S.P. Tripathy

Three chemotherapy studies of tuberculous meningitis in children.

Chemotherapy studies were undertaken in 180 patients with tuberculous meningitis. They were treated for 12 months with 1 of 3 regimens: the first consisted of streptomycin, isoniazid and rifampicin daily for the first 2 months, followed by ethambutol plus isoniazid for 10 months; in the second, pyrazinamide was added for the first 2 months, and in the third, rifampicin was reduced to twice weekly in the first 2 months. Steroids were prescribed for all the patients in the initial weeks of treatment. Approximately 50% of the patients were aged less than 3 years. On admission, 13% of the patients were classified as stage I, 77% as stage II and 9% as stage III. Cerebrospinal fluid (CSF) culture results were available for all the 180 patients and M. tuberculosis was isolated in 59 (33%). CSF smear results for acid fast bacilli were available only for the 103 patients admitted to the second and the third studies, and of these in 60 (58%) the CSF was positive either by smear or culture. The response to therapy was similar in the 3 studies. Despite administration of rifampicin for 2 months, the mortality was high. In all, 27% of the patients died of tuberculous meningitis, 39% had neurological sequelae and 34% recovered completely. There was a strong association between the stage on admission and the mortality rate, the deaths being highest in stage III. In the first study, when isoniazid was prescribed daily in a dosage of 20 mg/kg, 39% of the patients developed jaundice; however, when the dosage was reduced to 12 mg/kg, the incidence fell to 16%. In the third study, where rifampicin was administered twice a week, the incidence of jaundice was much lower (5%).

Treatment of pulmonary tuberculosis with short course chemotherapy in south India--5-year follow up.

A controlled clinical trial of three short-course chemotherapy regimens was undertaken in patients with newly diagnosed bacteriologically positive pulmonary tuberculosis. The patients were randomly allocated to receive one of three regimens: rifampicin, streptomycin, isoniazid and pyrazinamide daily for 2 months, followed by streptomycin, isoniazid and pyrazinamide twice weekly for 3 months (R/5) or for 5 months (R/7), or the same regimen as R/7 but without rifampicin (Z/7). A bacteriological relapse requiring retreatment occurred by 5 years in 7.1% of 126 R/5, 4.0% of 124 R/7 and 6.7% of 253 Z/7 patients with organisms initially sensitive to streptomycin and isoniazid; none of these differences is statistically significant. Of the 31 relapses, 16 occurred within 2 years of the completion of chemotherapy and the remaining 15 between 2 and 5 years. Among 65 patients with initial drug resistance to streptomycin or isoniazid or both, there were six bacteriological relapses requiring retreatment.

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.

Response to treatment with isoniazid plus PAS of tuberculous patients with primary isoniazid resistance.

The response to treatment with isoniazid plus PAS was studied in 30 patients with primary isoniazid resistance and 459 patients with initially isoniazid-sensitive cultures. The patients with primary isoniazid resistance responded substantially less well, as assessed by the extent of radiographic improvement, disappearance of cavitation, negativity on culture and bacteriological status at six and at 12 months; also, cultures isolated from these patients at six months were more often resistant to PAS. Even so, there was suggestive evidence that they had derived some benefit from treatment with isoniazid.

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%.

Classification of subjects as slow or rapid inactivators of isoniazid, based on the ratio of the urinary excretion of acetylisoniazid to isoniazid

Abstract Following an intramuscular injection of isoniazid 3 mg/kg body-weight, the urinary excretion of isoniazid and acetylisoniazid during the periods 0–l, l–2, 2–3 and 3–4 hours was determined for 124 patients with pulmonary tuberculosis. On the same occasion, the serum isoniazid concentration at 412 hours was determined by microbiologic assay. The ratios of acetylisoniazid to isoniazid in the urine collections at two, three and four hours were bimodally distributed. Rules were derived from these ratios for classifying subjects as slow or rapid inactivators of isoniazid. There was 100 per cent agreement between the classification based on each of these ratios and that based on the serum isoniazid concentration at 412 hours. deh einer intramuskularen Injektion von 3 mg/kg Korpergewicht Isoniazid wurde die Ausscheidung von Isoniazid and Azetylisoniazid im Urin wahrend der ersten, zweiten, dritten and vierten Stunde bei 124 Lungentuberkulosen bestimmt. Bei der gleichen Gelegenheit wurde auch die Serumkonzentiation von Isoniazid nach 412 Stunden mikrobiologisch bestimmt. Das Verhaltnis von Azetylisoniazid zu Isoniazid war in den Urinproben nach zwei, drei und vier Stunden bimodal verteilt. Aus diesen Verteilung wurden Regeln abgeleitet, um Individuen als langsame oder schnelle Inaktivierer von Isoniazid zu klassifizieren. Es bestand 100 % ige Ubereinstimmung zwischen dieser auf den VerhaItniswerten basierenden Einteilung and jener auf Grund der Serumkonzentration nach 4l2 Stunden.

METHOD FOR THE ESTIMATION OF ACETYLISONIAZID IN URINE

Abstract A method for the estimation of acetylisoniazid in urine is described. It is simple, sensitive and reliable and follows Beers law between 10 μg./ml. and 40 μg./ml. It yields complete recovery of acetylisoniazid from specimens of urine to which the compound has been added in known concentrations. In this procedure, the drug-containing urine itself serves as the blank if the reagents are mixed first and then the urine added. Isoniazid in high concentrations produces a colour reaction in this method. This interference is eliminated by potassium permanganate which destroys isoniazid but not acetylisoniazid under the conditions of the estimation.

A comparison of various methods for the detection of isoniazid and its metabolites in urine

Summary A comparison of different tests for the detection of free isoniazid and its metabolites was made on specimens of urine obtained from volunteers and patients who received isoniazid. The Kasik test for isonicotinic acid and the acetylisoniazid test were found to be of similar sensitivity and more sensitive than the combined N-M test. A paper test for free isoniazid was the least sensitive of all the methods studied and, in addition, exhibited the highest proportion of false positive results. The Belles and Littleman test for isonicotinic acid was as sensitive as the Kasik test but it can be performed only in laboratories equipped with a chemical hood and provided with trained laboratory staff. On account of its simplicity and high sensitivity, the acetylisoniazid test is recommended for routine use in assessing and controlling the regularity with which patients self-administer isoniazid.

A comparison of various measures of sensitivity of M. tuberculosis to pyrazinamide

A test, employing Lowenstein-Jensen medium acidified with hydrochloric acid to a preinspissation npH of 4.80-4.85, is described for determining the sensitivity to pyrazinamide of nstrains of M. tuberculosis. The test was performed on cultures from patients with no history nof previous chemotherapy with pyrazinamide, and on cultures from patients receiving ndaily treatment with pyrazinamide. nSensitivity was measured in terms of the minimal inhibitory concentration of the drug for nvarious sizes of the inoculum, and as proportions of the bacterial population resistant to nvarious concentrations of the drug. For each of these measures, the findings in patients nwith no history of previous chemotherapy with pyrazinamide were compared with those nobtained at 4-12 months after the start of daily treatment with pyrazinamide; the definition nof resistance was then chosen such that (a) it discriminated efficiently between the two npopulations, and (b) it classified only a small proportion of the former population as nresistant. nFour definitions of resistance were chosen – a minimal inhibitory concentration of 200 nμg/ml. or more employing an inoculum containing approximately 0.4 mg. (moist weight) nof bacilli per ml. and a 10-colony end-point, and proportions of 20 % or more on 25 μg/ml., n5 % or more on 50 μg/ml., and 1% or more on 100 μg/ml. The efficiency of the four definitions nwas of the same order. Further, highly satisfactory agreement was obtained nbetween pairs of definitions in the classification of individual cultures as sensitive or nresistant. nHigh viable counts on the drug-free acidified medium were associated with high minimal ninhibitory concentrations but had little effect on the proportions resistant. nWild strains with consistent resistance to pyrazinamide were rare. Finally, in patients nwith an unfavourable response to a daily regimen containing pyrazinamide, resistance nhad usually emerged four to six months after the start of treatment.

A study of the accuracy, and factors influencing accuracy, of home addresses of patients obtained by registry clerks and address cards in four large towns in South India

In 4 large towns in South India with illiteracy levels of 26% to 40%, the efficiency of registry clerks in eliciting the home addresses of 1338 out-patients was assessed, by verifying receipt of a letter posted to the patients. The efficiency was found to be very poor, namely 66%. Moreover, the accuracy of address was substantially poorer for illiterate patients and for patients living for relatively short durations at their present address. Our innovation, the address card, on which the home address was recorded by a knowledgeable literate person of the patients choice, was returned by 98% of the patients, and the addresses were found accurate in 84%; the findings were similar in the 4 towns and were unaffected by any patient characteristic. The substantially better results with the address card were found in both illiterate and literate patients. These findings establish the address card as a simple, inexpensive and efficient device for obtaining accurate addresses.