P.R. Somasundaram

Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide

Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculosis meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16-39% in children with tuberculous meningitis, 10% in patients with spinal tuberculosis (non-surgical cases), and 2-8% in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11% of 317 slow acetylators and 1% of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39%) was higher than that with 12 mg/kg (16%), and appreciably lower in patients given rifampicin twice-weekly (5%) rather than daily (21%). There was no indication that pyrazinamide contributed to the hepatic toxicity.

Effect of storage of sputum specimens at room temperature on smear and culture results

A study of 41 specimens of sputum stored for up to 28 days at room temperature in a tropical country showed that smear results were not affected by storage, the positivity being 83% before storage and 80-83% after. The culture positivity was 88% before storage, and 83%, 68%, 22%, 13% and 0% after 3, 7, 14, 21 and 28 days of storage respectively. The reduction in positivity on storage attains significance at 7 days (P = 0.05). Another study involved 163 specimens of sputum and storage for 3, 5 or 7 days. Each specimen was examined before storage and after 2 periods of storage, at random. The smear results were again not affected. There was, however, significant loss of viability, the proportion culture positive being reduced from 92% before storage to 83% at 3 days (P = 0.05), 71% at 5 days (P less than 0.01) and 63% at 7 days (P less than 0.001). The contamination rate was 5%, 7%, 12% and 18% respectively. It is concluded that sputum should not be stored at room temperature for longer than 3 days for culture but it can be stored for 4 weeks without any loss of smear-positivity.

Species level identification of non-tuberculous mycobacteria from South Indian BCG trial area during 1981

In 1981, non-tuberculous mycobacteria (NTM) were obtained from 8.6% of 16 907 sputum specimens in a trial in the Chingleput district of Madras state to test the efficacy of BCG vaccination in the prevention of tuberculosis, but from only 0.6% of 672 autoclaved specimens cultured as part of a quality control procedure. This finding suggested that the NTM were truly derived from the sputum of the BCG trial subjects. The mycobacterial species could be identified in 966 (96.6%) of the first 1000 isolates of NTM: 54.6% were potential pathogens and 73.0% were slow growing. The species isolated most frequently were M. avium/intracellulare (22.6% of all NTM), M. terrae (12.5%) and M. scrofulaceum (10.5%). Those species accounting for 8-5% of all NTM were M. fortuitum, M. chelonei, M. flavescens, M. gordonae and M. vaccae.

Five year results of a 3-month and two 5-month regimens for the treatment of sputum-positive pulmonary tuberculosis in South India

A controlled study of three short-course regimens was undertaken in South Indian patients with newly diagnosed, sputum-positive pulmonary tuberculosis. The patients were allocated at random to one of three regimens: a) Rifampicin, streptomycin, isoniazid and pyrazinamide daily for 3 months (R3); b) the same regimen as above but followed by streptomycin, isoniazid and pyrazinamide twice-weekly for a further period of 2 months (R5); c) the same as R5 but without rifampicin (Z5). A bacteriological relapse requiring treatment occurred by 5 years in 16.8% of 113 R3, 5.2% of 97 R5, and 20.0% of 115 Z5 patients with organisms sensitive to streptomycin and isoniazid initially. The differences in the relapse rates between the R3 and R5 regimens and the R5 and Z5 regimens were statistically significant (p less than 0.01 for both). Considering patients with organisms initially resistant to streptomycin or isoniazid or both, 7 of 52 patients (4 R3, 2 R5, 1 Z5) had a bacteriological relapse requiring retreatment.

An investigation of the accuracy of the home address given by patients in an urban community in South India

Studies were undertaken in three tuberculosis clinics in Madras, a large Indian city with a good civic organization, to assess the accuracy of address recorded routinely by registry clerks at the patients first clinic attendance. The accuracy was poor, with 20% to 30% of the letters posted not reaching the patients. It was appreciably improved, by 10% to 20%, by supplementing the clerks efforts with questioning by a motivated, experienced health visitor. An address card, a card on which the patients address was recorded by the local postman or a literate neighbour, relative or friend, was returned by 90% to 94% of the patients, and the accuracy of addresses was found to be at least as good as that obtained with the health visitor. Even when all three sources of information were considered, the patients home could not be traced in 3% of cases and was found with difficulty in 4%.

A randomised study of two policies for managing default in out-patients collecting supplies of drugs for pulmonary tuberculosis in a large city in South India

A randomized controlled study was undertaken to compare 2 policies of default management in out-patients with smear-negative pulmonary tuberculosis attending a large chest clinic in Madras city. All the patients were due to collect monthly supplies of drugs for a year, for daily self-administration at home. In the routine (R) policy, if a patient failed to collect the drug supply on a due date, a reminder letter was posted on the fourth day and, if necessary, a health visitor visited the home a week later. In the intensive (I) policy, a health visitor visited the home on the 4th day and, if necessary, a week later and at 1 and at 2 months. The main analyses concern 150 patients (75 R, 75 I), of whom 16 R and 15 I patients had a positive culture. A total of 29 patients (11 R, 18 I) did not default at any time. For the remaining 64 R and 57 I patients, the mean numbers of defaults were 3.0 and 2.3, and the mean numbers of defaulter retrieval actions were 4.3 and 3.8, respectively. The home visit as the first action (I series) was successful in retrieving defaulters on 65% of 132 occasions, while the reminder letter (R series) was successful in 56% of 193 occasions (P = 0.1). Following the second action, which was a home visit in both the series, these proportions became 80% and 84%, respectively. in the I series, 22 third and 18 fourth actions were taken, but the patient was retrieved in only 4 and 0 instances respectively. The mean number of drug collections during the year was significantly higher in the I series (9.8) than in the R series (8.6). Finally, the proportions of patients who made 12 collections in a 15-month period, a satisfactory target under Indian Programme conditions, were 69% and 52%, respectively (P = 0.07).

Study of adverse reactions to a once-weekly regimen of streptomycin plus a slow-release preparation of isoniazid in high dosage for six months.

A once-weekly regimen of streptomycin (1 g) plus a slow-release preparation of isoniazid (matrix isoniazid) in high dosage, namely 50 mg/kg body-weight for rapid inactivators of isoniazid and 35 mg/kg for slow inactivators, was prescribed for 6 months to 64 tuberculous patients (27 rapid, 37 slow). The regimen was tolerated by most the of the patients. However, 4 rapid and 3 slow inactivators had a modification of the regimen, mainly for giddiness. There were no cases of peripheral neuropathy. No adverse effects on haemopoiesis or hepatic or renal functions were observed in any of the patients. It is concluded that it is feasible to administer matrix isoniazid in dosages considerably higher than ordinary isoniazid, in once-weekly chemotherapy.

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.

A novel system to obtain addresses of out-patients--assessment in routine clinic practice in Madras, S. India.

A novel method of obtaining accurate home addresses from out-patients was introduced as a routine procedure in 6 chest clinics of Madras City, following highly satisfactory results under study conditions. In this method, the patient is given a card (the address card), and asked to get his exact address entered on it by any knowledgeable person of his choice such as a landlord or neighbour. An assessment of the system was undertaken after it had been in operation for about 8 months. A complete and legible address was available for 82% of 3956 patients, the range in the 6 clinics being 74% to 91%. The main causes for failure were: not giving address card to patient (7%), patient not reattending the clinic (6%), and patient reattending but not returning the address card (3%). Corrective measures have now been introduced, and a re-assessment will be undertaken in due course.