S. Devadatta

A four-year follow-up of patients with quiescent pulmonary tuberculosis at the end of a year of chemotherapy with twice-weekly isoniazid plus streptomycin or daily isoniazid plus pas

Abstract This report describes the progress over a four-year period of follow-up of 119 patients who had bacteriologically quiescent pulmonary tuberculosis at the end of a year of chemotherapy with either a fully supervised twice-weekly regimen of isoniazid plus streptomycin (SHTW, 66 patients) or a standard self-administered daily regimen of isoniazid plus PAS (PH, 53 patients). (In the second year, that is in the first year of the follow-up, half the patients, selected at random, received maintenance chemotherapy with isoniazid and the other half a placebo.) The condition of the patients in the SHTW and PH series was similar, both at the time of their initial admission to treatment and at the start of the period of follow-up. One patient (PH) died of tuberculosis in the fiftienth month, having had a bacteriological relapse in the fourteenth month. Nine others (five SHTW, four PH) died of non-tuberculoss causes. The radiographic progress over the four-year period was similar in the SHTW and the PH series. On average, 42 cultures per patient were examined during the four-year period. A bacteriological relapse occurred in eight SHTW and eight PH patients; however, retreatment became necessary in only three (5 %) SHTW and five (10 %) PH patients, the others having had a spontaneous sputum conversion. Most of the relapses occurred with drug-sensitive cultures. It is concluded that bacteriological quiescence attained with a year of twice-weekly isoniazid plus streptomycin is at least as stable, over a four-year period of follow-up, as that attained with a year of daily isoniazid plus PAS.

A two-year follow-up of patients with quiescent pulmonary tuberculosis following a year of chemotherapy with an intermittent (twice-weekly) regimen of isoniazid plus streptomycin or a daily regimen of isoniazid plus pas

Summary In the main analysis of a years study of twice-weekly high dosage isoniazid plus streptomycin (SHTW) in comparison with a standard daily regimen of isoniazid plus PAS (PH) under domiciliary conditions, 66 SHTW and 53 PH patients had attained bacteriologically quiescent disease at one year. All the patients have now been followed-up over a two-year period. Of these, 66 SHTW and 52 PH patients had been allocated at random to treatment the second year with isoniazid alone or with placebo. No patient was prescribed antituberculosis drugs for the third year. The condition of the patients in the two series was broadly similar, both at the time of their original admission to treatment and also at the start of the period of follow-up. There were five deaths (four SHTW, one PH) in the follow-up period, all in the second year and all from non-tuberculous causes; all five patients produced only negative cultures in the second year and for at least six months immediately before death. The radiographic progress was similar for the two series in the second and third years, the majority of patients in both series showing little change. The patients were under intensive bacteriological investigation, an average of 14 cultures being examined per patient in the second year and nine in the third year. A bacteriological relapse occurred in five (8%) SHTW and six (12%) PH patients. In one and two patients respectively this was associated with a serious radiographic deterioration. An isolated positive culture was produced by 17% of the SHTW and 27% of the PH patients. Four of the SHTW patients had a relapse with streptomycin- and isoniazid-sensitive cultures and four of the PH patients with isoniazid-sensitive cultures. It is concluded that bacteriological quiescence following a year of twice-weekly isoniazid plus streptomycin is at least as stable, over a two-year period of follow-up, as that attained following a year of a standard daily oral regimen of isoniazid plus PAS.

A controlled comparison of streptomycin plus pyrazinamide and streptomycin plus PAS in the retreatment of patients excreting isoniazid-resistant organisms

Summary A controlled comparison has been made of streptomycin plus pyrazinamide (46 patients) and streptomycin plus PAS (36 patients) in the retreatment of patients with pulmonary tuberculosis. The patients had either failed to attain bacteriological quiescence on isoniazid alone or had relapsed bacteriologically after attaining quiescence; all were excreting strains of tubercle bacilli resistant to isoniazid but sensitive to streptomycin and PAS at the start of the trial. The disease status at 1 year was assessed in 41 patients on pyrazinamide and 24 on PAS, and of these, 29 (71%) and 12 (50%), respectively, had bacteriologically quiescent disease. Seven patients (2 on pyrazinamide, 5 on PAS) had their treatment terminated for toxicity, 1 due to a pyrazinamide polyarthritis, 2 on account of hypersensitivity to PAS, and 4 (1 on pyrazinamide, 3 on PAS) because of streptomycin toxicity. Nine patients (2 on pyrazinamide, 7 on PAS) became unco-operative and stopped treatment, and 2 patients (on pyrazinamide) died, 1 of a non-tuberculous condition. Thus, streptomycin plus pyrazinamide was slightly more effective therapeutically than streptomycin plus PAS and was not more toxic or less acceptable to the patients.

A controlled comparison of cycloserine plus ethionamide with cycloserine plus thiacetazone in patients with active pulmonary tuberculosis despite prolonged previous chemotherapy

Summary Twenty-seven patients with chronic pulmonary tuberculosis who had failed to respond to two previous chemotherapeutic regimens were allocated to treatment with cycloserine plus ethionamide (14 patients), or with cycloserine plus thiacetazone (13 patients). All had isoniazid-resistant strains and all but one had streptomycin-resistant strains at the start of the study. At the end of a year nine of 14 patients in the ethionamide series compared with three of 13 in the thiacetazone series had bacteriologically quiescent disease, one and three. respectively, had bacteriologically active disease; during the year, two patients (one in each series) deteriorated and had their chemotherapy changed and two patients (both on thiacetazone) died of tuberculosis. The difference in the proportions of unfavourable response attained statistical significance. There was one case of peripheral neuropathy due to ethionamide. Definite toxicity to thiacetazone was not observed. One of nine patients excluded from the main analysis had had intractable vomiting due to cycloserine.

A double-blind study to determine the maximum tolerated dose of ethionamide, when administered twice-weekly to patients with pulmonary tuberculosis.

ATI earlier report from this Centre (Tuber-culosis Chemotherapy Centre, Madras, 1964) showed that a fully supervised twice-weekly regimen of streptomycin plus high-dosage isoniazid was highly effective in the treatment of patients with newly-diagnosed bacteriologi-cally confirmed pulmonary tuberculosis. How-ever, this regimen involves intramuscular injections of streptomycin and may not always be easy to organize, especially in rural areas and in developing countries with limited resources. For this reason, it was decided to investigate the possibility of replacing strepto-mycin in the twice-weekly regimen by two oral drugs, namely ethionamide and PAS. Ethiona-mide was chosen since, apart from isoniazid and streptomycin, it was the most potent drug available at the time, and PAS was included with a view to enhance the efficacy of the regimen. Finally, it was decided that the patients should be given an intensive phase of daily treatment with streptomycin, PAS and isoniazid for two weeks. Experiments in the guinea-pig had shown that the size of the individual dose of a drug needed to be increased as the interval between successive doses was increased (Dickinson & Mitchison, 1966). As PAS is bulky and the dosage of isoniazid in the twice-weekly regimen was already high, namely 15 mg./kg. body-weight, it was decided to explore the possibility of increasing the dosage of ethionamide to a level higher than that usually employed (0.5— 1.0 g.) in daily regimens. An investigation was therefore undertaken to determine the maximum tolerated dose of ethionamide. when administered twice-weekly together with isonia-zid plus PAS. Since the assessment of ethio-namide intolerance is largely subjective, the study was conducted ‘double-blind’ with respect to the dosage of ethionamide.

Cycloserine plus ethionamide in the treatment of patients excreting isoniazid-resistant tubercle bacilli following previous chemotherapy

Summary Fifty patients with chronic pulmonary tuberculosis and cultures resistant to isoniazid were treated with a daily regimen of ethionamide (500 mg.) plus cycloserine in an intended dose of 500 mg., but possibly less because of deterioration. Most of the patients had streptomycin-resistant cultures also. Forty-three had received two previous regimens of chemotherapy. During the year, 10 (20%) patients became un-cooperative and refused further treatment, and in two the regimen was stopped on account of drug toxicity. Of the remaining 38 patients, 58% had bacteriologically quiescent disease at one year, 65% showed radiographic improvement and 61% had cavity closure or less cavitation than on admission. Major toxicity to ethionamide occurred in two patients and to cycloserine in two patients; minor side effects were reported by 18 patients.

The consistency of the virulence in the guinea-pig of tubercle bacilli isolated on different occasions from South India patients before treatment

Summary Isoniazid- and streptomycin-sensitive cultures of tubercle bacilli, isolated pretreatment from 12 South Indian patients when they first attended the Centre, and at 7 and 42 days thereafter, were tested for their virulence in the guinea-pig. The variation in virulence between patients was greater than the variation between cultures from the same patient. Thus, consistent differences exist between the virulence of strains of tubercle bacilli isolated from different Indian patients. No systematic alteration in virulence occurred during the 42-day period, during which no patient was receiving anti-tuberculosis chemotherapy. The variation in virulence between cultures obtained from the same patient was no greater than could be attributed to natural variation in the response of the guinea-pigs.