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BACKGROUND & OBJECTIVE: There is a need to understand the nature of drug resistance patterns and predictors of emergence of drug resistance in Mycobacterium tuberculosis. There could be common factors/mechanisms for resistance to the drugs, isoniazid and ethambutol, both acting on cell wall. The present study was conducted to analyze the antimycobacterial susceptibility patterns of M. tuberculosis isolates to determine the minimum inhibitory concentrations (MICs) of ethambutol for M. tuberculosis; and to find out possible association of ethambutol resistance with isoniazid resistance. METHODS: A total of 380 M. tuberculosis isolates were tested for their susceptibilities to ethambutol at 2, 4, 6 microg/ml, isoniazid at 1 microg/ml and rifampicin at 64 microg/ml using MIC method. RESULTS: 44.21, 24.73 and 14.21 per cent isolates were resistant to ethambutol at concentrations of 2, 4 and 6 microg/ml respectively. At 6 microg/ml of ethambutol concentration, 85.18 per cent ethambutol resistant isolates were resistant to isoniazid also. At the same ethambutol concentration a fraction of 28.75 per cent isoniazid resistant isolates were ethambutol resistant. INTERPRETATION & CONCLUSION: Ethambutol resistance was accompanied with isoniazid resistance in a large percentage of isolates whereas ethambutol resistance was weakly linked with multidrug resistance. On the other hand, association between isoniazid and ethambutol resistance was weak showing one way linkage.
Ethambutol, a synthetic bacteriostatic agent, is a first line agent against Mycobacterium tuberculosis. Although optic neuritis is the most serious adverse effect of ethambutol, most cases in the literature are reversible. Renal failure prolongs the half-life of ethambutol and increases the risk of ethambutol-induced optic neuritis. We present two patients with end stage renal disease (ESRD), who were on maintenance dialysis and suffering ethambutol-induced optic neuritis. The first woman had been suffering ESRD on hemodialysis for 2 years. After tuberculosis was diagnosed, she was prescribed three-combined anti-tuberculosis medications, including ethambutol 800 mg/day. Bilateral blurred vision suddenly occurred 4 months after the start of treatment, and she became totally blind despite discontinuing ethambutol. The second woman had been on hemodialysis for 5 months. Tuberculosis was diagnosed by lung biopsy. After 3 weeks of three-combined anti-tuberculosis medications including ethambutol (1,200 mg/day), reduced visual acuity and color vision defects occurred. One year after the discontinuation of ethambutol, visual acuity remained little improved. Physicians should be aware of ethambutol-induced optic neuritis and ethambutol should be used cautiously in patients with renal failure.
PURPOSE: Ethambutol can cause optic neuropathy and deficiencies in color-opponent visual processing in patients treated for tuberculosis. In fish, Ethambutol induces color vision deficiencies similar to those observed in humans and affects color coding in retinal ganglion cells. Color opponency in fish is mainly mediated by a horizontal cell feedback onto cones thought to be provided by spinules. The authors examined whether Ethambutol affects spinules and is, therefore, able to alter color processing at a distal stage, that is, at the first synaptic connection within the retina. METHODS: Ethambutol was injected into the vitreous of either dark- or light-adapted fish. After drug application, fish were held under different illumination conditions. Thereafter, the retinas were dissected and prepared for electron microscopy. Ultrathin tangential sections of retinas were examined at the level of the outer plexiform layer. RESULTS: In already light-adapted retinas, a high dose of Ethambutol (10 mM) reduced the number of spinules by 30%. Ethambutol application in the dark with subsequent light adaptation resulted in severe dose-related inhibition of light-induced spinule formation. In these experiments, low doses (0.1 mM) of Ethambutol caused 40% inhibition, and high doses (10 mM) caused 70% inhibition. Besides affecting spinules, Ethambutol occasionally induced a degeneration of cone pedicles. This neurotoxicity only occurred in cones exposed to light. CONCLUSIONS: Results show that Ethambutol alters synaptic connections between horizontal cells and cones in a dose-related fashion; Ethambutol treatment can be toxic for cone pedicles and can cause their degeneration; and the rod pathway is not affected by the drug. This indicates that Ethambutol influences the color-coding process already at the level of the cone-horizontal cell synapse.
PURPOSE: Ethambutol is an essential medication in the management of tuberculosis. However, it can cause an optic neuropathy of uncertain etiology. Ethambutol toxicity was therefore studied in rodent retinal cells, and agents that might block its toxicity were considered. METHODS: The toxicity of ethambutol and related agents was evaluated in rodent retinal dissociated cell preparations and whole eyes. Calcium fluxes and mitochondrial function were evaluated by fluorescent and staining techniques. For in vivo assays, adult rats were administered oral ethambutol over a 3-month period. Cell survival was assessed by stereology. RESULTS: Ethambutol is specifically toxic to retinal ganglion cells in vitro and in vivo. Endogenous glutamate is necessary for the full expression of ethambutol toxicity, and glutamate antagonists prevent ethambutol-mediated cell loss. Ethambutol causes a decrease in cytosolic calcium, an increase in mitochondrial calcium, and an increase in the mitochondrial membrane potential. CONCLUSIONS: The visual loss associated with ethambutol may be mediated through an excitotoxic pathway, inasmuch as ganglion cells are rendered sensitive to normally tolerated levels of extracellular glutamate. Ethambutol perturbs mitochondrial function. Its toxicity may depend on decreased ATPase activity and mitochondrial energy homeostasis. Glutamate antagonists may be useful in limiting the side effects seen with ethambutol.
BACKGROUND: The pharmacokinetics of rifampin and ethambutol in HIV-infected patients with tuberculosis (TB) are incompletely characterized. We examined the pharmacokinetics of rifampin and ethambutol in a cohort of patients with HIV-related TB who were treated in the United States. METHODS: Serum drug concentrations were determined 2, 6, and 10 h after dosing in 36 HIV-infected patients with TB who were taking rifampin and in 49 who were taking ethambutol. Observed serum concentrations were compared with published normal ranges and published data. RESULTS: With daily dosing of rifampin (600 mg), 26 (77%) of 34 patients (95% confidence interval [CI], 59%-89%]) had a low maximum concentration of rifampin (<8 microg/mL), and 12 (35%; 95% CI, 20%-54%) had a very low maximum concentration (<4 microg/mL). With intermittent rifampin dosing (600 mg), 13 (68%) of 19 patients (95% CI, 44%-85%) had a low maximum concentration of rifampin, and 5 (26%; 95% CI, 11%-50%) had a very low maximum concentration. With daily ethambutol dosing (20 mg/kg), 33 (69%) of 48 patients (95% CI, 55%-81%) had a low maximum concentration of ethambutol (<2 microg/mL), and 18 (38%; 95% CI, 24%-53%) had a very low maximum concentration (<1 microg/mL). With intermittent ethambutol dosing (50 mg/kg twice weekly or 30 mg/kg thrice weekly), 13 (72%) of 18 patients (95% CI, 47%-88%) had a low maximum concentration of ethambutol (<4 microg/mL), and 5 (28%; 95% CI, 12%-54%]) had a very low maximum concentration (<2 microg/mL). CONCLUSIONS: In HIV-infected patients with TB who are receiving rifampin and ethambutol, low maximum concentrations of rifampin and ethambutol were common. For patients with HIV-related TB, therapeutic monitoring of rifampin and ethambutol levels may help clinicians achieve target serum concentrations.
Ethambutol is known to rapidly inhibit biosynthesis of the arabinan component of the mycobacterial cell wall core polymer, arabinogalactan (K. Takayama and J. O. Kilburn, Antimicrob. Agents Chemother. 33:1493-1499, 1989). This effect was confirmed, and it was also shown that ethambutol inhibits biosynthesis of the arabinan of lipoarabinomannan, a lipopolysaccharide noncovalently associated with the cell wall core. In contrast to cell wall core arabinan, which is completely inhibited by ethambutol, synthesis of the arabinan of lipoarabinomannan was only partially affected, demonstrating a differential effect on arabinan synthesis in the two locales. Further studies of the effect of ethambutol on cell wall biosynthesis revealed that the synthesis of galactan in the cell wall core is strongly inhibited by the drug. In addition, ethambutol treatment resulted in the cleavage of arabinosyl residues present in the mycobacterial cell wall; more than 50% of the arabinan in the cell wall core was removed from the wall 1 h after addition of the drug to growing mycobacterial cultures. In contrast, galactan was not released from the cell wall during ethambutol treatment. The natural function of the arabinosyl-releasing enzyme remains unknown, but its action in combination with inhibition of synthesis during ethambutol treatment results in severe disruption of the mycobacterial cell wall. Accordingly, ethambutol-induced damage to the cell wall provides a ready molecular explanation for the known synergetic effects of ethambutol with other chemotherapeutic agents. Nevertheless, the initial direct effect of ethambutol remains to be elucidated.
Magnesium sulfate and spermidine were tested for their effects on binding of (14)C-ethambutol by Mycobacterium smegmatis. Concentrations were used that protected the organism from ethambutol inhibition. Sodium salts were examined as possible ethambutol antagonists to test the previously reported specificity of the divalent cation salt effect. Consistent with growth-protection experiments, 20 mM MgSO(4) or 2.0 mM spermidine prevented and reversed (14)C binding by cells shaken with 0.2 mug of (14)C-ethambutol per ml of Sauton medium at 37 C. Sodium salts were not effective ethambutol antagonists when tested at 20 mM, but at concentrations equivalent in ionic strength (mu) to that provided by 20 mM MgSO(4) they were effective. Thus, 20 mM MgSO(4), 80 mM NaCl, or 27 mM Na(2)SO(4) (mu = 0.08) all gave similar results in growth protection and binding experiments, suggesting that MgSO(4) antagonism is a nonspecific ionic effect. Because spermidine (mu </= 0.012) antagonized ethambutol at an ionic strength substantially less than that required for the metal salts, its effect may hinge on structural similarity to ethambutol rather than its cationic character. Drug and polyamine may compete for one site or a heterogeneous group of binding sites involving adsorption, transport, and intracellular target reactions. Until we know at which of these levels spermidine antagonizes ethambutol binding, the relationship between polyamines and ethambutol action will remain obscure. However, these studies have weakened the earlier argument for a divalent cation-requiring system as a specific ethambutol target site.
Our objective was to study the steady-state plasma and intrapulmonary orally administered ethambutol concentrations in healthy volunteers and subjects with AIDS. Ethambutol (15 mg/kg of body weight) was administered orally once daily to 10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women. The mean (+/-standard deviation [SD]) CD4 cell count for the 20 subjects with AIDS was (350 +/- 169) x 10(6) cells per liter. Blood was obtained for drug assay 2 h after the last dose and at the completion of bronchoalveolar lavage, performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) was calculated by the urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation. Ethambutol was measured by a new, sensitive and specific liquid chromotography-mass spectrometry method. The presence of AIDS, as defined in this study, or gender was without significant effect on the concentrations of ethambutol in plasma at 2 or 4 h or in ELF at 4 h following the last dose. Plasma drug concentrations (mean +/- SD) at 2 and 4 h were 2.1 +/- 1.2 and 2.1 +/- 0.8 microg/ml, respectively, and both values were not significantly different from the concentration of ethambutol in ELF at 4 h (2.2 +/- 1.1 microg/ml). The concentration of ethambutol was significantly greater in AC in all four groups (range, 44.5 +/- 15.6 to 82.0 +/- 39.4 microg/ml) than in ELF or plasma and was approximately 30 to 240 times the reported MIC for ethambutol-susceptible strains of Mycobacterium tuberculosis. The AC ethambutol concentration (mean +/- SD) in the smoking women (97.2 +/- 32.1 microg/ml) was more than twice the concentration in all other nonsmoking subjects (45.2 +/- 16.8 microg/ml) combined (P < 0.05). Two- and 4-h concentrations of ethambutol in plasma were not affected by AIDS status or gender. The high AC/plasma and AC/ELF concentration ratios suggest that substantial antimycobacterial activity resides in these cells. The data confirm earlier observations of active transport ex vivo of ethambutol into pulmonary macrophages.
The absorption and disposition of ethambutol was examined in six rabbits in a three-way crossover study. Each rabbit received 45-mg/kg doses of ethambutol in three treatments: one intravenous injections and two oral solutions, ethambutol alone and ethambutol in the presence of aluminum hydroxide (40 mg/kg). Half-lives of ethambutol ranged from 2.26 to 5.20 h when administered alone and 2.18 to 4.00 h when coadministered with the antacid; the difference was not significant (p greater than 0.3). Mean clearance after the oral administrations (189.2 mL/min/kg) was significantly greater than the mean intravenous clearance (43.7 mL/min/kg) (p less than 0.01), suggesting a first-pass metabolism of ethambutol when administered nonparenterally to rabbits. The volume of distribution ranged from 5.5 to 17.8 L/kg, suggesting an extensive distribution of ethambutol outside the central compartment and, possibly, a localized deposit within the body tissues. Mean bioavailability of ethambutol was approximately 28% and was not affected by the presence of aluminum hydroxide. The rate of ethambutol absorption, however, was slightly delayed by the antacid.
Recent studies showed that critical binding of ethambutol to Mycobacterium smegmatis was both inhibited and reversed by ions. This apparent ion-susceptible characteristic suggested that ethambutol is held at critical sites by electrostatic bonds. Dissociation constant, pH, and ionic strength studies were designed to further characterize ethambutol binding. M. smegmatis was grown in Sauton synthetic liquid medium (pH 7.4) under aerated conditions at 37 C. The pH or ionic strength of the medium was modified to meet the needs of particular experiments. Titration data revealed that ethambutol dihydrochloride has two apparent dissociation constants (pKa(1) = 6.35, pKa(2) = 9.35). Uptake experiments, in which pH was varied, showed that dihydrochloride and free base ethambutol were bound to a greater extent than the monohydrochloride. However, dihydrochloride and free base binding were not related to biological activity. Ethambutol exerted its maximal growth inhibitory effect at pH values near neutrality, where it exists primarily as the monohydrochloride and showed minimal binding. The increased ethambutol binding observed at pH 7.4 in media of lowered ionic strength was consistent with growth studies showing a reduction in the minimal inhibitory growth concentration in such media. However, nonspecific as well as critical binding was enhanced at low ionic strength. We conclude that binding of ethambutol by M. smegmatis involves a heterogeneous group of drug binding sites, only one of which is directly related to biological activity. Although nothing is known about the ethambutol target site itself, critical binding of the drug seems to require the single positively charged monohydrochloride form. Both hydrogen bonds and ionic linkages are probably involved.
This study compared the efficacies of clarithromycin-ethambutol and clarithromycin-ethambutol-clofazimine for the treatment of Mycobacterium avium complex (MAC) in AIDS patients. Thirty-four patients were randomized into two groups to receive clarithromycin 2 g/day and ethambutol 20 mg/kg/day, with or without clofazimine 200 mg/day. The evaluation was based primarily on blood cultures becoming negative after 2 months of therapy, but survival at 12 months and clinical evolution were also assessed. Inclusions were prematurely stopped because of a communication reporting increased mortality associated with clofazimine. At 2 months, the blood cultures of 55% of the clarithromycin-ethambutol group patients versus 81% of the clarithromycin-ethambutol-clofazimine group were negative; this difference is not significant (P=0.42). Only one relapse was observed during the study. No clarithromycin-resistant strain was isolated. No apparent difference in either survival or clinical evolution was observed in this small number of patients (median survival, 144 days in the clarithromycin-ethambutol group and 236 days in the clarithromycin-ethambutol-clofazimine group, P=0.44). The clarithromycin-ethambutol combination appears to be an effective and well-tolerated first-line therapy against MAC infections in AIDS patients.
Ethambutol, a tuberculostatic drug, induces red-green colour vision defects in man and goldfish. The ethambutol-induced red-green colour vision defect in goldfish was argued to originate in the retina because after ethambutol application: (1) inhibitive interactions in red-green (double) opponent ganglion cells are lost [Van Dijk & Spekreijse, 1982 (Investigative Ophthalmology and Visual Science, 24, 128-133); Wietsma & Spekreijse, 1992 (Investigative Ophthalmology and Visual Science Suppl., 33, 1032)] and (2) the depolarizing responses to red light in the biphasic horizontal cells are reduced. To account for these findings Spekreijse, Wietsma and Neumeyer [(1991) Vision Research, 31, 551-562] suggested that ethambutol induced dark adaptation in the retina. In this paper the dark adaptation hypothesis is tested with the following results: (1) ethambutol changes only transiently the receptive field size and spectral sensitivity of horizontal cells; (2) the spectral characteristics of horizontal cells do not change in long-term ethambutol-treated goldfish; (3) formation of spinules on horizontal cell dendrites in cone terminals, a parameter for light adaptation, remains unaffected. Therefore we conclude that ethambutol does not induce functional dark adaptation of horizontal cells and that the ethambutol-induced red-green colour vision deficiency does not originate in the horizontal cell layers.