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At least 19 recordsLinked to original sources

PubMed1995

Relative bioavailability of rifampicin, isoniazid and ethambutol from a combination tablet vs. concomitant administration of a capsule containing rifampicin and a tablet containing isoniazid and ethambutol.

Twenty male volunteers who were slow metabolisers of isoniazid, completed this single-blind, single-dose, randomised, cross-over study to compare the bioavailability of rifampicin (CAS 13292-46-1), isoniazid (CAS 54-85-3) and ethambutol (CAS 1070-11-7) from Myrin tablets (test preparation) with the bioavailability of these drugs from a combination of capsules containing rifampicin and tablets containing isoniazid and ethambutol (reference). There were 2 treatment periods and on clinic days volunteers were given either the reference (300 mig rifampicin plus 200 mg isoniazid and 600 mg ethambutol HCl), or the test preparation (300 mg rifampicin, 150 mg isoniazid and 600 mg ethambutol HCl). Serial blood samples were drawn from the volunteers and rifampicin, isoniazid and ethambutol assays were performed. The results of this study indicate that the test preparation is equivalent to the reference with respect to both the rate and the extent of absorption of rifampicin, isoniazid (after adjustment for the different doses of isoniazid and ethambutol).

Adolescent↗

PubMed1996

A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group.

BACKGROUND: Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. METHODS: We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. RESULTS: Among 187 patients who could be evaluated, blood cultures became negative more often in the three-drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P=0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). CONCLUSIONS: In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better.

AIDS-Related Opportunistic Infections↗

PubMed1989

Inefficacy of ethambutol, ethambutol plus isoniazid, INH plus rifampicin, co-trimoxazole and metronidazole in the treatment of kala-azar.

In an attempt to find an orally effective drug against kala-azar, ethambutol alone, ethambutol plus INH, INH plus rifampicin, co-trimoxazole and metronidazole were tried in the treatment of 70 patients of Indian kala-azar. Ethambutol and ethambutol plus INH were totally ineffective. INH and rifampicin were tried in 10 cases; in three there was some clinical improvement but all relapsed and were cured with sodium stibogluconate. Co-trimoxazole reduced fever in four out of 20 cases, but all relapsed within 2 months. In one case the general health was well maintained but the splenic aspirate contained a large number of parasites and there was no regression in the size of the spleen. The patient was ultimately cured with sodium stibogluconate. Metronidazole orally or intravenously was not effective. It is suggested that, as these drugs are ineffective, a search for an oral substitute to sodium stibogluconate should continue.

Antiprotozoal Agents↗

PubMed1998

Does in vitro susceptibility to rifabutin and ethambutol predict the response to treatment of Mycobacterium avium complex bacteremia with rifabutin, ethambutol, and clarithromycin? Canadian HIV Trials Network Protocol 010 Study Group.

The in vitro susceptibilities of baseline Mycobacterium avium complex (MAC) blood isolates from 86 patients with AIDS who were treated with clarithromycin, ethambutol, and rifabutin were determined to examine whether these results predict bacteriologic response to treatment. No patient received prior prophylaxis with clarithromycin or azithromycin. Minimum inhibitory concentrations (MICs) of clarithromycin for all isolates were < or = 2 micrograms/mL. The median MIC of rifabutin was between 0.25 and 0.5 microgram/mL, and all isolates were susceptible to < or = 2 micrograms of rifabutin/mL. The median MIC of ethambutol was 4 micrograms/mL, and the MIC90 was 8 micrograms/mL. There was no correlation between ethambutol susceptibility and subsequent bacteriologic clearance. At all time points through week 12, bacteriologic clearance occurred more frequently in patients with isolates for which MICs of rifabutin were lower, but this difference was statistically significant only at week 2. Susceptibility testing for baseline MAC isolates from AIDS patients not previously treated with clarithromycin or azithromycin does not appear to be useful in guiding therapy.

AIDS-Related Opportunistic Infections↗

PubMed1998

Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium.

Disseminated Mycobacterium avium complex (MAC) infection continues to be a common opportunistic infection in patients infected with human immunodeficiency virus (HIV). The optimal therapy for disseminated MAC infection is unclear. We compared azithromycin plus ethambutol with clarithromycin plus ethambutol in the treatment of disseminated MAC infection in HIV type 1-infected patients, examining the frequency of bacteremia clearance, time to clearance, and study drug tolerance after 16 weeks of therapy. Fifty-nine patients for whom blood cultures were positive for MAC were enrolled in the study from 10 university-affiliated Veterans Affairs Medical Centers. Thirty-seven patients were evaluable for determination of quantitative bacteremia and clinical outcomes. Clearance of bacteremia was seen at the final visit in 37.5% of azithromycin-treated patients and in 85.7% of clarithromycin-treated patients (P = .007). The estimated median time to clearance of bacteremia was also significantly different between the two treatment arms: 4.38 weeks for clarithromycin recipients vs. > 16 weeks for azithromycin recipients (P = .0018). Only one isolate developed macrolide resistance during therapy. Abatement of symptoms, other laboratory-evident abnormalities, and adverse effects were similar in the two groups. At the doses used in this study, clarithromycin/ethambutol produced a more rapid resolution of bacteremia than did azithromycin/ethambutol, and clarithromycin/ethambutol was more effective at sterilization of blood cultures after 16 weeks of therapy.

AIDS-Related Opportunistic Infections↗

PubMed1990

Effect of ethambutol on the phospholipids of ethambutol susceptible and resistant strains of Mycobacterium smegmatis ATCC 607.

Effect of ethambutol (EMB) on phospholipid composition and metabolism of EMB-susceptible and EMB-resistant strains of M. smegmatis ATCC 607 was studied. Treatment with ethambutol had different effect in both the strains resulting in decreased total phospholipid and cardiolipin content in EMB-susceptible strain and increased content in EMB-resistant strain, with no effect on fatty acyl group composition. These changes were further corroborated by the use of [1-14C]sodium acetate in these studies.

Drug Resistance, Microbial↗

PubMed1998

The role of copper on ethambutol's antimicrobial action and implications for ethambutol-induced optic neuropathy.

The principal side effect of the antimycobacterial agent ethambutol (EMB) is an optic neuropathy with clinical features very similar to a mitochondrial hereditary optic neuropathy (Leber's). The mechanism of EMB-induced optic neuropathy may be EMB's chelation of copper, thereby precluding normal cytochrome c oxidase activity and mitochondrial metabolism in the optic nerve. Before attempting to use therapeutic copper to replenish endogenous stores in an attempt to preclude EMB-induced optic neuropathy, we wished to determine whether EMB is still effective against mycobacteria in the presence of copper. EMB and copper, alone and in combination, were tested against six strains of Mycobacterium tuberculosis and five strains of Mycobacterium avium using a radiometric broth macrodilution assay. Copper did not effect EMB's antimicrobial actions against either species of mycobacteria. This in vitro study suggests that if copper were given to patients to prevent EMB-induced optic neuropathy, it would not compromise EMB's bacteriostatic properties.

Antitubercular Agents↗

PubMed1996

Truncated structural variants of lipoarabinomannan in ethambutol drug-resistant strains of Mycobacterium smegmatis. Inhibition of arabinan biosynthesis by ethambutol.

The anti-tuberculosis drug, ethambutol (Emb), was previously shown to inhibit the synthesis of arabinans of both the cell wall arabinogalactan (AG) and lipoarabinomannan (LAM) of Mycobacterium tuberculosis and other mycobacteria. However, an Emb-resistant mutant, isolated by consecutive passage of the Mycobacterium smegmatis parent strain in media containing increasing concentrations of Emb, while synthesizing a normal version of AG, produced truncated forms of LAM when maintained on 10 microg/ml Emb (Mikusová, K., Slayden, R. A., Besra, G. S., and Brennan, P. J. (1995) Antimicrob. Agents Chemother. 39, 2482-2489). We have now isolated and characterized the truncated LAMs made by both the resistant mutant and a recombinant strain transfected with a plasmid containing the emb region from Mycobacterium avium which encodes for Emb resistance. By chemical analysis, endoarabinanase digestion, high pH anion exchange chromatography, and mass spectrometry analyses, truncation was demonstrated as primarily a consequence of selective and partial inhibition of the synthesis of the linear arabinan terminal motif, which constitutes a substantial portion of the arabinan termini in LAM but not of AG. However, at higher concentrations, Emb also affected the general biosynthesis of arabinan destined for both AG and LAM, resulting in severely truncated LAM as well as AG with a reduced Ara:Gal ratio. The results suggested that Emb exerts its antimycobacterial effect by inhibiting an array of arabinosyltransferases involved in the biosynthesis of arabinans unique to the mycobacterial cell wall. It was further concluded that the uniquely branched terminal Ara6 motif common to both AG and LAM is an essential structural entity for a functional cell wall and, consequently, that the biosynthetic machinery responsible for its synthesis is the effective target of Emb in its role as a potent anti-tuberculosis drug.

Antigens, Bacterial↗

PubMed2001

First randomised trial of treatments for pulmonary disease caused by M avium intracellulare, M malmoense, and M xenopi in HIV negative patients: rifampicin, ethambutol and isoniazid versus rifampicin and ethambutol.

BACKGROUND: The treatment of pulmonary disease caused by opportunist mycobacteria is controversial. It is uncertain whether in vitro sensitivity testing predicts clinical response in the way it does for Mycobacterium tuberculosis. The literature suggests that the combination of rifampicin (R) and ethambutol (E) is important whereas isoniazid (H) may not be, but to date there have been no published reports of randomised controlled trials in the treatment of these conditions. The British Thoracic Society has conducted the first such trial, a randomised study of two regimens in HIV negative patients with pulmonary disease caused by M avium intracellulare (MAC), M malmoense, and M xenopi. METHODS: When two positive cultures were confirmed by the Mycobacterium Reference Laboratories for England, Wales and Scotland, the coordinating physician invited the patient's physician to enrol the patient. Patients were also recruited from Scandinavia. Randomisation to 2 years of treatment with RE or REH was performed from lists held in the coordinator's office. Clinical, bacteriological, and radiological progress was monitored at set intervals up to 5 years. RESULTS: From October 1987 to December 1992, 141 physicians entered 223 patients (106 with M malmoense, 75 with MAC, 42 with M xenopi). At entry the RE and REH groups were comparable over a range of demographic and clinical features. For each species there was no significant difference between RE and REH in the number of deaths, but when the three species were combined there were fewer deaths from the mycobacterial disease with RE (1% v 8%, p=0.018, odds ratio 0.10, exact 95% CI 0.00 to 0.76). For M malmoense the failure of treatment/relapse rates did not differ appreciably between the regimens, but for MAC there were fewer failures of treatment/relapses with REH (16% v 41%, p=0.033) With M xenopi there was a non-significant trend in the same direction (5% v 18%, p=0.41) and when all three species were combined there was a significant difference in favour of REH (11% v 22%, p=0.033). There was no correlation between failure of treatment/relapse and in vitro resistance. M xenopi was associated with the greatest mortality (57% at 5 years), MAC was the most difficult to eradicate, and M malmoense had the most favourable outlook (42% known to be alive and cured at 5 years). CONCLUSIONS: The results of susceptibility tests performed by the modal resistance method do not correlate with the patient's response to chemotherapy. RE and REH are tolerated better than previous regimens containing second or third line anti-mycobacterial drugs. Treatment of M malmoense with RE for 2 years is preferable to REH. The addition of H reduces the failure of treatment/relapse rates for MAC and has a tendency to do so also for M xenopi, but there is a suggestion that REH is associated with higher death rates overall. Better regimens are required.

Adolescent↗

PubMed1964