Elsevier

Tubercle

Volume 44, Issue 4, December 1963, Pages 393-416

Influence of pretreatment bacterial resistance to isoniazid, thiacetazone or pas on the response to chemotherapy of African patients with pulmonary tuberculosis: Co-operative Studies in East African Hospitals and Laboratories with the Collaboration of the East African and British Medical Research Councils*

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Summary

The relationship between pretreatment bacterial sensitivity to isoniazid, thiacetazone or PAS and the progress of East African patients with pulmonary tuberculosis treated with either isoniazid plus thiacetazone or isoniazid plus PAS has been studied in co-operative controlled trials.

Patients were randomly allocated to treatment for one year, in-patients with isoniazid 200 mg. plus PAS (sodium salt) 10g daily, isoniazid 300 mg. plus thiacetazone 150 mg. daily, isoniazid 200 mg. plus thiacetazone 150 mg. daily or isoniazid 300 mg. plus thiacetazone 100 mg. daily and out-patients with isoniazid 200 mg. plus PAS (sodium salt) 10 g. daily or isoniazid 200 mg. plus thiacetazone 150 mg. daily.

A total of 558 patients who complied with the clinical criteria for admission and who completed six months of treatment were divided into 497 patients with isoniazid-sensitive organisms initially (the INH-sensitive group) and 61 patients with isoniazid-resistant organisms in one or both of their pretreatment cultures (the INH-resistant group). All of the INH-resistant group denied, having received previous antituberculosis chemotherapy on admission, but when the 32 in-patients were requestioned later, six admitted to previous treatment with isoniazid.

Moderate or greater radiographic improvement occurred during the first six months of treatment in 52% of the INH-sensitive group and in 36% of the INH-resistant group. Cavities became smaller or disappeared in 81% of the INH-sensitive group and in 69% of the INH-resistant group.

The smear and culture results at three months were similar in the INH-sensitive and the INH-resistant groups receiving PAS plus isoniazid, but were more frequently negative in the INH-sensitive group than in the INH-resistant group treated with isoniazid plus thiacetazone. A negative culture at six months was obtained from 83% of 176 INH-sensitive patients and 52% of 21 INH-resistant patients treated with 10 PH and from 72% of 304 INH-sensitive patients and 38% of 39 INH-resistant patients treated with isoniazid plus thiacetazone. Cultures at six months were more often resistant to the second drug used in treatment (PAS or thiacetazone) in the INH-resistant group than in the INH-sensitive group.

A negative culture at six months was obtained as often from the patients with pretreatment resistance to the two drugs used in treatment as from those with resistance only to isoniazid. The bacteriological progress of the patient was best associated with the proportion of the pretreatment strain growing on 0·2 μg./ml. isoniazid. less well associated with the proportion growing on 1.5 or 50μg./ml. and not associated with the minimal inhibitory concentration of isoniazid.

Considerable variation was found between patients in the thiacetazone sensitivity of their pretreatment strains. The progress of 228 patients with initially isoniazid-sensitive organisms during treatment with isoniazid plus thiacetazone was studied in relation to pretreatment thiacetazone sensitivity. Moderate or greater radiographic improvement occurred during the first six months of treatment in 64% of 72 patients with pretreatment minimal inhibitory concentrations (MICs) of 1·0 μg./ml. thiacetazone or less, in 58% of 83 patients with MICs of 1·1–2·0 μg./ml. in 51% of 53 patients with MICs of 2·1–4·0 μg./ml., and in 22% of nine patients with MICs of more than 4·0 μg./ml. The corresponding proportions yielding a negative culture at six months were 79% of 75 patients, 75% of 87 patients, 68% of 53 patients and 50% of 10 patients, respectively. Similar associations were found between pretreatment sensitivity to thiacetazone and other measures of progress, namely, the emergence of isoniazid resistance at three months and at six months, and the classification of the bacteriological status of the patients at twelve months.

Initial PAS sensitivity was investigated in 215 patients with initially isoniazid-sensitive organisms who were treated with PAS plus isoniazid in four chemotherapy studies in East Africa. PAS resistance was found in a pretreatment culture from 19 patients, but it was often not confirmed in further tests on the same culture in the same or in a different laboratory.

The progress of the patients during treatment was similar in those with a PAS-resistant pretreatment culture and in those with sensitive cultures. Sporadic unconfirmed resistant results were obtained more often from East African than from British strains and it is suggested that strains of Indian origin which are known to have these characteristics, are sometimes present in East Africa.

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*

We are grateful for the co-operation of the numerous physicians and laboratory workers in East Africa who participated in the four chemotherapy investigations. They are listed in the main reports of the studies. The studies were co-ordinated in East Africa by Professor A. W. Williams, The Department of Medicine, Makerere College Medical School, Kampala; succeeded by Dr. P. W. Kent, The East Africa Tuberculosis Investigation Centre, Nairobi. The following British Medical Research Units co-operated in London: Tuberculosis Research Unit: Drs. H. Bunjé. Wallace Fox, Joan Hefferenan, J. Pepys and A. Wiener. Unit for Research on Drug Sensitivity in Tuberculosis: Drs. Jean M. Dickinson, D. A. Mitchison, and J. B. Selkon. Statistical Research Unit: Miss B. J. Kinsley, Dr. Ian Sutherland and Miss Ruth Tall. Radiological assessments were made in London by Dr. G. Simon.

The report was prepared by Dr. D. A. Mitchison and Miss Ruth Tall and should be referred to as: East African British Medical Research Council Pretreatment Drug Resistance Report (1963), Tubercle, Lond., 44, 393.

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