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Long-term Chemotherapy of Tuberculosis
691
LEADING ARTICLES
THE LANCET
.
LONDON::
SATURDAY, OOT. 2,
1954
Long-term Chemotherapy of Tuberculosis WE suggested last year that the risk of bacterial resistance in tuberculosis may have been exaggerated and that continued, even life-long, antibacterial treatment may sometimes be justified.’ To what extent prolonged treatment is now being applied in this country is unknown ; but opposition to it has probably decreased considerably. Yet some, it seems, are still so oppressed by the fear of resistant bacilli that they hesitate even to start treatment in those clearly needing it. Fox et al.,2 describing the five-year records of patients treated in the first Medical Research Council trial of streptomycin, emphasised that antibacterial treatment of acutely ill patients should not be delayed until they are admitted to hospital. Of their 31 patients from whom strains highly resistant to streptomycin had been isolated, 9 were alive after five years and in 4 the disease was apparently arrested. It is probably- impossible to assess the precise clinical significance of drug susceptibility measured in the laboratory. JOHNSTON and RIDDELL,3 at the Brompton Hospital, determined isoniazid sensitivity twice weekly in a group of 31 patients treated for at least six months with antibacterial drugs. Judging by monthly examinations (a common practice) only 19% would have been said to have produced resistant strains ; but judging by twice-weekly tests 55% had done so. Moreover, there were many examples of fluctuations in the susceptibility of successive strains from the same patient, especially when the strains were only slightly resistant ; strains of low resistance might be followed by a succession of susceptible ones. Recognising that more may be inferred from the bacteriologist’s report than is justified, JOHNSTON and RIDDELL suggest that " resistance " for clinical purposes might better be defined as failure of 5 pt.g. (not 1 (J.g., as is now fairly usual) of isoniazid per ml. to inhibit growth on solid medium. Quantitative observations by TOMPSETT4 of changes in the bacterial population during treatment with isoniazid have5 given similar results to those obtained by MITCHISON during treatment with streptomycin. In some patients the proportion of highly resistant bacilli rises rapidly and remains high ; whereas in other patients, even when treated for many months, the majority of organisms remain sensitive although the proportion of those with high resistance rises somewhat. A single test certainly has little prognostic value. On the other hand, sensitivity determinations are invaluable in investigating the sustained effectiveness of combinations of drugs. Dr. JOINER and his colleagues at Guy’s Hospital report such an investigation in this issue. They treated 14 patients with chronic
sensitivity
1.
Lancet, 1953, ii, 237.
2. Fox, W., Sutherland, I., Danicls, M. Quart. J. Med. 1954, 23, 347. 3. Johnston, R. N., Riddell, R. W. Amer. Rev. Tuberc. 1954, 70, 442. 4. Tompsett, R. Ibid, p. 91. 5. Mitchison, D. A. Thorax, 1950, 5, 144.
pulmonary tuberculosis with isoniazid and p-aminosalicylic acid (P.A.S.) for twenty-four weeks and compared the experience of this group with that of a similar group treated with streptomycin, P.A.S., and isoniazid, different pairs of these three drugs being given each month. The progress was measured by fortnightly
examination of the sputum and estimation of the erythrocyte-sedimentation rate (E.s.R.), and by monthly radiographs. Between the two groups there was no important difference in the radiographic changes and only a slight difference in the clinical course. On the other hand the bacteriological differences and changes in E.S.R. were regarded as significant. Whereas in the group treated with all three drugs the mean number of bacilli in sputum smears fell progressively, in those receiving only isoniazid and P.A.S. the initial fall in the first three months was followed by a rise in the next three months. Of 13 patients who received the three drugs 4 still had a positive sputum on direct examination at the end of treatment, compared with 8 of 14 who were treated with isoniazid and P.A.S. Only 3 receiving streptomycin, P.A.S., and isoniazid were found to have resistant strains in the sputum, compared with 7 in the other group. JOINER et al. conclude that the effect of isoniazid with P.A.S. in patients with chronic fibrocaseous disease is not sustained throughout six months’ treatment as well as that of the three drugs in pairs. This report deserves to be studied carefully. It might perhaps be criticised on some grounds. With such small numbers it is almost to impossible get comparable groups. Therefore, small differences in progress, even if statistically significant, cannot be attributed to the treatments with the same degree of probability as in larger trials. The groups in this investigation were indeed slisrhtiv different. U
.
More in the group treated with isoniazid and P.A.s. had abnormal E.S.R.S initially (13 of 14 compared with 11 of 13) ; and the mean E.S.R. was higher (39-2 mm. against 32-3 mm.-), as was the mean number of bacilli in sputum smears (133 against 90). The small differences on direct microscopy favour the three-drug group only at. twenty-four weeks, not at sixteen or twenty ; and when culture results are included the 26 % difference is reduced to 17 %. Some might argue that the method of estimating the bacillary content of the sputum is insufficiently precise to allow deductions to be drawn from the difference between mean counts of 0-01 and 4-75.
Nevertheless, the results of this valuable small trial certainly do suggest that rotating pairs of drugs may have - had a more lasting antibacterial effect ; and Dr. JOINER and his colleagues wisely claim no more. It would be unwise, on the other hand, to condemn prolonged use of isoniazid and P.A.S. on the present evidence. Further light will no doubt be thrown on the question by the Medical Research Council’s report on the bacteriological findings in patients treated with this combination for six months. While suspicion is being cast on isoniazid with P.A.S. in this country, the use of isoniazid alone in certain circumstances has been recommended in the U.S.A. This is indeed heresy. DEUSCHLE et al.6 treated 47 patients for a year with isoniazid ; and from the form of their report, with its detailed arguments and advocacy, they clearly expect opposition. Their use of this drug alone was based on the assertions that no instance of meningitis has been reported during isoniazid treatment of miliary tuberculosis ; 6. Deuschle, K., Ormond, L., Elmendorf, D., Muschenheim, McDermott, W. Amer. Rev. Tuberc. 1954, 70, 228.
C.,
692 that there is no evidence from clinical trials that it loses its clinical efficacy in pulmonary tuberculosis sooner than streptomycin and P.A.S. or streptomycin and isoniazid; and that resistant strains, unlike those resistant to streptomycin and P.A.S., differ biologically from sensitive strains in respects other than drug susceptibility. Their arguments are ingenious and stimulating. It is, therefore, particularly unfortunate that they have incorrectly cited the results of the Medical Research Council trials and drawn wrong conclusions from them. They declare that it has " not been possible to establish with absolute certainty that isoniazid with streptomycin is superior to isoniazid alone."
They state that in the Medical Research Council trial substantial radiographic improvement occurred in 26% on isoniazid alone and 29 % on isoniazid with streptomycin—a mere 3 % difference. These figures come from the interim report,7 in which the combination of isoniazid with streptomycin is not considered ; the group with 29% improvement had in fact received streptomycin The results of treatment with isoniazid and w ith P.A.S. streptomycin are given in the main report published later 8 ; there was substantial radiographic improvement in 38%, compared with 22% of the isoniazid group—a difference of 16%, which is statistically highly significant. The same mistake occurs in their discussion of the effects of isoniazid with P.A.S. They imply that the observed difference in substantial radiographic improvement between isoniazid with P.A.S. in the second trial 9 and isoniazid alone in the first 8 (wrongly given as 13 % instead of 17 %) is made less impressive because there was a difference between the groups treated with streptomycin and isoniazid in both trials (wrongly given as 20%, instead of 11%). In fact, the type of patients treated and the doses of drugs given were not the same in the two trials ; and DEUSCHLE et al. themselves remark that comparison between them is not very satisfactory.
unlikely that the firmly established practice of using drugs in combination will be upset in Britain by
It is
this report ; but there is much of value in it. It is for instance, well worth considering whether in certain circumstances, as in the home care of patients in the less advanced countries, it may be reasonable to give isoniazid alone, accepting the risks of lowered efficiency and more frequent bacterial resistance, rather than give no drugs at all. In many patients P.A.S. causes digestive disturbances, and the drug is not ideal for long-continued unsupervised consumption. MACKAYDICK and ROTHNIE 10 state that they have stopped administering it to British Army patients because of its unpleasantness and toxicity. On the other hand, DOONEIEF and HITE,11 from experience with P.A.S. and other drugs given continuously for periods of up to thirty-eight months, conclude that " the patient’s willingness to continue treatment for years is in proportion to the physician’s conviction that it is necessary and to his transmission of his belief to the
patient." Pyrazinamide seems now a more promising partner to isoniazid than when the first clinical trials were reported.12 SCHWARTZ and MOYER 13 gave it in doses of 3 g. daily, along with P.A.S., streptomycin, and isoniazid, to 181 patients before a case of mild jaundice occurred. 7 patients with advanced disease, all of whom had streptomycin-resistant strains in the sputum, received pyrazinamide and isoniazid continu7. 8. 9. 10. 11. 12. 13.
Medical Research Council. Brit. med. J. 1952, ii, 735. Medical Research Council. Ibid, 1953, i, 521. Medical Research Council. Ibid, 1953, ii, 1005. Mackay-Dick J., Rothnie, N. G. Tubercle, 1954, 35, 182. Dooneief, A. S., Hite, K. E. Amer. Rev. Tuberc. 1954, 70, 219. See Lancet, 1954, i, 767. Schwartz, W. S., Moyer, R. E. Amer. Rev. Tuberc. 1954, 70, 413.
for a year. Cultures became negative in all, and remained so throughout the trial. In the past few years there has been a noticeable trend towards ever longer antibacterial treatment. In the first Medical Research Council trial of streptomycin in acute pulmonary tuberculosis the drug was given initially for three months only. 58% of the patients died within five years, and almost all the deaths occurred in the first two and a half years.2 Of the group not treated with streptomycin during the trial period 67% died within five years, all but a few in the first eighteen months. We wonder what would have happened if all these patients could have been treated for the whole five years with the drugs now available.
ously
Towards Cleaner Air THE sanitary movement of the nineteenth century was centred on the purity of water-supplies ; today we talk of clean food ; but tomorrow we must have clean air. Apart from chemical pullution, the aerial spread of disease has a practical importance out of all proportion to our present knowledge of ways of controlling it. In 1933 WELLS 14 suggested that pathogenic microbes might be expelled as " droplet nuclei " from an infected nasopharynx and remain suspended and circulating in the air of a room. If this were the case and widespread dissemination of infected material accounted for much of the spread of illness in classroom or office, air hygiene by air sterilisation would be no idle dream. and other devices developed for " Slit samplers the number of organisms in a quantity of measuring room-air showed that aerial contamination certainly existed,15 : and WELLS et al. reported, in 1942,16 results of a four-year study of the indirect use of ultravioletlight screening in American schools. Their conclusion that this means of air sterilisation had appreciably reduced the spread of measles and chickenpox encouraged the Medical Research Council’s Air Hygiene Committee to conduct a large-scale field trial of similar methods in the primary schools of Southall. In three of these schools, ultraviolet lamps were fitted so as to irradiate the upper air of the classrooms and other common-rooms. In these schools and in three other schools (similar but not thus irradiated) in the same socially homogeneous suburb complete records were kept of the absences from all causes over the ensuing three years. A specially appointed medical officer, Dr. HILDA CHANNON, and Dr. D. D. REID were responsible for collecting and collating records; while Dr. R. E. O. WILLIAMS with Miss ANN HIRCH collected and examined the bacterial content of samples of the classroom air and of throat and nasal swabs from children in both irradiated and control schools. Dr. O. M. LIDWELL, assisted by Miss E. M. CROFT and Miss ANN HOPE, made repeated assays of environmental conditions, such as temperature, ventilation, and humidity, at regular intervals in both sets of schools throughout the three years of the trial. An M.R.C. special report 17 sets out the results of this laborious investigation, which imposed a cheer"
14. Wells, W. F. Amer. J. publ. Hlth, 1933, 23, 58. 15. Bourdillon, R. B., Lidwell, O. M., Lovelock, J. E. (with others), Studies in Air Hygiene. Spec. Rep. Ser. Med. Res. Coun., Lond. no. 262. H.M. Stationery Office, 1948. 16. Wells, W. F., Wells, M. W., Wilder, T. S. Amer. J. med. Sci. 11. 1942, 206, 17. Air Disinfection with Ultra-violet Irradiation. Spec. Rep. Ser. med. Res. Coun., Lond. no. 283. H.M. Stationery Office. 1954. Pp. 88. 7s. 6d.
LEADING ARTICLES
THE LANCET
.
LONDON::
SATURDAY, OOT. 2,
1954
Long-term Chemotherapy of Tuberculosis WE suggested last year that the risk of bacterial resistance in tuberculosis may have been exaggerated and that continued, even life-long, antibacterial treatment may sometimes be justified.’ To what extent prolonged treatment is now being applied in this country is unknown ; but opposition to it has probably decreased considerably. Yet some, it seems, are still so oppressed by the fear of resistant bacilli that they hesitate even to start treatment in those clearly needing it. Fox et al.,2 describing the five-year records of patients treated in the first Medical Research Council trial of streptomycin, emphasised that antibacterial treatment of acutely ill patients should not be delayed until they are admitted to hospital. Of their 31 patients from whom strains highly resistant to streptomycin had been isolated, 9 were alive after five years and in 4 the disease was apparently arrested. It is probably- impossible to assess the precise clinical significance of drug susceptibility measured in the laboratory. JOHNSTON and RIDDELL,3 at the Brompton Hospital, determined isoniazid sensitivity twice weekly in a group of 31 patients treated for at least six months with antibacterial drugs. Judging by monthly examinations (a common practice) only 19% would have been said to have produced resistant strains ; but judging by twice-weekly tests 55% had done so. Moreover, there were many examples of fluctuations in the susceptibility of successive strains from the same patient, especially when the strains were only slightly resistant ; strains of low resistance might be followed by a succession of susceptible ones. Recognising that more may be inferred from the bacteriologist’s report than is justified, JOHNSTON and RIDDELL suggest that " resistance " for clinical purposes might better be defined as failure of 5 pt.g. (not 1 (J.g., as is now fairly usual) of isoniazid per ml. to inhibit growth on solid medium. Quantitative observations by TOMPSETT4 of changes in the bacterial population during treatment with isoniazid have5 given similar results to those obtained by MITCHISON during treatment with streptomycin. In some patients the proportion of highly resistant bacilli rises rapidly and remains high ; whereas in other patients, even when treated for many months, the majority of organisms remain sensitive although the proportion of those with high resistance rises somewhat. A single test certainly has little prognostic value. On the other hand, sensitivity determinations are invaluable in investigating the sustained effectiveness of combinations of drugs. Dr. JOINER and his colleagues at Guy’s Hospital report such an investigation in this issue. They treated 14 patients with chronic
sensitivity
1.
Lancet, 1953, ii, 237.
2. Fox, W., Sutherland, I., Danicls, M. Quart. J. Med. 1954, 23, 347. 3. Johnston, R. N., Riddell, R. W. Amer. Rev. Tuberc. 1954, 70, 442. 4. Tompsett, R. Ibid, p. 91. 5. Mitchison, D. A. Thorax, 1950, 5, 144.
pulmonary tuberculosis with isoniazid and p-aminosalicylic acid (P.A.S.) for twenty-four weeks and compared the experience of this group with that of a similar group treated with streptomycin, P.A.S., and isoniazid, different pairs of these three drugs being given each month. The progress was measured by fortnightly
examination of the sputum and estimation of the erythrocyte-sedimentation rate (E.s.R.), and by monthly radiographs. Between the two groups there was no important difference in the radiographic changes and only a slight difference in the clinical course. On the other hand the bacteriological differences and changes in E.S.R. were regarded as significant. Whereas in the group treated with all three drugs the mean number of bacilli in sputum smears fell progressively, in those receiving only isoniazid and P.A.S. the initial fall in the first three months was followed by a rise in the next three months. Of 13 patients who received the three drugs 4 still had a positive sputum on direct examination at the end of treatment, compared with 8 of 14 who were treated with isoniazid and P.A.S. Only 3 receiving streptomycin, P.A.S., and isoniazid were found to have resistant strains in the sputum, compared with 7 in the other group. JOINER et al. conclude that the effect of isoniazid with P.A.S. in patients with chronic fibrocaseous disease is not sustained throughout six months’ treatment as well as that of the three drugs in pairs. This report deserves to be studied carefully. It might perhaps be criticised on some grounds. With such small numbers it is almost to impossible get comparable groups. Therefore, small differences in progress, even if statistically significant, cannot be attributed to the treatments with the same degree of probability as in larger trials. The groups in this investigation were indeed slisrhtiv different. U
.
More in the group treated with isoniazid and P.A.s. had abnormal E.S.R.S initially (13 of 14 compared with 11 of 13) ; and the mean E.S.R. was higher (39-2 mm. against 32-3 mm.-), as was the mean number of bacilli in sputum smears (133 against 90). The small differences on direct microscopy favour the three-drug group only at. twenty-four weeks, not at sixteen or twenty ; and when culture results are included the 26 % difference is reduced to 17 %. Some might argue that the method of estimating the bacillary content of the sputum is insufficiently precise to allow deductions to be drawn from the difference between mean counts of 0-01 and 4-75.
Nevertheless, the results of this valuable small trial certainly do suggest that rotating pairs of drugs may have - had a more lasting antibacterial effect ; and Dr. JOINER and his colleagues wisely claim no more. It would be unwise, on the other hand, to condemn prolonged use of isoniazid and P.A.S. on the present evidence. Further light will no doubt be thrown on the question by the Medical Research Council’s report on the bacteriological findings in patients treated with this combination for six months. While suspicion is being cast on isoniazid with P.A.S. in this country, the use of isoniazid alone in certain circumstances has been recommended in the U.S.A. This is indeed heresy. DEUSCHLE et al.6 treated 47 patients for a year with isoniazid ; and from the form of their report, with its detailed arguments and advocacy, they clearly expect opposition. Their use of this drug alone was based on the assertions that no instance of meningitis has been reported during isoniazid treatment of miliary tuberculosis ; 6. Deuschle, K., Ormond, L., Elmendorf, D., Muschenheim, McDermott, W. Amer. Rev. Tuberc. 1954, 70, 228.
C.,
692 that there is no evidence from clinical trials that it loses its clinical efficacy in pulmonary tuberculosis sooner than streptomycin and P.A.S. or streptomycin and isoniazid; and that resistant strains, unlike those resistant to streptomycin and P.A.S., differ biologically from sensitive strains in respects other than drug susceptibility. Their arguments are ingenious and stimulating. It is, therefore, particularly unfortunate that they have incorrectly cited the results of the Medical Research Council trials and drawn wrong conclusions from them. They declare that it has " not been possible to establish with absolute certainty that isoniazid with streptomycin is superior to isoniazid alone."
They state that in the Medical Research Council trial substantial radiographic improvement occurred in 26% on isoniazid alone and 29 % on isoniazid with streptomycin—a mere 3 % difference. These figures come from the interim report,7 in which the combination of isoniazid with streptomycin is not considered ; the group with 29% improvement had in fact received streptomycin The results of treatment with isoniazid and w ith P.A.S. streptomycin are given in the main report published later 8 ; there was substantial radiographic improvement in 38%, compared with 22% of the isoniazid group—a difference of 16%, which is statistically highly significant. The same mistake occurs in their discussion of the effects of isoniazid with P.A.S. They imply that the observed difference in substantial radiographic improvement between isoniazid with P.A.S. in the second trial 9 and isoniazid alone in the first 8 (wrongly given as 13 % instead of 17 %) is made less impressive because there was a difference between the groups treated with streptomycin and isoniazid in both trials (wrongly given as 20%, instead of 11%). In fact, the type of patients treated and the doses of drugs given were not the same in the two trials ; and DEUSCHLE et al. themselves remark that comparison between them is not very satisfactory.
unlikely that the firmly established practice of using drugs in combination will be upset in Britain by
It is
this report ; but there is much of value in it. It is for instance, well worth considering whether in certain circumstances, as in the home care of patients in the less advanced countries, it may be reasonable to give isoniazid alone, accepting the risks of lowered efficiency and more frequent bacterial resistance, rather than give no drugs at all. In many patients P.A.S. causes digestive disturbances, and the drug is not ideal for long-continued unsupervised consumption. MACKAYDICK and ROTHNIE 10 state that they have stopped administering it to British Army patients because of its unpleasantness and toxicity. On the other hand, DOONEIEF and HITE,11 from experience with P.A.S. and other drugs given continuously for periods of up to thirty-eight months, conclude that " the patient’s willingness to continue treatment for years is in proportion to the physician’s conviction that it is necessary and to his transmission of his belief to the
patient." Pyrazinamide seems now a more promising partner to isoniazid than when the first clinical trials were reported.12 SCHWARTZ and MOYER 13 gave it in doses of 3 g. daily, along with P.A.S., streptomycin, and isoniazid, to 181 patients before a case of mild jaundice occurred. 7 patients with advanced disease, all of whom had streptomycin-resistant strains in the sputum, received pyrazinamide and isoniazid continu7. 8. 9. 10. 11. 12. 13.
Medical Research Council. Brit. med. J. 1952, ii, 735. Medical Research Council. Ibid, 1953, i, 521. Medical Research Council. Ibid, 1953, ii, 1005. Mackay-Dick J., Rothnie, N. G. Tubercle, 1954, 35, 182. Dooneief, A. S., Hite, K. E. Amer. Rev. Tuberc. 1954, 70, 219. See Lancet, 1954, i, 767. Schwartz, W. S., Moyer, R. E. Amer. Rev. Tuberc. 1954, 70, 413.
for a year. Cultures became negative in all, and remained so throughout the trial. In the past few years there has been a noticeable trend towards ever longer antibacterial treatment. In the first Medical Research Council trial of streptomycin in acute pulmonary tuberculosis the drug was given initially for three months only. 58% of the patients died within five years, and almost all the deaths occurred in the first two and a half years.2 Of the group not treated with streptomycin during the trial period 67% died within five years, all but a few in the first eighteen months. We wonder what would have happened if all these patients could have been treated for the whole five years with the drugs now available.
ously
Towards Cleaner Air THE sanitary movement of the nineteenth century was centred on the purity of water-supplies ; today we talk of clean food ; but tomorrow we must have clean air. Apart from chemical pullution, the aerial spread of disease has a practical importance out of all proportion to our present knowledge of ways of controlling it. In 1933 WELLS 14 suggested that pathogenic microbes might be expelled as " droplet nuclei " from an infected nasopharynx and remain suspended and circulating in the air of a room. If this were the case and widespread dissemination of infected material accounted for much of the spread of illness in classroom or office, air hygiene by air sterilisation would be no idle dream. and other devices developed for " Slit samplers the number of organisms in a quantity of measuring room-air showed that aerial contamination certainly existed,15 : and WELLS et al. reported, in 1942,16 results of a four-year study of the indirect use of ultravioletlight screening in American schools. Their conclusion that this means of air sterilisation had appreciably reduced the spread of measles and chickenpox encouraged the Medical Research Council’s Air Hygiene Committee to conduct a large-scale field trial of similar methods in the primary schools of Southall. In three of these schools, ultraviolet lamps were fitted so as to irradiate the upper air of the classrooms and other common-rooms. In these schools and in three other schools (similar but not thus irradiated) in the same socially homogeneous suburb complete records were kept of the absences from all causes over the ensuing three years. A specially appointed medical officer, Dr. HILDA CHANNON, and Dr. D. D. REID were responsible for collecting and collating records; while Dr. R. E. O. WILLIAMS with Miss ANN HIRCH collected and examined the bacterial content of samples of the classroom air and of throat and nasal swabs from children in both irradiated and control schools. Dr. O. M. LIDWELL, assisted by Miss E. M. CROFT and Miss ANN HOPE, made repeated assays of environmental conditions, such as temperature, ventilation, and humidity, at regular intervals in both sets of schools throughout the three years of the trial. An M.R.C. special report 17 sets out the results of this laborious investigation, which imposed a cheer"
14. Wells, W. F. Amer. J. publ. Hlth, 1933, 23, 58. 15. Bourdillon, R. B., Lidwell, O. M., Lovelock, J. E. (with others), Studies in Air Hygiene. Spec. Rep. Ser. Med. Res. Coun., Lond. no. 262. H.M. Stationery Office, 1948. 16. Wells, W. F., Wells, M. W., Wilder, T. S. Amer. J. med. Sci. 11. 1942, 206, 17. Air Disinfection with Ultra-violet Irradiation. Spec. Rep. Ser. med. Res. Coun., Lond. no. 283. H.M. Stationery Office. 1954. Pp. 88. 7s. 6d.