The clinical significance of positive cultures and of isoniazid-resistant tubercle bacilli during the treatment of pulmonary tuberculosis; report to the Tuberculosis Chemotherapy Trials Committee of the Medical Research Council.

Within a few months of the introduction of isoniazid (isonicotinic acid hydrazide) in the treatment of pulmonary tuberculosis, reports appeared of the frequent and rapid emergence of isoniazidresistant bacteria when the drug was used alone (Medical Research Council, 1952; Ferebee and Long, 1953; Lotte and Poussier, 1953; U.S. Veterans Administration, 1953). In view of earlier experience with streptomycin (Medical Research Council, 1948; Ferebee and Appel, 1951), this was regarded as an undesirable feature of isoniazid therapy. First it was presumed that a patient yielding resistant organisms would derive no further, or at best reduced, benefit from continued treatment with the drug. Secondly there was a risk that contacts might be infected with isoniazid-resistant organisms. In Great Britain, as a consequence, the widespread use of isoniazid alone stopped, and research was directed to the prevention of isoniazid resistance by the use of other anti-tuberculosis drugs in combination with isoniazid. Various combinations have since been shown to reduce considerably the incidence of isoniazid resistance (Medical Research Council, 1953c, 1955; Pitts, Tempel, Miller, Sands, Fitzpatrick, and Weiser, 1953; U.S. Public Health Service, 1953; U.S. Veterans Administration, 1953, 1954). It has been suggested that bacterial resistance to isoniazid may in some patients be transitory (Ashino, 1953; Petit, 1953a and b; Ogilvie, 1954). Other data, however, show little evidence of a general reversion of resistant strains towards sensitivity over a period of at least six months after stopping treatment with isoniazid (Medical Research Council, 1954). It has also been shown that organisms which are highly resistant to isoniazid may be of low pathogenicity in some animal species (Barnett, Bushby, and Mitchison, 1953; Barry, Conalty, and Gaffney, 1953; Middlebrook and Cohn, 1953; Meissner, 1954; Mitchison, 1954), but it is not known whether this applies in man. Because the strains do not rapidly return to sensitivity and because their pathogenicity may have altered, it is important to examine the clinical progress of patients in whom isoniazid-resistant organis rs have emerged. A preliminary study of the clinical significance of isoniazid resistance was made in the first report of the Medical Research Council isoniazid trial (1952), but the bacteriological information was then far from complete. A full study over a three-month period, derived from the complete information for all patients who received isoniazid alone in that trial, is now presented. The essence of this study has been to divide the patients into groups based upon the results of cultures and sensitivity tests after two months' treatment in the trial, and to compare the clinical progress of the groups over the three-month period. Details of the organization of the isoniazid trial were given in the first two reports (Medical Research Council, 1952, 1953a); the list of hospitals, and the names of the clinicians, bacteriologists, and pathologists on whose observations the present report is based, were given at the end of the second report. Patients were admitted in one of three main disease groups: GROUP 1.-Acute rapidly progressive pulmonary tuberculosis believed to be of recent origin. GROUP 2.-Other forms of pulmonary tuberculosis considered suitable for chemotherapy: this group included a wide range of disease and contained both acute and chronic cases.