STREPTOMYCIN IN PULMONARY TUBERCULOSIS (Reprinted from BMJ 1948:ii:790-1)

BMJ 1998;317:1248 ( 31 October )

TB randomised controlled trial (1948)

STREPTOMYCIN IN PULMONARY TUBERCULOSIS

(Reprinted from BMJ 1948:ii:790-1)

LONDON SATURDAY OCTOBER 30 1948

In few infections is it so difficult to assess the results of treatment as in pulmonary tuberculosis, with its varied clinical picture and unpredictable course. Remarkable recoveries can take place with no treatment except rest in bed. In the Medical Research Council's trial of streptomycin in pulmonary tuberculosis, the report on which is published in this issue, there was a satisfactory control series of patients; this made it possible for the first time to make a fair estimate of the effects of the drug in one form of the disease. The method of investigation is discussed in the next leading article. The trial was designed to do no more than answer the question, Is streptomycin of any value at all in pulmonary tuberculosis? Although no attempt was made to determine either the types of disease likely to respond most favourably or the most effective dosage of the drug, much valuable information beyond the limited scope of the inquiry has in fact emerged.

The type of disease chosen was "acute progressive bilateral pulmonary tuberculosis of presumably recent origin, bacteriologically proved, unsuitable for collapse therapy, age group 15 to 25 (later extended to 30)." The treated (S) cases received 2 g. daily of streptomycin divided into four 6-hourly doses. Most patients were treated for four months, but some of the earlier ones for longer periods up to six months. The control (C) patients were treated by bed-rest alone in the same hospitals and with the same regime as the S cases apart from streptomycin administration. Although a few of the C patients became suitable for various forms of collapse therapy (artificial pneumoperitoneum with phrenic paralysis in all but one case) before the end of the observation period, these measures were not thought to have had an appreciable influence on the progress of most of them during the course of the trial. Both S and C cases were observed for a period of six months from the beginning of the investigation.

The results were analysed by changes in the radiographic appearances. These were assessed by a panel of three without knowledge of whether the films being viewed were those of S or C patients. The overall results leave no doubt of the beneficial effect of streptomycin. Of 55 S patients four (7%) and of 52 C patients 14 (27%) died within the six months. This difference is statistically significant. Of the S patients 27 (51%) and of the C patients four (8%) were judged radiologically to have improved considerably. Assessment of the changes in successive two-month periods showed that the improvement in S cases could often be seen during the earlier months, while the improvement in some of the C cases tended to occur later. Analysis of the results according to the degree of illness of the patients on admission showed that the difference in response to treatment between the S and the C cases was very much greater in those patients who were more acutely ill with higher temperatures on admission to the trial. There was relatively little difference between the results in the S and the C patients whose maximum evening temperature during the first week did not exceed 99.9° F. (37.75° C.), the differences between the two groups as a whole being accounted for almost entirely by the more severely ill patients.

The extent of improvement in both S and C cases was greatest in those with no initial gross cavitation; of the 23 S patients without large cavities 17 improved considerably and none died. Streptomycin did not have a marked effect on the presence of tubercle bacilli in the sputum. Complete bacteriological information was available in 54 of the 55 S cases. Of these 54, four had died by the end of the trial; tubercle bacilli were found on direct examination of the sputum in 32 cases and by cultural methods in another 10. In only eight could bacilli not be found by any method, as compared with two of the C cases. There were no striking differences in the changes of weight between the two groups; in assessing the significance of this the gastric upset caused in many patients by the streptomycin must be taken into account. The condition of the patients in the two groups was reviewed by the clinicians in charge at the end of a year from the beginning of the trial. The differences between the two groups were then less evident than at six months. Twelve (22%) of the S cases and 24 (46%) of the C cases had died, while 31 (56%) of the S cases and 16 (31%) of the C cases had improved. The difference in mortality is statistically significant. The general impression derived from the study of the two groups is that the results from streptomycin treatment were best in those patients whose lesions were active at the beginning of treatment but had not yet formed cavities. Presumably these were the lesions which were truly of recent origin. When large cavities were present the results were not so good, and in less acutely ill patients the difference in progress between the S and the C cases was smaller.

The most important toxic effect was on the vestibular apparatus: giddiness was noticed by 36 of the 55 patients, usually in the fourth or fifth week of treatment. Nausea and vomiting occurred often, but these symptoms were often relieved by "benadryl." In no case did treatment have to be stopped because of toxic effects.

Complete information was obtained about the streptomycin sensitivity of the organisms isolated from 42 of the 55 treated patients. The sensitivity of all the strains isolated before treatment approximated to that of the standard H37Rv. In 35 of the 42 cases strains showing resistance 32 or more times that of H37Rv were isolated after treatment; in 13 of these the resistance was more than 2,000 times that of H37Rv. The time at which these resistant strains were detected was estimated as the midpoint between the times of isolation of the last sensitive strain and of the first resistant strain. The mean figure on this basis was the 53rd day after starting treatment. When frequent cultures were obtained it was found that resistance rose rapidly to a maximum level which was subsequently maintained. Comparison of the date of appearance and degree of streptomycin resistance with clinical results brought out the fact that on the whole those patients from whom highly resistant strains were isolated early did less well than those whose organisms showed lesser degrees of resistance later. Seven patients whose organisms did not develop resistance over 32 times that of H37Rv improved steadily. The figures are not large enough to correlate the clinical results, the degree of streptomycin resistance acquired by the organism, and the other relevant factors such as the type of lesion present at the beginning of treatment.

This investigation has achieved its limited object by proving that streptomycin is of value in the treatment of acute forms of pulmonary tuberculosis. Many further problems remain to be solved, however, before the indications for the use of this new remedy in pulmonary tuberculosis can be regarded as firmly established. There are already enough favourable reports to justify the use of streptomycin in the treatment of ulcerative lesions of the main bronchi at the pre-stenotic stage where these are affecting prognosis. Its value in ulcerative tuberculous lesions of the larynx, pharynx, and tongue is also well established. Patients with old and apparently stable lesions who develop, while under observation, acute spread of the disease in previously unaffected parts of the lung may be expected to respond well, since they can be treated when the lesions are at the very earliest stage. Whether or not streptomycin should be used as a routine prophylactic against extension of the disease after surgical treatment for pulmonary tuberculosis remains to be seen. It is certainly of great importance to determine, for instance, whether streptomycin should be given prophylactically to patients undergoing thoracoplasty or whether it is better reserved for the treatment of the smaller number in whom the disease actually extends after operation. The answer to this question cannot be deduced a priori; even if patients treated prophylactically showed better immediate results, in the long run they might be worse off, since those among them who later had a recurrence of infection suitable for streptomycin treatment might prove to be harbouring resistant organisms and to be no longer responsive to the drug. The question of the proper use of streptomycin as an adjunct to collapse therapy, both medical and surgical, must be settled.

Streptomycin resistance is perhaps the most important problem of all. From the point of view of the individual patient the probability that the organisms will develop resistance after a relatively short period of treatment means that a course of streptomycin may be effectual only once during possibly a long and chequered illness. From the point of view of the community there is the risk that patients with unsuitable lesions ineffectively treated may disseminate streptomycin-resistant organisms, so that an increasing number of new cases of all forms of tuberculosis may in future be found to be unresponsive to streptomycin. It therefore seems in the best interests both of the individual patient and of the community that streptomycin should be used for the treatment of pulmonary tuberculosis with a proper understanding of the difficulties and dangers and only when the indications for its use are clear. Streptomycin may, of course, be outmoded in the treatment of tuberculosis by new and more potent antibiotics. Even so, the enormous amount of work done upon it will not have been wasted. Laboratory and clinical techniques which have been evolved can no doubt be applied to the problems of other antibiotics, and the Medical Research Council's controlled trial will serve as a model for future investigations of substances introduced for the treatment of pulmonary tuberculosis.
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