The Emergence of Isoniazid-Resistant Cultures in Patients with Pulmonary Tuberculosis during Treatment with Isoniazid alone or Isoniazid plus PAS

Selkon, J B and Devadatta, S and Kulkarni, K G and Mitchison, D A and Narayana, A S L and Narayanan Nair, C and Ramachandran, K (1964) The Emergence of Isoniazid-Resistant Cultures in Patients with Pulmonary Tuberculosis during Treatment with Isoniazid alone or Isoniazid plus PAS. Bulletin of the World Health Organization, 31 (2). pp. 273-294. ISSN 00429686

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Abstract

Previous reports from the Tuberculosis Chemotherapy Centre, Madras, have described a comparison of four regimens (three of isoniazid alone and one of isoniazid plus PAS) in the treatment of pulmonary tuberculosis and an investigation of the serum isoniazid levels in the patients concerned. The present report studies the emergence of isoniazidresistant organisms in these patients during treatment. All patients with an unsatisfactory response to treatment yielded resistant cultures, showing that the isoniazid dosage was never too low to inhibit sensitive organisms. From the degree of resistance of the first resistant cultures and of the six-month cultures from the patients treated with isoniazid alone it was concluded that resistance emerged in two stages. In the first stage, very early in treatment, highly resistant mutant bacilli grew freely whatever the isoniazid dosage, but mutants of lower resistance were prevented from growing to an extent dependent on the peak isoniazid concentration in the serum. Consequently, when the isoniazid dosage was increased the proportion of patients with resistant organisms decreased, since fewer low-resistance strains were able to develop. In the second stage, organisms with relatively low resistance continued to multiply, though still partially inhibited by isoniazid, and became more resistant, particularly in slow inactivators. The first-stage events determined the results of treatment since, once resistance had emerged, its extent was unrelated to the patient’s eventual progress. These findings emphasize the importance of early intensive chemotherapy and adjustment of the isoniazid dosage according to peak serum concentrations rather than concentrations measured three or six hours after the dose. Concomitant administration of PAS prevented emergence of isoniazid resistance in many patients and in others delayed its emergence and reduced its degree, possibly because growth in the secondstage was slow.

Item Type:	Article
Subjects:	Tuberculosis > Clinical Research
Divisions:	Clinical Research
Depositing User:	Dr. Rathinasabapati R
Date Deposited:	17 Jul 2013 09:37
Last Modified:	08 Mar 2016 04:45
URI:	http://eprints.nirt.res.in/id/eprint/63

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