Tubercle Bacilli Resistant to Isoniazid

This is the authors' abstract. We don't add key points for this paper.

Barnett, Bushby, and Mitchison (1953a, 1953b) found among strains of tubercle bacilli an apparent relation between their degree of resistance to isoniazid and their virulence in guinea-pigs and mice.Strains with a high degree of resistance were of low virulence, whereas those with only a slight increase in resistance were fully virulent.However, only three out of the eight strains employed were recently isolated from human lesions.Furthermore, even with these three strains the virulence of sensitive cultures isolated from the same patients before treatment with isoniazid was not tested.To meet these objections the virulence of eight pairs of freshly isolated sensitive and resistant strains has been investigated in guinea-pigs.The response to treatment at a level comparable to that used in man was also found by treating half of the animals with 4 mg. of isoniazid per kg.per day, given by subcutaneous injection. MethodsStrains.-The eight pairs of sensitive and resistant strains were obtained from the sputum of eight patients in the Medical Research Council (1952) trials of isoniazid.The sensitive strains, obtained before treatment with isoniazid, had been subcultured not more than three times over a period of up to six months before preparation of the inoculum.The resistant strains, obtained during or up to three months after treatment with isoniazid, were isolated on isoniazid-free Lowenstein slopes and were then subcultured twice on slopes containing isoniazid in concentrations shown in Table II.In this way admixture of organisms with a lower degree of resistance was eliminated.The inoculum for infecting the guinea-pigs was obtained by suspending the growth from 12-to 17-day-old Lowenstein cultures in Tween-albumin medium.Quantitative sensitivity tests on Lowenstein medium and viable counts on oleic-acid-albumin agar were set up from all the suspensions as described by Barnett et al. (1953b).Guinea-pig Experiments.-Aninjection of 0.1 -mg.(moist weight) of each strain was given into the right thigh of six guinea-pigs.One subgroup of three of these animals received no treatment and the other three were given 2 mg. of isoniazid per kg.subcutaneously at both 10 a.m. and 5 p.m. daily, except on Saturdays, when only one dose was given, and on Sundays, when none was given.Treatment was begun immediately after infection and was continued till the animals either died or were killed.Pairs of guinea-pigs, consisting of one treated and one untreated animal, were killed after 6, 10, and 14 weeks.If any animal died spontaneously, none was killed in that subgroup at the next appointed time.At the necropsy a histological examination was made of the spleen, liver, and lungs of all animals in which there was little or no macroscopic tuberculosis, and of some of the remaining animals with visible disease.The degree of tuberculosis was scored out of a possible total of 100 as described by Barnett et al. (1953b).Portions of the spleens from animals infected with the resistant strains and from treated animals infected with the sensitive strains were cul- *In receipt of a grant from the Medical Research Council.