Drug-resistant tuberculosis.
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Biomedical subjects
Publications and source records attributed to L S Farer.
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During the past decade, six short-course (6-month) chemotherapy regimens were studied in which drugs were given daily and intermittently. Four regimens containing isoniazid, rifampin, and ethambutol caused little toxicity but yielded relapse rates (8-21%) which were unacceptably high. The safety of giving rifampin (450 or 600 mg) twice weekly was confirmed, however, and there was evidence that daily therapy during the 4-month continuation phase was no more effective than twice weekly isoniazid and rifampin. Once weekly therapy during the continuation phase was clearly inadequate. The use of four drugs (isoniazid, rifampin, pyrazinamide, and streptomycin) given daily during the initial 2 months of therapy followed by 4 months of twice weekly isoniazid and rifampin resulted in a nearly 100% cure rate. However, this regimen was not well tolerated by patients. Deleting streptomycin improved the tolerability of the regimen but appears to have slightly increased the frequency of treatment failure and relapse. A suggested model for choosing treatment regimens is presented.
Multinational clinical trials are valuable to the understanding of global health problems, but they pose special problems. Our experience with a multinational trial of isoniazid (INH) preventive therapy for tuberculosis revealed marked variation among the seven participating countries in the amount of tuberculosis screening prior to the trial; this variation contributed to the observed differences in the risk of tuberculosis among the countries. The incidence of 'uncooperativeness' and drug side-effects, and the proportion of participants who complied with and completed treatment also varied significantly from country to country. These differences in completion and compliance served to differentially alter the expected risk of tuberculosis among the three regimens being studied. For all factors investigated, variation from country to country was greater than variation from dispensary to dispensary within a country. This suggests that cultural and other national characteristics are more potent determinants of health care practices and behaviours than patient and health care practitioner characteristics.
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In recent years, the decrease in reported tuberculosis in the United States has been due almost entirely to a drop in the number of cases of pulmonary disease. There has been little change in the average number of extrapulmonary cases reported. A retrospective survey of extrapulmonary tuberculosis has shown that it differs from pulmonary tuberculosis with regard to sex and race distribution, diagnosing physician's speciality and proportion of cases bacteriologically confirmed. There is variation within extrapulmonary cases according to specific anatomic site with regard to the above characteristics as well as age distribution. These epidemiologic differences in tuberculosis of different sites are unexplained.
To determine the frequency, magnitude, and causes of the booster phenomenon in tuberculin testing, a total of 1,478 employees from 10 hospitals throughout the United States received sequential intradermal tests using PPD-T. In addition, approximately 70 per cent were initially tested with PPD-G. Boosting was found in all age groups tested, but increased with age. It occurred as soon as one week after an initial tuberculin test, but rarely before that time. The boosted reactions were apparently caused either by remote tuberculous infection or recent or remote sensitization by one or more of the nontuberculous mycobacteria. In areas endemic for nontuberculous mycobacteria, they are the most likely cause of the sensitivity that may be boosted. On the basis of these findings, it is recommended that when repeated tuberculin testing is required as part of a hospital control program, a second identical tuberculin test be given one week after the first. When subsequent tests are given, this should permit separation of boosted reactions from reactions caused by new infections. Persons who do not boost when giben repeat tests at one week, but whose tuberuclin reactions change to positive after one year, should be considered to have newly acquired tuberculous infection and managed accordingly.
A total of 822 patients with newly diagnosed pulmonary tuberculosis were assigned randomly to one of 3 daily rifampin-isoniazid (RIF-INH) regimens: 450, 600, or 750 mg of RIF in combination with 300 mg of INH. After an initial 20 weeks of therapy with RIF-INH, patients recieved 300 mg of INH and 15 mg of ethambutol (EMB) per kg of body weight for either 12 or 18 months after their sputum cultures became negative. The rate of bacteriologic conversion of sputum among the 3 RIF-INH regimens was compared for 552 patients who completed the 20 weeks of RIF-INH therapy. Apporximately 60 per cent of these patients also completed their assigned INH-EMB therapy and were examined for relapse for at least one year after therapy was stopped. There was no significant difference in the rate of sputum conversion or rate of relapse between the group of patients who received 600 mg of RIF and those who received 750 mg of RIF. However, the 450-mg RIF regimen was significantly less effective than the other 2 regimens, as manifested by a lower rate of sputum conversion and a higher rate of treatment failures. Further analysis showed that RIF dosages of less than 9 mg per kg of body weight per day may be inadequate for treatment of pulmonary tuberculosis. The acceptability of these regimens was high, and the incidence of adverse reactions requiring discontinuation of RIF-INH therapy was quite low (3.3 per cent). A large proportion of patients (44 per cent) developed increased concentrations of transaminase during therapy with RIF-INH. These abnormalities were usually transient and, in most cases, of no clinical significance. In the relapse analysis, 12 months of chemotherapy after sputum conversion was shown to be as effective as 18 months of therapy after conversion of these RIF-containing regimens.
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