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PubMed2003

Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine.

To understand why once-weekly isoniazid/rifapentine therapy for tuberculosis was less effective than twice-weekly isoniazid/rifampin, we studied human immunodeficiency virus-seronegative patients with either failure (n = 4), relapse (n = 35), or cure (n = 94), recruited from a comparative treatment trial. In multivariate analyses that were adjusted for severity of disease, low plasma concentrations of isoniazid were associated with failure/relapse with once-weekly isoniazid/rifapentine (median isoniazid area under the concentration-time curve for 12 hours after the dose [AUC(0-12)] was 36 microg x hour/ml in failure/relapse versus 56 microg x hour/ml in control cases p = 0.005), but not with twice-weekly isoniazid/rifampin. Furthermore, two patients who relapsed with Mycobacterium tuberculosis monoresistant to rifamycin had very low concentrations of isoniazid. Finally, isoniazid acetylator status determined by N-acetyltransferase type 2 genotype was associated with outcome with once-weekly isoniazid/rifapentine (p = 0.03) but not twice-weekly isoniazid/rifampin. No rifamycin pharmacokinetic parameter was consistently and significantly associated with outcome (p > 0.10). Because low isoniazid concentrations were associated with failure/relapse, a drug with consistently greater area under the concentration-time curve than isoniazid may be needed to achieve highly active once-weekly therapy with rifapentine.

Adult↗
PubMed1999

Tolerability of twice-weekly rifabutin-isoniazid combinations versus daily isoniazid for latent tuberculosis in HIV-infected subjects: a pilot study.

The tolerability of and adherence to intermittent short-term rifabutin-isoniazid preventive treatment was assessed in subjects dually infected with Mycobacterium tuberculosis and the human immunodeficiency virus (HIV). In a randomised, open-label, phase II pilot study, 44 subjects received either rifabutin 300 mg and isoniazid 750 mg twice weekly for 3 months (group A, n = 16) or the same regimen with rifabutin at 600 mg (group B, n = 14), or isoniazid 300 mg/day for 6 months (group C, n = 14). Three, two and four subjects in groups A, B, and C, respectively, did not complete their treatment (one case of flu-like syndrome in group B; one methadone withdrawal syndrome in group A; and patient decision in two cases in group A and four in group C). Overall, adverse events were reported by four, nine, and seven subjects in groups A, B and C, respectively. Intermittent combined rifabutin + isoniazid for 3 months had lower default rates than daily standard isoniazid for 6 months. The regimen with rifabutin at 300 mg dose compared favourably to standard isoniazid, and warrants larger efficacy studies to assess its role for the prevention of latent tuberculosis in HIV-infected subjects.

AIDS-Related Opportunistic Infections↗
PubMed2001

[A case of isoniazid-resistant tuberculosis diagnosed during chemoprophylaxis with isoniazid].

A 15-year-old man, who was a classmate with the index case of a large outbreak of tuberculosis in a junior high school in Kochi city, showed strongly positive reaction to tuberculin skin test in March 1999. After taking a chest X-ray film, which showed no abnormal finding, chemoprophylaxis with isoniazid was started in April 1999. He was compliant with therapy, and had no symptom until July 1999, when he was checked again by chest X-ray and abnormal finding was suspected. He visited a hospital for further examinations, and chest X-ray revealed cavitary lesion and sputum smears showed acid-fast baccili. Cultures of the sputum was positive for Mycobacterium tuberculosis, and drug susceptibility tests revealed that the organism was resistant to isoniazid (5 micrograms/ml) and sensitive to RFP, SM, and EB. RFLP analysis of Mycobacterium tuberculosis isolated from the index-case patient and the present patient demonstrated an identical pattern, although the organism obtained from the index-case patient was sensitive to isoniazid, RFP, SM, and EB. Mycobacterium tuberculosis isolated from other 7 patients in the same outbreak showed an identical pattern in RFLP analysis and were also sensitive to isoniazid. The present patient was a close contact with the highly infectious index-case patient. The patient was estimated to be infected around September to October, 1998, and chemoprophylaxis with isoniazid was started in April 1999, when the tubercle baccili had grown considerably, but not enough to show radiographic abnormality. These two factors might be attributable to rarely seen development of isoniazid resistance in this case.

Adolescent↗
PubMed1960

A concurrent comparison of isoniazid plus PAS with three regimens of isoniazid alone in the domiciliary treatment of pulmonary tuberculosis in South India.

Recent studies have shown that treatment of pulmonary tuberculosis with isoniazid plus p-aminosalicylic acid (PAS) at home is, in the majority of cases, as satisfactory as treatment with the same combination of drugs in sanatorium and does not appear to expose the patient's contacts to any special risk. Before mass domiciliary chemotherapy can be introduced, however, a question that has to be decided is what drug or drugs and what dosage and rhythm of administration will be most effective.THIS PAPER PRESENTS THE RESULTS OF A CONTROLLED COMPARISON OF FOUR CHEMOTHERAPEUTIC REGIMENS: (a) 3.9-5.5 mg/kg body-weight of isoniazid plus 0.2-0.3 g/kg body-weight of PAS (sodium salt) daily in two doses (the standard combined chemotherapy); (b) 7.8-9.6 mg/kg body-weight of isoniazid alone daily in one dose; (c) 7.8-9.6 mg/kg body-weight of isoniazid alone daily in two doses; (d) 3.9-5.5 mg/kg body-weight of isoniazid alone daily in two doses. Isoniazid plus PAS proved to be the most satisfactory regimen; it was clinically effective and there were very few toxic manifestations.

Aminosalicylic Acid↗
PubMed1962

The course of pulmonary tuberculosis in patients excreting organisms which have acquired resistance. Response to continued treatment for a second year with isoniazid alone or with isoniazid plus PAS.

This study from the Tuberculosis Chemotherapy Centre, Madras, summarizes the progress during the second year of the patients in a concurrent comparison of four domiciliary chemotherapeutic regimens (isoniazid plus PAS and three regimens of isoniazid alone) who had bacteriologically active or bacteriologically relapsed pulmonary tuberculosis, with isoniazid-resistant organisms, at the end of the first year of treatment.Of the 57 patients who continued on the same chemotherapy during the second year, nine had attained bacteriological quiescence by the end of that year, 15 still had bacteriologically active disease and 33 had during the year had a serious radiographic deterioration necessitating a change of treatment. An association was observed between the response to treatment in the second year and both the extent of cavitation and the degree of culture-positivity at the end of the first year, but no association was found between the response to treatment in the second year and the level of isoniazid-resistance, the catalase activity, the susceptibility to hydrogen peroxide or the virulence in the guinea-pig of cultures isolated in the last months of the first year.It is concluded that persisting bacteriological positivity at the end of one year's treatment with isoniazid, either alone or in combination with PAS, is likely to lead to serious radiographic deterioration, irrespective of the level of isoniazid-resistance or of the catalase activity of the cultures of tubercle bacilli, and that, consequently, treatment of patients with bacteriologically active pulmonary tuberculosis must aim at rendering the sputum culture-negative in all instances.

4-Aminobenzoic Acid↗
PubMed2005

Short-course therapy with rifampin plus isoniazid, compared with standard therapy with isoniazid, for latent tuberculosis infection: a meta-analysis.

BACKGROUND: A major difficulty associated with the use of standard therapy with isoniazid for latent tuberculosis infection is poor patient adherence to therapy because of the prolonged course required. Shorter courses of therapy involving > or =2 drugs have been proposed as an alternative to standard therapy, but they have not undergone enough testing. METHODS: We performed a meta-analysis to determine the equivalence of daily short-course therapy with rifampin plus isoniazid for 3 months and standard therapy with isoniazid for 6-12 months. The end points that were evaluated were development of active tuberculosis, severe adverse drug reactions, and death. We searched published information in the Cochrane Library, MEDLINE, and Embase databases, as well as unpublished information in the Cambridge Scientific Abstracts Internet database, Conference Papers Index, AIDS and Cancer Research Abstracts, and ClinicalTrials.gov. We also scanned the reference lists of articles. We only included trials in which individuals were randomly allocated to receive treatment. Two reviewers independently applied the criteria for trial selection, assessed trial quality, and extracted data. RESULTS: Five trials comprising 1926 adults from Hong Kong, Spain, and Uganda were identified. The mean duration of follow-up varied from 13 to 37 months. Overall, development of active tuberculosis was equivalent in association with both regimens (pooled risk difference, 0%; 95% confidence interval [CI], -1% to 2%; percentage of total variation across the studies that is the result of heterogeneity rather than chance [I2], 0%; P=.86). Severe adverse effects were reported with a similar frequency for both regimens (pooled risk difference, -1%; 95% CI, -7% to 5%) but with statistically significant heterogeneity detected (I2, 78%; P=.001). However, a subanalysis of high-quality trials (including 74% of the sample size) suggested that both regimens were equally safe. In 3 trials (comprising 1390 patients) that provided data on mortality, the regimens showed equivalence (pooled risk difference, -1%; 95% CI, -4% to 2%; I2, 2.7%; P=.38). CONCLUSION: Short-course therapy with rifampin plus isoniazid was equivalent to standard therapy with isoniazid in terms of efficacy, the proportion of severe side effects that occurred, and mortality.

Antitubercular Agents↗
PubMed1977

Acetylator phenotyping of tuberculosis patients using matrix isoniazid or sulphadimidine and its prognostic significance for treatment with several intermittent isoniazid-containing regimens.

1. The acetylator phenotype of over 600 pulmonary tuberculosis patients treated with intermittent isoniazid-containing regimens in two controlled clinical trials was determined using either sulphadimidine or a slow-release isoniazid formulation. 2. Both methods unequivocally classified over 99% of the patients as being either slow or rapid acetylators. 3. Rapid and slow acetylation did not differ in their ability of hydrolyse acetylisoniazid to isonicotonic acid plus monoacetylhydrazine, or to conjugate isonicotinic acid with glycine. 4. Rapid acetylators acetylated the monoacetylhydrazine liberated in vivo more rapidly than slow acetylators, demonstrating that this compound is also polymorphologically acetylated in man. 5. The acetylator phenotype of the patients was without prognostic significance when they were treated on a twice-weekly basis with isoniazid plus streptomycin plus pyraziniamide, or with isoniazid plus rifampicin. However, when patients were treated once every week for 12 months with isoniazid plus rifampicin, 5% of the rapid acetylators had an unsatisfactory response as contrasted to the complete success of the treatment in the slow acetylators.

Acetylation↗
PubMed1961

Rate of inactivation of isoniazid in South Indian patients with pulmonary tuberculosis. 2. Clinical implications in the treatment of pulmonary tuberculosis with isoniazid either alone or in combination with PAS.

A series of studies on the rate of inactivation of isoniazid in Indian patients with pulmonary tuberculosis undergoing domiciliary chemotherapy with isoniazid, alone or in combination with p-aminosalicylic acid, has recently been undertaken by the Tuberculosis Chemotherapy Centre, Madras. In the first study, the serum isoniazid levels of the patients were determined four-and-a-half hours after intramuscular administration of a standard dose of 3 mg/kg body-weight of isoniazid and, according to whether the serum level was 0.58 mug/ml or above, or less than 0.58 mug/ml, the patient was classified as a slow or as a rapid inactivator. The present paper describes the second of these studies, in which the response to treatment of the slow and the rapid inactivators was compared. The results of this investigation suggested that there might be an association between response to treatment and rate of inactivation of isoniazid, since the slow inactivators were more often culture-negative during treatment and showed a higher proportion of individuals with bacteriologically quiescent disease at 12 months and a lower proportion with radiographic deterioration at six months than the rapid inactivators, while the slow inactivators who deteriorated radiographically or clinically to an extent warranting a change of treatment during the two years did so later than the corresponding rapid inactivators. There was slight evidence that the slow and the rapid inactivators differed in the speed of conversion to bacteriological negativity of those patients whose disease was bacteriologically quiescent at 12 months, but no evidence that they differed in the degree of positivity of sputum specimens that were positive on culture at six, nine or 12 months, or in the frequency with which the patients showed moderate or greater radiographic improvement at six months.

Humans↗
PubMed2004

Chemiluminescence detection of isoniazid using Ru(phen)3(2+)-isoniazid-Ce(IV) system.

In our experiment, it was observed that isoniazid could enhance the chemiluminescence (CL) emission of tris-(1,10-phenanthroline)ruthenium(II) (Ru(phen)3(2+))-cerium(IV) (Ce(IV)) system and this enhancement effect was dependent on the concentration of isoniazid, based on which, a novel CL system was established for the detection of isoniazid. Under the optimum experimental conditions, the dynamic range and detection limit are 7.0 x 10(-2) to 6.5 microg ml(-1) and 2.5 x 10(-2) microg ml(-1), respectively. The R.S.D. is 3.4% (n = 11). The proposed method has been applied to detect the content of isoniazid in the injection solution with satisfactory results. The possible mechanism of the CL reaction was studied.

Calibration↗
PubMed2002

Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial.

BACKGROUND: Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week. METHODS: We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat. FINDINGS: 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups. INTERPRETATION: Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.

Antibiotics, Antitubercular↗
PubMed1979

Isoniazid prophylaxis among Alaskan Eskimos: a final report of the bethel isoniazid studies.

As a result of numerous trials, isoniazid prophylaxis was shown to be effective in preventing tuberculosis in many different populations and under a variety of conditions. However, the duration of the protective effect has been of some concern. In a previous report, the protective effect of isoniazid prophylaxis among Alaskan Eskimos was shown to persist through the fifteenth year after its administration. In this final report, the protective effect is shown to persist for more than 19 years. The magnitude of the effect is related to the amount of isoniazid taken. The results of the study are consistent with the hypothesis that the decrease in risk of tuberculosis produced by isoniazid preventive therapy is lifelong.

Alaska↗
PubMed1984

Urinary metabolic profile of isoniazid in patients who develop isoniazid-related liver damage.

The urinary metabolite profile of isoniazid has been studied in patients receiving the drug as therapy for tuberculosis and the profile in patients suffering liver damage due to isoniazid compared with that in control patients. There were no consistent differences between control patients and those suffering liver damage in the excretion of isoniazid metabolites. It may be that susceptibility to the hepatotoxicity of isoniazid is not due to metabolic differences, although a number of other possible explanations are discussed. It is not at present possible to predict which patients will be susceptible from metabolic studies.

Acetylation↗
PubMed1961

Prevalence and early attack rate of tuberculosis among close family contacts of tuberculous patients in South India under domiciliary treatment with isoniazid plus PAS or isoniazid alone.

The authors present a report from the Tuberculosis Chemotherapy Centre, Madras, on the prevalence and attack rate of tuberculosis among close family contacts of tuberculous patients in South India undergoing domiciliary chemotherapy either with isoniazid plus PAS or with one of three regimens of isoniazid alone. The report gives (a) the prevalence of tuberculosis among the contacts at the time of diagnosis of the disease in the patients and (b) the incidence of tuberculosis in the contacts during the first year of treatment of the patients. The contacts were divided into four series, corresponding to the four chemotherapeutic regimens of the patients.The prevalence of active tuberculosis was found to be particularly high among children under five years of age, being 12.0% as compared with 7.6% for all age-groups combined. The incidence of active tuberculosis during the year of treatment of the patients was also found to be highest in the under five years' age-group-a further indication that child contacts are especially vulnerable to infection. The incidence was considerably higher in the first quarter of the year than in the other quarters, and it was lowest in the last quarter. This finding, together with the fact that the attack rates in the four contact series were not related either to the duration of bacteriological positivity in the patients or to the period of excretion of isoniazid-resistant organisms by the patients, suggests that the major risk to contacts in the first year results from exposure to the patient before treatment rather than from exposure during treatment. These results thus confirm the findings in an earlier study by the Centre of the contacts of patients in a controlled comparison of chemotherapy with isoniazid plus PAS at home and in sanatorium.

Aminosalicylic Acid↗
PubMed1990

Studies on immunomodulatory properties of isoniazid. IV. Effect of isoniazid on T lymphocyte activation by phorbol ester tumor promoter.

Human peripheral blood T cells or continuous T cell lines were treated with phorbol myristate (PMA), a direct protein kinase C activator. The effect of isoniazid on PMA-treated cells was investigated. It was found that low doses of isoniazid augmented proliferation of T cells treated with PMA or stimulated with PMA and phytohemagglutinin. Similar results were shown in the Jurkat cell line. There was no influence of isoniazid upon proliferation of PMA-treated HT-2 cells, interleukin 2-dependent cell line. The obtained results suggest that, at least one target mechanism of isoniazid is located in T cell activation pathway after protein kinase C activation.

Adjuvants, Immunologic↗
PubMed1990

Studies on immunomodulatory properties of isoniazid. I. Effect of isoniazid on mitogen- and anti-CD3 antibody-induced proliferation of human peripheral blood mononuclear cells and T cells.

Isoniazid, a tuberculostatic agent, induced in some patients lupus-like syndrome. Pathomechanism of this autoimmune phenomenon is unknown, and it is suggested that is associated with disturbances in immunoregulatory processes. Human peripheral blood mononuclear cells or T cells were isolated from healthy donors and were stimulated with phytohemagglutinin or antibody against CD3 cell receptor antigen. Proliferation, measured as thymidine uptake, was determined in in vitro cultures of the cells. Isoniazid added to cell cultures decreased proliferation at higher doses, and produced a slight increase in proliferation in concentration 10(-5)-10(-6) M. Isoniazid alone has no mitogenic activity. The viability of the cells, determined as the Trypan blue exclusion test, was decreased only at the presence of the highest used dose of isoniazid (10(-2) M), thus the results were not influenced by the toxic effects of the drug.

Adult↗
PubMed1990

Studies on immunomodulatory properties of isoniazid. III. Effect of isoniazid on proliferation of interleukin-dependent and interleukin-independent cell line.

The effect of various concentrations of isoniazid on proliferation of the interleukin 2-dependent cell line, HT-2 and continuous T cell line Jurkat was studied. It was found that high doses of isoniazid increased proliferation of the HT-2 cells in presence of suboptimal doses of interleukin 2. Low doses had no effect on proliferation. The unstimulated Jurkat cells increased proliferation in presence of low doses of isoniazid while phytohemagglutinin-stimulated cells responded to high doses of the drug only. It is hypothesized that biphasic effect of isoniazid is caused by cumulation of direct and indirect effects of T cell activation as well as toxic influence on the cells.

Animals↗
PubMed1977

Isoniazid-rifampin fulminant hepatitis. A possible consequence of the enhancement of isoniazid hepatotoxicity by enzyme induction.

The authors report 6 cases of fulminant hepatitis in patients treated with isoniazid and rifampin. In 4 of these patients, the treatment had been started within 3 days after a general anesthesia. The course of the disease was remarkably similar in all 6 patients: (1) the time interval from the beginning of the isoniazid-rifampin administration to the onset of jaundice was 6 to 10 days; (2) disorders of consciousness appeared less than 3 days after the onset of jaundice; (3) serum transaminases were 26 to 80 times the upper limit of normal; (4) the main liver lesion was centrilobular necrosis; (5) hypersensitivity manifestations were absent; (6) all 6 patients recovered. Fulminant hepatitis might be attributable to a hepatotoxic metabolite of isoniazid, the production of which would be attributable to a hepatotoxic metabolite of isoniazid, the production of which would be increased as a consequence of the enzyme-inducing effect of rifampin and, possibly, other drugs administered for general anesthesia.

Adolescent↗