) no chemotherapy. The amount of tuberculous disease was scored and the spleen cultured in groups killed at intervals from 0--7 1/2 months after the end of chemotherapy. The regimens containing rifampicin were no more bactericidal during treatment than the corresponding regimens without rifampicin, but the onset of relapse after chemotherapy was delayed for at least 2 months following the rifampicin-containing regimens. Ethambutol alone did not protect guinea-pigs, nor did it influence the response to isoniazid or to isoniazid plus rifampicin. It was concluded that rifampicin may act selectively on a small proportion of the bacterial population and that it may be unnecessary to prescribe it for long periods in short course chemotherapy in man. Ethambutol does not appear likely to contribute to the sterilizing activity of short course regimens though it may prevent the emergence of drug resistance.

Animals↗
PubMed1997

Reversibility of ethambutol optic neuropathy.

Ethambutol hydrochloride is one of the routinely used drugs as the first line of antitubercular agents. The delayed onset of ocular toxicity is usually thought to be reversible following rapid withdrawal of the drug. We collected ten consecutive patients with severe visual defects due to ethambutol toxicity, and these patients had received presumably safe ethambutol dosages. Although ethambutol was stopped immediately in all cases, only five patients (50%) experienced visual improvement after a period of 12 months to 3 years follow-up. The other five patients (50%) had permanent visual impairment without recovery. There were no predisposing or risk factors to contribute to poor visual outcome. In the group over 60 years old, only 20% (1/5) experienced visual improvement; in the group less than 60 years old, 80% (4/5) had some visual recovery, the difference between these two age groups being statistically significant. We need more patient collections to answer whether the older patients with ethambutol optic neuropathy have poor prognoses. Ethambutol optic neuropathy, in our follow-up study, is not always reversible, especially in the older population. It may cause permanent visual disability. There is no so-called "safe-dosage". We suggest reconsideration regarding the use of ethambutol as one of the first-line antitubercular drugs, especially in older patients.

Adult↗
PubMed2007

Decreased retinal nerve fibre layer thickness detected by optical coherence tomography in patients with ethambutol-induced optic neuropathy.

BACKGROUND: It is difficult to assess the degree of optic nerve damage in patients with ethambutol-induced optic neuropathy, especially just after the onset of visual loss, when the optic disc typically looks normal. AIM: To evaluate changes in retinal nerve fibre layer thickness (RNFLT) using optical coherence tomography (OCT) in patients with optic neuropathy within 3 months of cessation of ethambutol treatment. DESIGN: A retrospective observational case series from a single neuro-ophthalmology practice. METHODS: 8 patients with a history of ethambutol-induced optic neuropathy were examined within 3 months after stopping ethambutol treatment. All patients underwent a neuro-ophthalmologic examination, including visual acuity, colour vision, visual fields and funduscopy. OCT was performed on both eyes of each patient using the retinal nerve fibre layer analysis protocol. RESULTS: The interval between cessation of ethambutol treatment and the initial visit ranged from 1 week to 3 months. All patients 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 RNFLT, there was a statistically significant decrease in the mean RNFLT of the temporal, superior and nasal quadrants (p = 0.009, 0.019 and 0.025, respectively), with the greatest decrease in the temporal quadrant (mean decrease 26.5 mum). CONCLUSIONS: A decrease in RNFLT is observed in all quadrants in patients with ethambutol-induced optic neuropathy who have recently discontinued the medication. This decrease is most pronounced in the temporal quadrant of the optic disc.

Aged↗
PubMed1999

[Optic nerve neuropathy by ethambutol toxicity].

OBJECTIVE: To investigate the clinical manifestations, treatment and prevention of optic nerve damage by ethambutol toxicity. METHODS: Retrospective analysis was done on 17 patients of tuberculosis who had been treated with ethambutol and shown ocular symptoms. RESULTS: Changes in visual acuity, fundal appearance, visual field and color sensation were major abnormal findings. According to the neural damage, the patients were diagnosed as axial neuritis 7 cases, periaxial neuritis 2 cases, mixed type 3 cases and there were no significant changes on fundus, color sensation or visual field in 5 cases. In 17 cases, none of the patient showed the appearance of retinitis. The impairment of visual acuity and the duration of damage were related to the daily dosage significantly. After stop of ethambutol and vasodilators or neurotrophic drugs were given, the function of optic nerves were recovered. CONCLUSIONS: To prevent the damage of optic nerves by the toxicity of ethambutol, the appropriate small dosage of ethambutol is recommended, regular examination and monitoring of visual function is necessary. The physicians should be fully aware of the diagnosis and clinical manifestations of ocular toxicity of ethambutol, as soon as the diagnosis is made, ethambutol should be stopped immediately and appropriate therapy should be given.

Antitubercular Agents↗
PubMed1980

Clearance calculations in hemodialysis: application to blood, plasma, and dialysate measurements for ethambutol.

With the increasing use of artificial kidneys, numerous reports have appeared describing the pharmacokinetics of administered drugs in dialysis patients. Unfortunately, different investigators use different measures of dialysis clearance in reporting their results. Few studies have appeared in which actual measurements have been made in blood and dialysate as well as in plasma to experimentally show the variability of individual measurements and to demonstrate the inaccuracy of certain clearance measurements. We do so here, using the drug ethambutol. The effect of the artificial kidney on the removal of ethambutol was investigated in four uremic patients undergoing chronic hemadialysis. Ethambutol was administered by i.v. infusion over 30 min. Hemodialysis started at the end of drug infusion. Blood, plasma, and dialysate samples were collected periodically over 3 hr and analyzed for ethambutol content. Dialysis clearance was calculated by arterial-venous difference and by simultaneous dialysate measurement. The extraction efficiency of the hollow fiber dialyzers ranged from 36.2% to 43.8% in terms of blood and from 38.0% to 45.4% in terms of plasma. The mean clearance values due to dialysis were 108.08 and 88.1 ml/min measured with plasma and blood as body fluids of reference, respectively. Dialysis clearance calculated by dialysate measurement had a mean of 85.9 ml/min expressed as plasma and 74.7 ml/min expressed as blood. This study demonstrates that dialysis clearance when calculated using A-V difference and plasma flow is generally underestimated, particularly for a drug which extensively partitions into red blood cells. Ethambutol had a partition coefficient (blood/plasma) of greater than 1 in all four patients. The beta phase exhibited a mean half-life of approximately 2 hr on dialysis in comparison to off dialysis half-lives of 7 hr or longer in renal failure. Although ethambutol exhibits a markedly reduced half-life of the drug during hemodialysis, its recovery in the dialysis fluid during a 3-hr dialysis period constitutes only a small fraction of the dose administered.

Adult↗
PubMed1978

Effects of the antituberculous agent ethambutol on myelinated nerve.

The action of the antituberculous agent ethambutol on the myelinated nerve was studied in two ways: (1) Resting and compound action potentials of the desheathed sciatic nerve were measured; (2) Na+ and K+ currents through the node of Ranvier were investigated by means of the voltage clamp. Reversible dose-dependent decreases of the compound action potential and of the conduction velocity were observed when ethambutol was applied in concentrations of 1--7 mM for 15 min; prolongation up to 60 min caused irreversible changes in membrane function and a decrease in Ca content. Ethambutol induced a hyperpolarizing change of the resting potential. When the nerve was depolarized in Ca2+-free solutions, ethambutol repolarized the nerve membrane. Ethambutol instantly reduced sodium and potassium currents through the nodal membrane. Presumably ethambutol acts primarily as a Ca2+ chelating cation on negative charges at the nerve membrane.

Action Potentials↗
PubMed1999

Effect of the tuberculostaticum ethambutol and stimulus intensity on chromatic discrimination in man.

In goldfish it has been shown that ethambutol shifts the threshold for wavelength discrimination without affecting the absolute sensitivity of the cones. In this study we demonstrate that a similar colour vision disturbance occurs in tuberculosis patients treated with ethambutol. After 2 months of ethambutol treatment, chromatic discrimination was measured with a computerized forced two choice (CD) test with isoluminant coloured stimuli and with three other colour vision tests: the Ishihara, the Oscar and the Lanthony Desaturated 15 Hue tests. The scores of the patient group (n = 19) on these four colour vision tests were compared with the scores of a group of control subjects (n = 33) and a group of congenital red/green colour-blind subjects (n = 5). A reduction of the stimulus intensity of 1 log unit caused a significant reduction in red/green chromatic discrimination, measured with the CD test in both, control subjects and patients. This intensity dependent reduction was significantly greater for patients than for controls. In this respect, man and goldfish behave similarly. Furthermore, the CD test showed the same ethambutol-induced reduction in chromatic discrimination at low intensity for the blue/green part of the spectrum. This has not been measured in goldfish. The origin of this ethambutol-induced colour vision disturbance must be at a post-photoreceptor site, because the Ishihara and Oscar tests, both designed to screen for photoreceptor-based, or primary red/green colour vision disturbances, did not discriminate between patients and control subjects. Thus, as in goldfish, we find that in patients ethambutol shifts the threshold for chromatic discrimination without changing the absolute sensitivity.

Adolescent↗
PubMed1986

Subclinical impairment of colour vision in patients receiving ethambutol.

Colour discrimination was assessed by means of the Farnsworth-Munsell 100-Hue test in 54 patients being treated for tuberculosis with ethambutol and 50 patients who were treated for tuberculosis by drugs other than ethambutol. The ethambutol group showed significantly more errors than controls along the deuteran axis. The sub-group of ethambutol treated patients who had been taking the drug for more than 2 months showed significantly more errors along the tritan axis. It is concluded that subclinical colour discrimination impairment is relatively common in patients receiving ethambutol and that a deuteran type of defect is an early and a tritan type of defect is a later manifestation of ethambutol toxicity.

Adult↗
PubMed1972

Uptake and binding of 14C-ethambutol by tubercle bacilli and the relation of binding to growth inhibition.

Studies were designed to characterize ethambutol uptake by Mycobacterium tuberculosis (H37Ra) and to relate uptake to the time-dependent, concentration-independent nature of growth inhibition by ethambutol. When cells grown aerated at 37 C in Sauton medium were exposed for 7 hr to 0.2, 0.5, 1.0, 2.5, and 5.0 mug of (14)C-ethambutol per ml, uptake increased with time and was a linear function of concentration. The process was inhibited at 22 C. Studies with chloramphenicol, sodium azide, and 2,4-dinitrophenol indicated that uptake is independent of requirements for protein synthesis and energy. The organism did not accumulate ethambutol against a concentration gradient. It can be concluded that ethambutol enters the cells in a passive manner. Kinetic studies of (14)C loss from tubercle bacilli pretreated with labeled drug suggested the existence of two ethambutol fractions within the cell: a highly variable labile pool and a second fraction that is small and quite firmly bound. Levels of cell-bound drug may be independent of total uptake, but this possibility was not established unequivocally. Definitive evidence showing identity in the concentrations of bound drug regardless of total uptake could explain the apparent discrepancy between concentration-dependent uptake and concentration-independent growth inhibition.

Carbon Radioisotopes↗
PubMed1962

Mode of action of ethambutol.

Forbes, M. (Lederle Laboratories Division, Pearl River, N.Y.), N. A. Kuck, and E. A. Peets. Mode of action of ethambutol. J. Bacteriol. 84:1099-1103. 1962.-Ethambutol [2,2'-(ethylenediimino) di-1-butanol] arrested multiplication of Mycobacterium smegmatis cells and eventually effected their death. The inhibitory effect of the drug on multiplication did not become apparent until several hours after its addition to the culture. The drug had no effect on the survival of nonproliferating cells. It had little or no effect on the metabolism of nonproliferating cells, but cells from cultures whose growth had been inhibited by ethambutol showed evidence of impaired metabolism. C(14)-labeled ethambutol was taken up rapidly by both proliferating and nonproliferating cells. The observations are consistent with the hypothesis that ethambutol exerts its antibacterial effect by interfering with the synthesis of a metabolite(s) needed for multiplication. Depletion of the metabolite(s) results in arrest of multiplication, impairment of metabolism, and loss of viability. Resistance to ethambutol cannot be explained by the failure of the cells to take up the drug, since the drug was equally bound by resistant and sensitive cells.

Antitubercular Agents↗
PubMed2005

Multifocal ERG in ethambutol associated visual loss.

AIM: To determine the anatomical site and extent of electrophysiological dysfunction in patients with ethambutol associated visual loss. METHODS: A comparative case series. Four patients with ethambutol associated visual loss underwent multifocal electroretinography (mERG). Two patients had advanced visual loss while two had early signs of toxicity. The N1-P1, N1, P1 amplitudes, N1, and P1 latencies were compared to 10 age and sex matched controls. RESULTS: mERG abnormalities were detected in the ethambutol treated patients. The N1 amplitude was significantly lower in the ethambutol treated patients than in the control group. CONCLUSION: Ethambutol is possibly toxic to the retina, and not only the optic nerve. The multifocal ERG may be of value to diagnose and monitor patients taking ethambutol.

Aged↗
PubMed1987

Use of contrast sensitivity measurement in the detection of subclinical ethambutol toxic optic neuropathy.

Contrast sensitivity was measured by means of Arden grating plates in 100 patients on medication for pulmonary tuberculosis. The scores were abnormal in 38.2% of the patients whose therapy included ethambutol for three months, and 36.7% of the patients on similar treatment for six months. In comparison with age matched groups of patients on a regimen where streptomycin replaced ethambutol a statistically significant number of the patients on ethambutol had abnormal scores. This study suggests that Arden contrast sensitivity plates would be effective in detecting subclinical toxic optic neuropathy due to ethambutol and therefore could be used for routine monitoring of ocular function of patients on ethambutol. Loss of contrast sensitivity may explain why some patients on ethambutol with normal visual acuity and colour perception may still complain of visual disturbance.

Adult↗
PubMed1990

The effects of exposure time, drug concentration, and temperature on the activity of ethambutol versus Mycobacterium tuberculosis.

In a series of dynamic in vitro studies designed to assess the activity of ethambutol (EMB) against Mycobacterium tuberculosis, we made the following observations. Ethambutol showed bactericidal action with 10 micrograms/ml concentration when in constant contact with M. tuberculosis. At a lower concentration, bactericidal action was evident up to 6 days; after that time, this effect was lost owing to the development of drug-resistant mutants. The bactericidal action of ethambutol in this model was similar to that of rifampin and isoniazid. Pulsed exposure for 96 h caused a four-log reduction in cfu counts, but the growth resumed rapidly. The bactericidal action of ethambutol was maximal at 37 degrees C and less at low temperatures. Ethambutol showed little activity against cultures growing at 8 degrees C continuously that were incubated for only 1 h at 37 degrees C. Against cultures growing at 8 degrees C that were brought to 37 degrees C for 6 h, its action was similar to that of rifampin. Ethambutol combined with other drugs showed bactericidal action, although the activity was less than that of the combination isoniazid-streptomycin.

Ethambutol↗