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PubMed2002

A high-pressure liquid chromatographic-tandem mass spectrometric method for the determination of ethambutol in human plasma, bronchoalveolar lavage fluid, and alveolar cells.

A technique is presented for the specific and sensitive determination of ethambutol concentrations in plasma, bronchoalveolar lavage (BAL), and alveolar cells (AC) using a high-pressure liquid chromatographic (HPLC)-tandem mass spectrometric (MS-MS) method. The preparation of samples requires a deproteinization step with acetonitrile. The retention times for ethambutol, neostigmine bromide, and propranolol are 2.0, 1.4, and 1.1 min, respectively, with a total run time of 2.8 min. The detection limits for ethambutol are 0.05 microg/mL for plasma and 0.005 microg/mL for the BAL supernatants and AC suspensions. The assay has excellent performance characteristics and has been used to support a study of the intrapulmonary pharmacokinetics of ethambutol in human subjects.

Antitubercular Agents↗

PubMed1996

Effect of ethambutol on emergence of clarithromycin-resistant Mycobacterium avium complex in the beige mouse model.

An animal model was developed for studying macrolide-resistant Mycobacterium avium complex (MAC) and to measure the effect of ethambutol on resistance. MAC-infected beige mice were given clarithromycin daily; the frequency of clarithromycin-resistant MAC after 8 and 12 weeks was 10(-3) and 10(-2), respectively. Combined ethambutol plus clarithromycin did not increase anti-MAC activity, but clarithromycin-resistant MAC was less frequent (P < .05). The frequency of clarithromycin-resistant MAC in mice receiving the combination was significantly higher than that in untreated mice. These results are consistent with two human trials, which showed that adding ethambutol reduced the frequency of clarithromycin-resistant MAC. Results of the present study suggest that with an initially high level of MAC infection, the addition of ethambutol may only delay resistance. This mouse test system will be useful for investigating the influence of the level of MAC infection and the effect of other drugs on the frequency of resistant MAC.

Animals↗

PubMed1993

In-vitro evaluation of clarithromycin, temafloxacin, and ethambutol in combination against Mycobacterium avium complex.

The in-vitro activity of clarithromycin, temafloxacin, and ethambutol were assessed by MIC, FIC and intra-macrophage killing determinations alone and in various combinations against ten pigmented and ten non-pigmented strains of Mycobacterium avium complex bacteria. Alone, either clarithromycin or temafloxacin were found to be active against M. avium, but the best results were obtained from combinations of drugs. Clarithromycin and temafloxacin together were found to have an additive effect against two of ten pigmented variants and one of ten non-pigmented variants. Clarithromycin and ethambutol demonstrated a synergistic effect against two pigmented and one non-pigmented strain, and an additive effect against five and three pigmented and non-pigmented strains, respectively. For temafloxacin and ethambutol, additive effects were observed in four and two pigmented and non-pigmented strains, respectively. In cultures of macrophages both clarithromycin and temafloxacin alone reduced the numbers of bacteria growing intracellularly after six days, but the most effective bactericidal combination was clarithromycin, temafloxacin, and ethambutol together.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Enhancement of drug susceptibility of multi-drug resistant strains of Mycobacterium tuberculosis by ethambutol and dimethyl sulphoxide.

Strategies to augment conventional methods of drug delivery in treatment of multiple drug resistant tuberculosis are needed to achieve optimum results with available drugs. We have studied the effect of sub-minimum inhibitory concentrations (sub-MIC) of ethambutol and dimethyl sulphoxide on drug susceptibility of Mycobacterium tuberculosis strains both in vitro and in macrophages. At sub-MIC ethambutol between caused four and 64 fold increase in susceptibility to isoniazid rifampicin and streptomycin in four M. tuberculosis strains, resistant to these drugs. Incubation of the organisms with isoniazid and sub-MIC of dimethyl sulphoxide (2.5%) resulted in an eight-fold increase in susceptibility to the drug. Previous exposure of the organisms to sub-MIC of dimethyl sulphoxide also caused similar enhancement of susceptibility. Both ethambutol and dimethyl sulphoxide at the sub-MIC of sulphoxide also caused similar enhancement of susceptibility. Both ethambutol and dimethyl sulphoxide at the sub-MIC enhanced the activity of the anti-tuberculosis drugs against multiple drug resistant M. tuberculosis strains growing inside macrophages. Our data indicate that the agents which modify cell wall permeability can enhance the susceptibility of multiple drug resistant strains to drugs to which they were originally resistant. This could provide a new approach to treating drug resistant tuberculosis.

Cell Line↗

PubMed1981

Effects of ethambutol on accumulation and secretion of trehalose mycolates and free mycolic acid in Mycobacterium smegmatis.

We examined the early effects of ethambutol on the synthesis of trehalose monomycolate, trehalose dimycolate, and free mycolic acid in actively growing cells of Mycobacterium smegmatis. At about 1 min after the addition of 3.0 micrograms of ethambutol per ml, the cellular level of trehalose monomycolate began to increase over the control culture. This was followed 8 to 12 min later by the cellular increases in free mycolic acid and trehalose dimycolate over the control culture and the inhibition of incorporation of mycolic acid into the cell wall. Exposure of M. smegmatis to ethambutol for more than 30 min caused all of these lipids to leak out of the cells more rapidly than in the control cells. The mechanism by which ethambutol initiates these events is unknown, but these early imbalances in lipid synthesis may be responsible for the lethal action of this drug.

Cord Factors↗

PubMed1989

Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis.

Ethambutol at 3.0 micrograms/ml inhibited the transfer of label from D-[14C]glucose into the D-arabinose residue of arabinogalactan in whole cells of a drug-susceptible strain of Mycobacterium smegmatis. This inhibition began almost immediately after exposure of the cells to the drug. When drug-resistant M. smegmatis was used in a similar experiment, no such drug inhibition was detected. A much higher concentration of ethambutol (greater than 50 micrograms/ml) was required to show this inhibition. The drug also inhibited synthesis of arabinose-containing oligosaccharides when a cell-free enzyme system was used. These results suggest that the site of action of ethambutol is somewhere on the pathway between the conversion of D-glucose to D-arabinose and the transfer of arabinose into arabinogalactan. The primary mode of action of ethambutol appears to be inhibition of arabinogalactan synthesis.

Cell Wall↗

PubMed1994

Activity of KRM 1648 alone or in combination with ethambutol or clarithromycin against Mycobacterium avium in beige mouse model of disseminated infection.

Rifamycins are active against slowly growing mycobacteria, such as Mycobacterium tuberculosis and Mycobacterium kansasii, but the majority of rifamycins thus far investigated both in vitro and in vivo are inactive or have only modest activity against the Mycobacterium avium complex (MAC). We investigated the activity of three doses of the semisynthetic benzoxazinorifamycin KRM 1648, alone or in combination with ethambutol or clarithromycin, in beige mice challenged with the MAC strain 101. Our results show the following. (i) KRM 1648 was significantly effective against MAC infection as determined by the reduction of the number of bacteria in the blood, liver, and spleen when administered at doses of 20 and 40 mg/kg of body weight per day but not at 10 mg/kg/day, compared with untreated controls. (ii) KRM 1648 (40 mg/kg/day) administered in combination with ethambutol (100 mg/kg/day) resulted in significant reduction in bacteremia compared with values for untreated controls (P 0.001), KRM 1648 alone (P = 0.019), and ethambutol alone (P = 0.003). Furthermore, the combination of KRM 1648 and ethambutol was associated with a significant decrease of the number of bacteria in the spleen and the liver compared with values for both untreated controls and each drug alone (P < 0.001 for all comparisons). (iii) KRM 1648 (40 mg/kg/day) administered in combination with clarithromycin (200 mg/kg/day) resulted in a significant decrease of the number of bacteria in the blood and the spleen compared with the number for untreated controls (P < 0.001 for all comparisons). In our experience, using MAC 101 as the challenging organism, KRM 1648 is the first the number of bacteria in the blood and spleen compared with the number for untreated controls (P >0.001 for all comparions). In our experience, using MAC 101 as the challenging organism, KRM 1648 is the first rifamycin with significant activity in vivo against MAC infection in beige mice.

Animals↗

PubMed2001

Activity of moxifloxacin by itself and in combination with ethambutol, rifabutin, and azithromycin in vitro and in vivo against Mycobacterium avium.

Moxifloxacin activity against Mycobacterium avium complex (MAC) was evaluated in vitro against 25 strains. The MIC was determined to range from 0.125 to 2.0 microg/ml. In addition, U937 macrophage monolayers infected with MAC strain 101 (serovar 1) were treated with moxifloxacin (0.25 to 8 microg/ml) daily, and the number of intracellular bacteria was quantitated after 4 days. Moxifloxacin showed inhibitory activity at 0.5 microg/ml and higher. To assess the activity of moxifloxacin containing regimens in vivo, we infected C57BL bg(+)/bg(+) mice with 3 x 10(7) MAC strain 101 bacteria intravenously. One week later treatment was begun with the following: (i) moxifloxacin (50 mg/kg/day or 100 mg/kg/day), ethambutol (100 mg/kg/day), or a combination of moxifloxacin and ethambutol; or (ii) moxifloxacin (100 mg/kg/day), azithromycin (200 mg/kg/day), or rifabutin (40 mg/kg/day) as oral monotherapy; or (iii) all permutations of two-drug therapy or all three drugs in combination. All groups contained at least 14 animals, and the control group received the drug vehicle. After 4 weeks, quantitative blood cultures were obtained and the number of bacteria in liver and spleen was quantitated. Moxifloxacin, ethambutol, and azithromycin were active as single agents in liver, spleen, and blood. Rifabutin showed inhibitory activity only in the blood. Two-drug combinations containing azithromycin were no more active than azithromycin alone. Similarly, the three-drug combination was not more active than azithromycin alone in the spleen. Rifabutin did not add to the activity of any other single agent or two-drug combination. Moxifloxacin at both concentrations in combination with ethambutol was significantly more active than each drug alone.

Animals↗

PubMed2005

Role of embB codon 306 mutations in Mycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than ethambutol resistance.

Mutations at position 306 of embB (embB306) have been proposed as a marker for ethambutol resistance in Mycobacterium tuberculosis; however, recent reports of embB306 mutations in ethambutol-susceptible isolates caused us to question the biological role of this mutation. We tested 1,020 clinical M. tuberculosis isolates with different drug susceptibility patterns and of different geographical origins for associations between embB306 mutations, drug resistance patterns, and major genetic group. One hundred isolates (10%) contained a mutation in embB306; however, only 55 of these mutants were ethambutol resistant. Mutations in embB306 could not be uniquely associated with any particular type of drug resistance and were found in all three major genetic groups. A striking association was observed between these mutations and resistance to any drug (P < 0.001), and the association between embB306 mutations and resistance to increasing numbers of drugs was highly significant (P < 0.001 for trend). We examined the association between embB306 mutations and IS6110 clustering (as a proxy for transmission) among all drug-resistant isolates. Mutations in embB306 were significantly associated with clustering by univariate analysis (odds ratio, 2.44; P = 0.004). In a multivariate model that also included mutations in katG315, katG463, gyrA95, and kasA269, only mutations in embB306 (odds ratio, 2.14; P = 0.008) and katG315 (odds ratio, 1.99; P = 0.015) were found to be independently associated with clustering. In conclusion, embB306 mutations do not cause classical ethambutol resistance but may predispose M. tuberculosis isolates to the development of resistance to increasing numbers of antibiotics and may increase the ability of drug-resistant isolates to be transmitted between subjects.

Antitubercular Agents↗

PubMed1976

High-dose ethambutol: its role in intermittent chemotherapy. A six-year study.

The outcome of 81 patients receiving supervised ambulatory treatment with twice-weekly isoniazid and ethambutol is reported. The patients were divided into 2 groups, one of which received its entire outpatient treatment with isoniazid and ethambutol, the other receiving isoniazid and ethambutol after initial treatment with isoniazid and streptomycin. In both groups, there was a 100 per cent favorable response at completion of therapy and no relapes detected among those patients followed after treatment. We compared our results with other studies of intermittent-supervised therapy and concluded that twice-weekly isoniazid and ethambutol given up to 18 months after an adequate phase of daily treatment is a highly effective and well-tolerated regimen.

Adult↗

PubMed1992

Prospective comparative study of ofloxacin or ethambutol for the treatment of pulmonary tuberculosis.

The efficacy of ofloxacin, rifampicin and isoniazid was prospectively compared with the regimen of ethambutol, rifampicin and isoniazid for the primary treatment of pulmonary tuberculosis in 124 patients. All drugs were given orally daily for nine months. Culture conversion rates three months after starting treatment were 98 percent in the ofloxacin group and 94 percent in the ethambutol group; by six months all patients in both groups were culture-negative. Significant radiological improvement of pulmonary infiltrates was observed in 83 percent of the ofloxacin group and 85 percent of the ethambutol group one year after starting treatment. No relapse in either group was observed during a two-year follow-up period after the cessation of chemotherapy. Ofloxacin appears to be as useful as ethambutol in the treatment of pulmonary tuberculosis when either drug is combined with isoniazid and rifampicin.

Adolescent↗

PubMed2006

Update on ethambutol optic neuropathy.

Ethambutol optic neuropathy is a well-recognised adverse ocular event in patients who receive ethambutol for the treatment of mycobacterial infections. Much has been published on this condition; however, understanding of patient outcomes and the mechanism by which ethambutol optic neuropathy occurs, as well as data published in textbooks and reference books, tend to lag behind what is currently known. The purpose of this article is to update the clinician on what is currently accepted in regards to the clinical presentation of ethambutol optic neuropathy and what type of eye care should be provided to patients treated with this medication. In addition, new treatment recommendations are suggested to assist clinicians in complying with currently accepted standards of care.

Antitubercular Agents↗

PubMed2004

Liquid chromatographic determination of ethambutol in serum samples based on intramolecular excimer-forming fluorescence derivatization.

A selective liquid chromatographic method has been developed for the assay of ethambutol in serum samples. The assay involves intramolecular excimer-forming derivatization with 4-(1-pyrene)butanoyl chloride (PBC) and isocratic reversed-phase chromatography with fluorescence detection. After acetonitrile-deproteinization of the serum sample, the derivatization reaction of ethambutol with PBC was completed within 30 min at 50 degrees C. N,N'-Diethylethylenediamine was used as an internal standard. The detection limit of ethambutol was 23 ng/ml serum, corresponding to 180 fmol on column at a signal-to-noise ratio of 3. The present method was selective enough to analyze ethambutol in rabbit serum without any tedious sample clean-up procedure because biogenic monoamines gave no peak in the chromatogram. The method was applicable to drug monitoring in rabbit serum.

Animals↗

PubMed2003

Ocular ethambutol toxicity.

Ethambutol is an antimicrobial agent used frequently to treat tuberculosis. The most commonly recognized toxic effect of ethambutol is optic neuropathy, which generally is considered uncommon and reversible in medical literature. We describe a 43-year-old man who developed signs and symptoms of bilateral optic neuropathy during treatment with ethambutol. This case and a review of the literature show the severe and unpredictable nature of ethambutol toxicity and its potential for irreversible vision loss despite careful ophthalmologic monitoring.

Adult↗

PubMed2003

Ethambutol and optic neuropathy.

PURPOSE: To demonstrate the association between ethambutol and optic neuropathy. METHOD: Thirteen patients who developed optic neuropathy after being treated with ethambutol for tuberculosis of the lung or lymph node at Siriraj Hospital between 1997 and 2001 were retrospectively reviewed. The clinical characteristics and initial and final visual acuity were analyzed to determine visual outcome. RESULTS: All patients had optic neuropathy between 1 to 6 months (mean = 2.9 months) after starting ethambutol therapy at a dosage ranging from 13 to 20 mg/kg/day (mean = 17 mg/kg/day). Seven (54%) of the 13 patients experienced visual recovery after stopping the drug. Of 6 patients with irreversible visual impairment, 4 patients had diabetes mellitus, glaucoma and a history of heavy smoking. CONCLUSION: Early recognition of optic neuropathy should be considered in patients with ethambutol therapy. A low dose and prompt discontinuation of the drug is recommended particularly in individuals with diabetes mellitus, glaucoma or who are heavy smokers.

Adult↗

PubMed2004

Pharmacokinetics of ethambutol in children and adults with tuberculosis.

SETTING: Five hospitals in the United States. OBJECTIVE: To describe ethambutol pharmacokinetics in children and adults with active tuberculosis (TB). DESIGN: Prospective, open-labeled study in 56 adults and 14 children with active tuberculosis who received ethambutol as part of their multidrug TB regimens. RESULTS: Most serum samples were collected up to 10 h post dose and assayed using a validated gas chromatography assay with mass selective detection (GC/MS). Concentration data were analyzed using non-compartmental and population pharmacokinetic methods. Drug exposure increased with dose, but less than proportionally at doses >3000 mg. Lower than expected maximum serum concentrations (Cmax <2 microg/ml) were common in adults. Very low Cmax (<1 microg/ml) were common in children, as was delayed absorption (time to Cmax >3 h). Many Cmax were at or below typical TB minimal inhibitory concentrations. Cmax values for HIV-positive patients were 20% lower than HIV-negative patients with daily doses, but were similar with larger twice-weekly doses. CONCLUSIONS: Adult TB patients often had lower than expected ethambutol serum concentrations, and most pediatric TB patients had very low ethambutol serum concentrations. Higher doses and therapeutic drug monitoring may be indicated for many of these patients.

Absorption↗

PubMed2005

Rapidly developing optic neuritis secondary to ethambutol: possible mechanism of injury.

Optic neuritis has been described among the toxic effects of Ethambutol. This side effect is dose related. The mean duration of Ethambutol induced optic neuritis (EON) is three months. We report a case of EON after few days of exposure to Ethambutol and the symptoms resolved after discontinuation of Ethambutol. This most likely represents an idiosyncratic reaction which is different as compared to dose related optic neuritis.

Adult↗

PubMed1991

[Visually evoked cortical potentials for early detection of optic neuritis in ethambutol therapy].

Ethambutol leads to chronic, severe optic neuritis with sudden onset in approximately 5-14% of all patients. Therefore, the ability of visually (pattern) evoked potentials for the early diagnosis of ethambutol-induced optic neuritis was tested. During ethambutol therapy prolonged latency was documented in 5 of 15 cases (33%). One of these 5 cases showed a reversible decrease in visual acuity. Thus, during treatment with ethambutol visually (pattern) evoked potentials may reveal a surprisingly high percentage of subclinical optic neuritis. These patients need close supervision in order to facilitate early discontinuation of the drug when neuritis develops.

Adolescent↗