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PubMed1996

In vitro bactericidal and in vivo therapeutic activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis.

The in vitro and in vivo activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis H37Rv were compared with those of rifampin. Bactericidal activity was evaluated by using a silicone-coated slide culture method. The MBC of KRM-1648 was 0.15 to 0.3 microgram/ml for 24 h of exposure, while that of rifampin was > 160 microgram/ml under the same conditions. Against experimental murine tuberculosis, KRM-1648 exhibited significant therapeutic effects, in terms of prolonged survival times for mice compared with those with rifampin treatment, even at lower doses, such as 1 and 3 mg/kg. At a dose of 3 mg/kg, KRM-1648 was at least as effective as rifampin at 10 mg/kg. The combination of KRM-1648 (3 mg/kg) plus isoniazid (3 mg/kg) plus ethambutol (10 mg/kg) exhibited much more activity than did rifampin (10 mg/kg) plus isoniazid (3 mg/kg) plus ethambutol (10 mg/kg). These findings suggest that KRM-1648 is a promising candidate for the treatment of tuberculosis.

Animals↗

PubMed1970

Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis.

The fluctuation test shows that Mycobacterium tuberculosis mutates to resistance to isoniazid, streptomycin, ethambutol and rifampin spontaneously and at random. The average mutation rates for the drugs, in the same order, were calculated to be 2.56 x 10(-8), 2.95 x 10(-8), 10(-7), and 2.25 x 10(-10) mutation per bacterium per generation. The relatively high mutation rate to ethambutol resistance and the low mutation rate to rifampin resistance were confirmed by analyzing the increase in the proportion of mutants with time in a growing population of the tubercle bacilli. The highest proportions of mutants to be expected in unselected populations of the tubercle bacilli were calculated from the results of fluctuation tests.

Culture Media↗

PubMed2005

Deletion of the Mycobacterium tuberculosis pknH gene confers a higher bacillary load during the chronic phase of infection in BALB/c mice.

The role of the serine/threonine kinase PknH in the physiology and virulence of Mycobacterium tuberculosis was assessed by the construction of a pknH deletion mutant. Deletion of the pknH gene did not affect sensitivity to the antimycobacterial drug ethambutol, although it was previously thought to be involved in regulating expression of emb genes encoding arabinosyl transferases, the targets of ethambutol. Nevertheless, transcription analyses revealed that genes associated with mycobacterial cell wall component synthesis, such as emb and ini operons, are downstream substrates of the PknH signaling cascade. In vitro survival studies revealed that a mutant with a deletion of the pknH gene displayed increased resistance to acidified nitrite stress, suggesting that nitric oxide is one of the potential environmental triggers for PknH activation. The effect of pknH deletion on mycobacterial virulence was investigated in BALB/c mice. In this model, the DeltapknH mutant was found to survive and replicate to a higher bacillary load in mouse organs than its parental strain and the pknH-complemented strain. In contrast, another closely related kinase mutant, the DeltapknE mutant, obtained from the same parental strain, was not affected in its virulence phenotype. Infection of THP-1 cells or in vitro growth studies in 7H9 medium did not reveal a significant in vitro growth advantage phenotype for the DeltapknH mutant. In conclusion, we propose that the serine/threonine kinase PknH plays a role in regulating bacillary load in mouse organs to facilitate adaptation to the host environment, possibly by enabling a regulated chronic infection by M. tuberculosis.

Animals↗

PubMed1995

Colorimetric method for determining MICs of antimicrobial agents for Mycobacterium tuberculosis.

A colorimetric method for quantitative measurement of the susceptibility of Mycobacterium tuberculosis to antimicrobial agents is described. The method utilizes an oxidation-reduction dye, Alamar blue, as an indicator of growth. By this method, MICs of isoniazid, rifampin, streptomycin, and ethambutol were determined for 50 strains of M. tuberculosis. Colorimetric MIC results were available on the 7th, 10th, or 14th day of incubation for 29 (58%), 14 (28%), and 7 (14%) of the 50 strains, respectively. When MIC susceptibility results were compared with results obtained by the agar proportion method, increased levels of resistance detected by agar proportion were associated with higher MICs obtained by the colorimetric method. Tentative interpretive criteria for colorimetric MIC results which showed good agreement with results obtained by the agar proportion method were established. Interpretive agreement between the two methods was 98% for isoniazid, rifampin, and ethambutol and 94% for streptomycin. Overall, there was agreement between the two methods for 194 of 200 test results (97%). The colorimetric method is a rapid, quantitative, nonradiometric method for determining the antimicrobial susceptibility of M. tuberculosis.

Antibiotics, Antitubercular↗

PubMed1985

Short course chemotherapy for tuberculosis of lymph nodes: a controlled trial. British Thoracic Society Research Committee.

One hundred and fifty two patients with tuberculosis of lymph nodes were enrolled in a randomised trial of nine versus 18 months' chemotherapy. The regimens consisted of rifampicin plus isoniazid for nine or 18 months, supplemented initially by ethambutol for eight weeks. At 36 months data from 113 patients were available for analysis, of whom 56 had received the short course regimen. Progress during chemotherapy was uneventful in 84 of the 113 patients. Fresh nodes appeared in 13 patients and existing nodes increased in size in 13; these events occurred within the first eight months of treatment. In 10 patients residual nodes were palpable at the end of chemotherapy. Events including enlargement of nodes, appearance of new nodes, fluctuation, and formation of sinuses occurred in 12 patients after the end of chemotherapy. The incidence of these events was similar in both groups, and they did not result in an unfavourable outcome. Nine months' treatment with rifampicin and isoniazid supplemented initially by ethambutol should be adequate for tuberculosis of lymph nodes, but confirmation must await a longer period of follow up.

Adolescent↗

PubMed1983

Pulmonary infection with Mycobacterium kansasii in Wales, 1970-9: review of treatment and response.

Thirty-five patients (88% male) with pulmonary infection caused by Mycobacterium kansasii have been reviewed. Sixty-six per cent had pre-existing lung disease, chronic bronchitis and emphysema accounting for half of the disorders. Unilateral lesions were present in 69% of patients whose chest radiographs were reviewed and 90% had cavitating disease. The development of unilateral or bilateral disease appeared to be independent of any delay in starting treatment. Five patients died while receiving treatment, but none of these deaths was due to M kansasii infection. The remaining 30 patients were successfully treated with drug regimens, all of which included rifampicin and 86% of which included ethambutol. There was 100% sputum conversion, with no relapses after a mean follow-up period of five-and-a-half years. Rifampicin and ethambutol given for a mean period of 15 months appeared to be a non-toxic, effective combination.

Adult↗

PubMed1985

Treatment of pulmonary tuberculosis in patients notified in England and Wales in 1978-9: chemotherapy and hospital admission. Medical Research Council Tuberculosis and Chest Diseases Unit.

The treatment of adult patients, both white and of Indian, Pakistani, or Bangladeshi ethnic origin, with previously untreated pulmonary tuberculosis who were notified in England and Wales from 1 October 1978 to 31 March 1979 has been surveyed. Chemotherapy was completed as planned by the physician in charge in 820 (65%) of the 1253 patients. Eleven per cent of patients died before chemotherapy could be completed, 8% defaulted, and 6% had chemotherapy modified because of drug toxicity, and for 8% there were miscellaneous reasons for failure to complete chemotherapy. Of the 1003 patients who completed chemotherapy, 804 (80%) were prescribed isoniazid and rifampicin throughout, 667 (67%) receiving ethambutol in addition, either in the initial phase (550) or throughout chemotherapy (117). A further 129 (13%) had a regimen based on isoniazid and ethambutol throughout, and the remaining 70 had miscellaneous combinations of drugs. For the 544 patients who received a two phase regimen of isoniazid and rifampicin throughout with one or two additional drugs initially and who completed chemotherapy as planned, the median duration of chemotherapy was 10.8 months, 122 (22%) patients being treated for more than 12 months. For all 1001 patients who completed chemotherapy (whether or not as planned) and for whom the duration was known, the median duration was 11.8 months and 311 (31%) had more than 12 months' treatment. The great majority (79%) of the patients were admitted to hospital initially, the commonest reason being for investigation and diagnosis.

Adolescent↗

PubMed1996

Pulmonary Mycobacterium kansasii infection: comparison of the clinical features, treatment and outcome with pulmonary tuberculosis.

BACKGROUND: In the United Kingdom Mycobacterium kansasii is the most common pulmonary non-tuberculous mycobacteria to cause disease in the non-HIV positive population. METHODS: The clinical features, treatment, and outcome of 47 patients (13 women) of mean (SD) age 58 (17) years with culture positive pulmonary M kansasii infection were compared with those of 87 patients (23 women) of mean (SD) age 57 (16) years with culture positive pulmonary M tuberculosis infection by review of their clinical and laboratory records. Each patient with M kansasii infection was matched for age, sex, race and, where possible, year of diagnosis with two patients with M tuberculosis infection. RESULTS: All those with M kansasii infection were of white race. Haemoptysis was more common in patients infected with M kansasii but they were less likely to present as a result of an incidental chest radiograph or symptoms other than those due to mycobacterial infection. Patients with M kansasii were also less likely to have a history of diabetes, but the frequency of previous chest disease and tuberculosis was similar. An alcohol intake of > 14 units/week was less frequent in those with M kansasii, but there were no significant differences in drug history, past and present smoking habit, occupational exposures, social class, or marital status. Patients with M kansasii received a longer total course of antimycobacterial therapy and, in particular, extended treatment with ethambutol and rifampicin was given. There was no significant difference in outcome between pulmonary M kansasii or M tuberculosis infection. CONCLUSIONS: There are group differences between the clinical features of the two infections but, with the possible exception of diabetes and alcohol intake, these features are unlikely to be diagnostically helpful. Treatment of M kansasii infection with ethambutol, isoniazid, and rifampicin in these patients was as effective as standard regimens given to patients infected with M tuberculosis.

Adult↗

PubMed1996

Comparison of characteristics of patients and treatment outcome for pulmonary non-tuberculous mycobacterial infection and pulmonary tuberculosis.

BACKGROUND: Patients with non-tuberculous mycobacteria are usually started on conventional antituberculous triple therapy once acid fast bacilli are detected, before the exact type of mycobacteria has been identified. The ability to identify the characteristics of patients with tuberculous and non-tuberculous mycobacteria may be helpful in identifying before treatment those patients more likely to have non-tuberculous infection. METHODS: A retrospective study was conducted of all patients in one unit in whom non-tuberculous mycobacteria were identified in sputum or bronchoalveolar washings in the period 1987-93. The pattern of drug resistance was determined from laboratory records, and all case notes and chest radiographs were reviewed to identify the underlying disease and treatment outcome. All cases were compared with a matched control group of patients with culture positive Mycobacterium tuberculosis diagnosed during the same period. RESULTS: In the period studied there were 70 non-tuberculous and 221 tuberculous isolates. The non-tuberculous bacteria were typed as follows: M xenopi 23 (33%), M kansasii 19 (27%), M fortuitum 14 (20%), others 14 (20%). Of those with non-tuberculous mycobacteria, 83% were white subjects compared with 47% for tuberculosis. Patients with non-tuberculous mycobacteria were older than those with tuberculosis. Pre-existing lung disease or AIDS was present in 81% of patients with non-tuberculous mycobacteria and in 17% of patients with tuberculosis. Sensitivity to rifampicin and ethambutol was seen in 95% of M xenopi and 96% of M kansasii isolates. Relapse occurred in 60% of cases infected with M xenopi, 20% infected with M kansasii, and in 7% of cases with tuberculosis. CONCLUSIONS: In the population studied non-tuberculous mycobacteria occurred most frequently in elderly white subjects with pre-existing lung disease. If mycobacteria are detected in this group, consideration should be given to the possibility of non-tuberculous infection before embarking on treatment. A combination containing rifampicin and ethambutol is effective. The relapse rate for infection with M xenopi is high and prospective studies of the effect of the above combination of antituberculosis drugs are needed.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

E-test: an alternative method for susceptibility testing of Mycobacterium tuberculosis.

OBJECTIVE: The purpose of this study was to compare the agar proportion method with the E-test method for susceptibility testing of Mycobacterium tuberculosis. MATERIALS AND METHODS: A total of 100 isolates were tested for isoniazid, rifampin, streptomycin and ethambutol susceptibility using an indirect-proportion method as well as the E-test method. RESULTS: Categorical agreement between the methods was 100% for isoniazid, rifampin, streptomycin, and ethambutol. CONCLUSION: The E-test method appears to be an alternative method to agar proportion for testing the susceptibility of M. tuberculosis isolates to the first-line antituberculous agents.

Agar↗

PubMed1988

Antimycobacterial drugs and the production of reactive oxidants by polymorphonuclear leucocytes in vitro.

The effect of five antimycobacterial drugs isoniazid, rifampicin, streptomycin, pyrazinamide and ethambutol on the generation of reactive oxidants by polymorphonuclear leucocytes was investigated in vitro, using N-formyl-L-methionyl-L-leucyl-phenylalanine (FMLP) activated and spontaneous luminol-enhanced chemiluminescence and myeloperoxidase-mediated iodination. Streptomycin, pyrazinamide and ethambutol had no effect on the assays at the concentrations investigated. Isoniazid as concentrations of 1.25 and 5 micrograms/ml and rifampicin at 100 micrograms/ml significantly inhibited iodination. Rifampicin also caused dose-dependent inhibition of chemiluminescence which was partly due to its light-absorbing activities. It is concluded that isoniazid, and to a lesser extent, rifampicin at therapeutic concentrations possess anti-oxidative properties.

Antitubercular Agents↗

PubMed1988

The results of 9-month isoniazid-rifampin therapy for pulmonary tuberculosis under program conditions in San Francisco.

The outcome of treatment for pulmonary tuberculosis using isoniazid and rifampin for 9 months supplemented by ethambutol for the initial 2 months was evaluated in a cohort of 233 patients. All patients had sputum cultures positive for Mycobacterium tuberculosis sensitive to isoniazid and rifampin. Of the 233 patients, 200 completed the regimen without change. Four patients had adverse reactions necessitating discontinuation and four became pregnant and had ethambutol substituted for rifampin. All eight were treated successfully with altered regimens. Ten patients were lost to follow-up, seven died, and eight were transferred to other jurisdictions. No patients failed to convert their sputum during therapy. At completion of therapy, three patients (1.5%) were found to have positive sputum. Follow-up 6 months after completion of treatment in 174 successfully treated patients revealed four (2.3%) with positive sputum. No further relapses were detected on evaluation 12 months after treatment was completed. All seven patients who failed therapy or relapsed were retreated successfully using the same regimen. These data provide a reference standard against which newer treatment regimens, such as the 6-month regimen currently in use, can be compared. In addition, the value of routine evaluations in detecting relapses at the time treatment is completed and 6 months later was substantiated, but 12-month follow-up was not useful.

Adolescent↗

PubMed1978

Controlled trial of 6-month and 8-month regimens in the treatment of pulmonary tuberculosis. First report.

Four short-course antituberculosis regimens allocated at random were studied; (1) streptomycin, isoniazid, and rifampin given daily for 6 months; (2) these 3 drugs plus pyrazinamide given daily for 2 months, followed by twice-weekly administration of streptomycin, isoniazid, and pyrazinamide; (3) a regimen that differed from regimen 2 only in that ethambutol replaced pyrazinamide, and (4) streptomycin plus isoniazid plus rifampin plus pyrazinamide given 3 times per week for 4 months, followed by streptomycin plus isoniazid plus pyrazinamide administered twice per week. The last 3 regimens were given for 6 or 8 months at random. All except 1 of 680 patients with tubercle bacilli drug-susceptible before treatment had a favorable bacteriologic response during chemotherapy. The relapse rates during the first 6 months after chemotherapy were low, except in the ethambutol series, in which 19 per cent of the patients relapsed after 6 months of treatment, and 8 per cent relapsed after 8 months. A substantial proportion of the patients with strains initially resistant to either isoniazid or streptomycin had a favorable response to their allocated regimen, but the results were not as good for those patients with strains resistant to both drugs. An important finding is that the incidences of immunologic febrile reactions to rifampin and of rifampin-dependent antibodies were very low during the 3-times-weekly regimen.

Adolescent↗

PubMed1980

Short-course (6 month) cooperative tuberculosis study in Poland: results 18 months after completion of treatment.

This study compared the efficacy and toxicity of 4 drug regimens containing rifampin, isoniazid, and ethambutol administered both daily and intermittently for a total duration of 6 months (26 wk). There were 411 patients with newly diagnosed, previously untreated, pulmonary tuberculosis admitted to the study. All patients received isoniazid, rifampin, and ethambutol daily in a hospital for the first 8 wk of treatment. One group continued to receive these 3 drugs daily as outpatients for an additional 18 wk; a second group received the same drugs twice weekly, and a third group received the 3 drugs once weekly during the 18-wk "continuation phase." A fourth group of patients received 2 drugs, isoniazid and rifampin, twice weekly during the continuation phase. Drug toxicity was not a major problem; drugs were permanently discontinued in only 1% of the patients. All 4 regimens were highly effective in achieving sputum negativity. By the fifty month, 100% of the patients had become culture negative. However, the relapse rate was found to be relatively high for all regimens (range, 7 to 20%). Patients with extensive disease, large cavities, heavy growth on pretreatment cultures, slow sputum conversion, persistent cavities, heavy use of alcohol, and concomitant diseases were more likely to relapse. In order to achieve relapse rates acceptable in developed countries, regimens containing rifampin and isoniazid must either be given for longer than 6 months or strengthened by the addition of supplemental drugs during the initial phase.

Adolescent↗

PubMed1982

A controlled trial of six months chemotherapy in pulmonary tuberculosis. Second report: results during the 24 months after the end of chemotherapy. British Thoracic Association.

Two 6-month regimens of isoniazid and rifampicin supplemented for the first 2 months by streptomycin and pyrazinamide or by ethambutol and pyrazinamide were compared with a 9-month regimen of isoniazid and rifampicin supplemented for the first 2 months by ethambutol. All 444 patients who completed chemotherapy had negative sputum cultures by the end of treatment. Of these, 393 have been followed for 24 months after the end of chemotherapy. Relapse has occurred in 1 of 125 SHRZ6 patients, 3 of 132 EHRZ6, and 2 of 136 EHR9 patients. These observations suggest that both 5-month regimens are as effective as the currently recommended 9-month regimen and have the advantages of being shorter, cheaper, and equally well tolerated.

Antitubercular Agents↗

PubMed1983

Antituberculosis drug resistance in south Texas.

The incidence of antituberculosis drug resistance in South Texas has been tabulated. Age, sex, and ethnic group were not found to significantly influence the incidence of resistance. The incidence of resistance to isoniazid (NH) was 16.4%, ethambutol, 3.9%, rifampin, 10.6%, and streptomycin, 7.8%. There was a 7.3% rate of resistance to INH and/or ethambutol or rifampin for any individual organism (i.e., to 2 of the 3 most commonly used antituberculosis drugs). We conclude that the incidence of single and multiple antituberculosis drug resistance in South Texas is higher than previously reported.

Adolescent↗

PubMed1984

Controlled clinical trial comparing a 6-month and a 12-month regimen in the treatment of pulmonary tuberculosis in the Algerian Sahara. Algerian working group/British Medical Research Council cooperative study.

A 6-month short-course chemotherapy regimen and a 12-month standard duration regimen have been compared in the treatment of pulmonary tuberculosis in a rural area of Algeria in a population with a relatively high proportion of nomads. The 6-month regimen was isoniazid and rifampicin throughout, with ethambutol and pyrazinamide in addition for an initial 2-month intensive phase. The 12-month regimen was isoniazid and ethambutol throughout, supplemented by streptomycin during the first month. All 601 patients admitted had one or more sputum smears positive on examination in the local laboratory. Most patients were admitted to hospital initially for 1 to 2 months, where they received their chemotherapy under full supervision; thereafter, it was self-administered. In both nomads and settled residents known to have fully sensitive strains pretreatment, the 6-month regimen was highly effective, with no failures during chemotherapy and only 3% relapses after stopping chemotherapy in 131 patients compared with a combined failure rate during chemotherapy and relapse rate of 17% in the 154 patients receiving the 12-month regimen (p less than 0.001). The results in patients with isoniazid-resistant strains pretreatment were also significantly better for the 6-month than for the 12-month regimen, none of 15 and 7 of 15 patients, respectively, being classified as failures or relapses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2003

Bactericidal and sterilizing activities of antituberculosis drugs during the first 14 days.

Colony-forming units of Mycobacterium tuberculosis in sputum were counted at 2-day intervals in 100 patients treated with 22 regimens of isoniazid, rifampin, pyrazinamide, ethambutol, or streptomycin, given alone or in combinations. The exponential fall in colony-forming units was measured by linear regression coefficients of the log counts during the initial 2-day phase of rapid, drug-determined killing and during the subsequent 12 days of much slower sterilizing activity. The regression coefficients during the first 2 days varied significantly according to the drug; the greatest effects in multiple regression analyses were due to isoniazid (p < 0.001) and rifampin (p = 0.027). The rapid kill obtained with isoniazid was unaffected by addition of other drugs, so that a change in activity after adding an unknown drug to isoniazid would not be measurable. In multiple regression analysis of the coefficients during Days 2-14, rifampin and streptomycin had significant effects (p = 0.007 and 0.006, respectively), indicating that both drugs had important sterilizing activity, streptomycin particularly early. Isoniazid and pyrazinamide had no significant effects. In analyses of combined drug regimens only, ethambutol had an effect (p = 0.01) in reverse direction to that of rifampin, suggesting it antagonized the sterilizing activity of other drugs.

Antibiotics, Antitubercular↗