Bull. Org. mond. Sante 1960, 23 427-461 Bull. Wld Hlth Org.

Antimicrobial Therapy of Pulmonary Tuberculosis *

WALSH McDERMOTT, M.D.'

The discovery, some nine years ago, ofthe highly specific antituberculous drug, isoniazid, marked an important advance in the antimicrobial therapy of tuberculosis, first practised successfully with streptomycin and p-aminosalicylic acid (PAS) in the late 'forties. Isoniazid is relatively non-toxic and, unlike streptomycin, can be administered orally, so that it is eminently suitable for use, either alone or in combination with PAS, in the domi- ciliary treatment of tuberculous patients. The wisdom of employing it on a large scale in home-treatment programmes, however, has been questioned on the ground that such wide- spread use might result in a spread of tubercle bacilli resistant to the drug. This contro- versial subject is discussed in some detail in this general review of the chemotherapy of tuberculosis. The author is convinced that, so far, the benefits of isoniazid therapy have outweighed the disadvantages and, though well aware of the possible consequences in terms of isoniazid-resistance, sees no reason at the present time for not making full use of this valuable weapon in the antituberculosis armamentarium.

INTRODUCTION

It is now approximately fifteen years since the first mena that had already been quite well established successful demonstration of the antimicrobial from the chemotherapy of other infections. One therapy of tuberculosis and it is highly appropriate can always find fault with what is going on around that we take stock of the situation at this time. The one, however, and despite these annoyances things fifteen-year period has been one of great achieve- have, on the whole, certainly progressed very well. ment. It has decidedly altered the management of If we do not have answers to every one of our major tuberculosis and, indeed, has made it a " manage- questions, we have final answers for some, and able" disease. Moreover, with the introduction of concerning most of the others we at least have a isoniazid, nine years ago, the prospect arose that it reasonable basis for practicable procedures. might be possible to do something about the thous- ands of tuberculous patients in many areas of the The chemotherapy of pulmonary tuberculosis can world who were then, and are still now, going un- be conveniently divided into consideration of the treated. Without discounting the great achievements patients with untreated disease and of those with of this era, it is likewise appropriate to dwell a unsuccessfully treated disease. Depending on in- moment on our sins. The two principal ones, it dividual circumstances, the patients with previously seems to me, are: first, that we have been curiously untreated disease can be treated either at home or in slow to exploit the enormous technological develop- hospital. For the patients with unsuccessfully ment represented by the introduction of isoniazid, treated disease, however, for several reasons-not- and secondly, that we have shown too great a ably, drug toxicity and the type of pulmonary lesion tendency to spend our time in rediscovering pheno- usually present-treatment is best given in a hospital. It is impossible, therefore, to consider the chemo- * Paper submitted at the seminar on tuberculosis held in therapy of pulmonary tuberculosis today without Sydney, Australia, in May-June 1960 under the auspices of giving some consideration to the problems of bed the WHO Regional Office for the Western Pacific. rest, because so many of the problems involved in l Livingston Farrand Professor of Public Health, Cornell University Medical College, The New York Hospital-Cornell choices of chemotherapy depend upon acceptance of Medical Center, New York, N.Y., USA. the principle of domiciliary care. 919 -427 428 W. MCDERMOTT

HOSPITAL VERSUS HOME TREATMENT

At the outset let us accept that in the treatment of Bed rest pulmonary tuberculosis there must always be con- In the light of the available evidence, what is the siderable domiciliary care with self-administered situation with respect to bed rest for the patient with chemotherapy. The reason for this is that our anti- pulmonary tuberculosis? Let me preface these tuberculous drugs, like our other antimicrobial remarks by saying that, like many others, I believe agents, are not eradicative. Consequently, all agree that in the pre-chemotherapy era bed rest accom- that the chemotherapy of tuberculosis must be pro- plished something. Although I suspect that what it longed, in most instances for so long as two or three accomplished was not exactly what it was thought to years. As even the most conservatively managed be doing, nevertheless, it certainly seemed to be a patient with pulmonary tuberculosis would be worth-while procedure. It cannot be too strongly spending, at the most, only a year or so in hospital, emphasized, however, that the apparent values of at least two-thirds of his treatment will necessarily bed rest were never established in any scientifically have to be on a self-administered basis in his home. conducted clinical investigation. On the contrary, Whether we like it or not, therefore, we are in the the whole case for bed rest was entirely one of faith domiciliary treatment field even if it were possible to and belief based on clinical impressions. give every patient twelve to eighteen months of strict bed rest in a tuberculosis sanatorium at the initiation In general, it was believed that bed rest was a positive of therapy. To this extent at least, we cannot escape treatment in the sense that it promoted the healing of facing the problem involved in how much respons- the pulmonary lesion. In reflecting on the occurrences of that day, I have come belatedly to the opinion that bed ibility can be assumed by the patient in administer- rest probably was not a positive treatment in this sense, ing his own daily chemotherapy with only periodic but that its benefits, and I believe they were important -fortnightly or monthly-supervision by physicians benefits, were limited to its being a prophylactic. By and other personnel. this I mean that I believe the benefits of the reasonably For this type of domiciliary care, the follow-up strict bed rest management of pulmonary tubercjlosis chemotherapy of the initially hospitalized patient, we were exerted entirely, or almost entirely, on the uninvolved need no ethical justification for we are simply doing portions of the lung. It was well established in the something in addition to what was done in the pre- credible clinical folklore that the patient with cavitary chemotherapy days. What does require ethical tuberculosis was considerably less apt to suffer a spread of his disease while on bed rest than if he were maintain- justification, however, is the use of tuberculosis ing full physical activity. The cavitary disease itself chemotherapy in the non-hospitalized patient as an might or might not improve under bed rest, but at least initial measure, thus bypassing the use of the hospital it did not seem to show much tendency to increase. On altogether. If we are to use this type of domiciliary examining this tradition, I have been struck by the fact care, it is important that we be clear as to the that a large proportion of the spreads of disease that scientific evidence favouring the position that it is are seen with the cavitary patient are not so much spreads ethically justifiable. by local extension as they are the development of wholly new areas of disease in the same or the contralateral lung. It was this sort of occurrence that seemed to be prevented to an impressive extent by maintaining the ADVANTAGES OF HOSPITALIZATION IN patient in bed. PULMONARY TUBERCULOSIS The thought has occurred to me that it might be that the uninvolved lung, which is continually at risk from Hospitalization of the tuberculosis patient serves aspirated tubercle bacilli from the cavitary disease, is two purposes: it provides the only satisfactory put into a bettzr position to withstand such challenge opportunity for supervised bed rest, and it removes when the patient is not excessively fatigued. Without attempting to define the word fatigued any more pre- the infectious patient from his environment. It is cisely, it ce.-tainly seems that most persons develop their important to realize that these two purposes are quite tuberculous disease in a setting of prolonged fatigue. different, one being for the benefit of the patient However the influence of fatigue may be accomplished, himself and the other being for the benefit of the it seems to create a situation in which pulmonary tissue community at large. is more susceptible to challenge with tubercle bacilli. ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 429

It is possible, therefore, that in the pre-chemotherapy In the initial phases of the study, on admission to the era, the sole effect of bed rest was to put the as yet unin- hospital, each patient was put to bed for one month. volved lung into a better position to cope with challenges Then, during the second month, she was maintained out by tubercle bacilli, the cavity itself healing or not by of bed throughout the day and went through a period mechanisms quite unrelated to the bed rest. of active physical exercise, including supervised calisthe- In the sense that this concept can no longer be subjected nics. At the end of this month, she would go back to to test, it is idle speculation. Yet it is not completely idle, bed rest again. Over a period of many months each for if the primary effects of bed rest were to protect the patient would thus go through an alternating cycle of as yet uninvolved lung, it may well be that with isoniazid monthly periods of either bed rest or physical activity. we have a means whereby we can do just that-namely, As confidence was gained, it was no longer insisted protect the uninvolved lung in an ambulatory patient. upon that the first month be spent in bed and, in the Consequently, isoniazid may represent more of a sub- latter part of the study, a number of patients had their stitute for bed rest than we have hitherto considered first month of chemotherapy when they were in the it to be. physical activity phase, with alternating months of bed rest thereafter. Before the of The many guides for following tuberculous infection, introduction tuberculosis chemo- such as the roentgenographic course, the isolation of therapy, there were no acceptable clinical studies on tubercle bacilli from the respiratory secretions, the ery- the advantage of bed rest and the influence of throcyte sedimentation rate, the leukocyte count, C- physical activity on the healing process in pulmonary protein determinations, etc., all showed a generally tuberculosis. Since the introduction of tuberculosis favourable course. In no case was any change noted chemotherapy, however, there have been two ex- when the patient's way of life was changed from one of cellent clinical investigations on the influence of bed rest to one of physical activity. The only possible physical activity on the healing of pulmonary tuber- change was seen with respect to body-weight. In some culosis. The first of these was conducted by Hirsch patients who initially started on the bed rest phase, and his associates at the the favourable trend in weight gain during the first Rockfeller Institute in New month was accelerated during the second month when York and was published in 1957. The second study they went on physical activity. Other than this favour- has been reported only in the past few months and is able trend there was no indication at all that the influence from the Tuberculosis Chemotherapy Centre, of the physical activity could be detected in this setting Madras, India, which is maintained jointly by the in which hospitalized patients were receiving theoreti- Indian Council of Medical Research, the Madras cally adequate chemotherapy. State Government, the Medical Research Council of Great Britain (MRC) and the World Health Or- It is quite clear that this study was not designed to ganization (Tuberculosis Chemotherapy Centre, measure the effects of bed rest on the tuberculous 1959). Both studies show that, in the presence of process itself, but simply to see whether physical theoretically adequate tuberculosis chemotherapy, it activity of the sort that would be occurring in the is impossible to detect any influence of physical home could be found to exert an unfavourable activity on the generally favourable healing process influence on the healing process during chemo- of the tuberculous lesion. The two studies were quite therapy. Obviously there are other differences be- different in respect of specific questions posed and in tween life in hospital and life at home than the the methodology. question of physical activity. The sheer excitement of life in the crowded, urban, lower economic areas In the earlier study, at the Rockefeller Institute, the in which many patients live could conceivably be patients were all maintained in hospital throughout the much more stimulating than the quiet environment study. The patient group consisted entirely of young of the hospital. But the amount of physical activity women with actively progressing, moderately advanced, should have been about the same in the two sets of or far advanced pulmonary tuberculosis for which they circumstances, and in any case it was not possible to had received no chemotherapy. During the course of see that it exerted any influence on the healing the investigation, all patients received intensive tubercu- process. losis chemotherapy consisting in the daily administration of streptomycin and isoniazid and PAS in suitable doses. The Madras study, recently publish-d in the Bulletin All existing laboratory tests for following the course of the World Health Organization, was of different of tuberculous infection were performed in the Institute design in that one group of patients was maintained laboratories. The patients were not divided into groups, in hospital and the other was allowed to live at home. but by the design of the experiment each patient served The chemotherapy for the two groups was the same- as her own control. namely, isoniazid and PAS. In addition, the diet of 430 W. MCDERMOTT both groups was supplemented with small quantities of that almost half of the patients with infectious or powdered milk. The patients in hospital, however, were potentially infectious tuberculosis were not in maintained on a nutritious hospital diet, whereas the hospitals. patients at home subsisted on their normal poor diet. Today, when the necessity for bed rest no longer Despite every possible precaution to ensure that the two groups would be comparable, the luck of the draw obtains, the patient would be kept in hospital solely was such that among the female half of the series, an for isolation purposes and hence would be fully appreciably greater number of more advanced cases ambulatory. Ambulatory patients in a hospital were included in the home group than in the hospital represent very difficult problems in management, group. The male half of the study, though, resulted in particularly when they are essentially asymptomatic, comparable cases in both hospital and home. as would be the case with tuberculosis. Nevertheless, After one year of observation, among the male patients, the question before us is not what is ideal, but what there was no evidence that the effectiveness of therapy is ethically justifiable. was in any way lessened by residence at home. In both At present I believe a distinction can be made on the home and hospital groups there was the same per- centage of substantial roentgenographic improvement, the basis of the nature of the lesion. Certainly, cavity closure, and reversal of infectiousness as deter- patients with highly infectious lesions, such as those mined by the disappearance of culturable tubercle bacilli involved in laryngeal disease or old and previously from the sputum. unsatisfactorily treated cavities, should be kept in From these two studies, in New York and in hospital, if possible, until they are not infectious. In Madras, it is clear that, whatever may have been the the case of the chronic cavitary lesion, however, situation before the development of chemotherapy, there occasionally comes a time when isolation is the there can be no reasonable doubt today that, given sole purpose of the hospitalization and would have theoretically adequate chemotherapy, the tuber- to be maintained for the remainder of the patient's culous patient who does not receive bed rest in a lifetime. Certainly, in such instances, if the patient's hospital is at no disadvantage in terms of his disease permits it, he should be allowed to live at recovery from the disease. home, provided that no extraordinary risk is borne by his immediate household associates. One other study of domiciliary versus hospital What about the household associates of the treatment that deserves mention is the one conducted patient who receives all of his treatment at home? ' by the Tuberculosis Society of Scotland (1958). In the majority of cases with adequate chemotherapy As only patients with tuberculosis in a non-infectious today, reversal of infectiousness occurs within the state were included, this study is admittedly not as first three to six months of therapy. Consequently, conclusive as the Rockefeller Institute and Madras the period during which the household associates are studies. Nevertheless, in this Scottish study, as in at risk is limited in most cases to three to six months. the others, there was no detectable difference in Moreover, throughout this period the risk diminishes course or outcome between a group of domiciled sharply, because long before tubercle bacilli dis- patients who continued to work and a comparable appear completely from the bronchopulmonary group that received the same chemotherapy in secretions, the microbial populations are reduced to hospital. a low level. Moreover, especially with isoniazid, Isolation of infectious cases many of the bacilli are biologically altered in the Thus we are provided with ethical justification for direction of lessened pathogenicity. Consequently, one aspect of a domiciliary programme for patients in the known treated patient, the risks of the house- with previously untreated pulmonary tuberculosis. hold associates, though present, are very consider- What about the other useful purpose served by ably reduced. The exception to this would be hospitalization-namely, the removal of the infec- represented by the patient with cavitary disease who, tious case from the community at large? Obviously, despite continued therapy, continued to discharge this is a different matter. In Utopian terms it large numbers of tubercle bacilli into the environ- would be correct, even with today's chemotherapy, ment. In the far more common situation, in which to isolate every patient until the disease had attained rapid healing is occurring and indeed in either non-infectious status. Even in the most highly situation, the household associates have usually been developed areas of the world, however, this has never fairly thoroughly exposed before the patient's really been done uniformly. For example, the 1 See article by R. H. Andrews et al. on page 463 of this United States Public Health Survey of 1956 revealed issue. ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 431

disease was detected. Naturally, if one is to treat long ago, the disease may relapse to the infectious pulmonary tuberculosis in the home from the state and to all intents and purposes may endure in beginning, it would be irresponsible to do so without this state for a matter of many months, perhaps a at the same time taking measures to protect the year, before the fact is discovered. In short, there is household associates. These measures should be always some risk in having a tuberculous patient adapted to the circumstances, but they should in- in the home, even in the case of patients discharged clude BCG vaccination in uninfected, or presumably after three years of sanatorium care. The risks seem uninfected, contacts, disease prophylaxis in persons little if any greater for the properly protected house- who are already tuberculin reactors, and possibly, hold associates of the patient with disease that is although I do not personally favour it, the use of under proper treatment than for associates of isoniazid as infection prophylaxis for those who are patients discharged from the hospital as having not tuberculin reactors. In any case, provided that arrested disease. some measures are taken to protect the associates, the fact that in the majority of instances the patient's Thus, from the standpoint of isolation too, the own contagiousness is being rapidly reduced by the ethical justification for maintaining a domiciliary chemotherapy creates a situation in which the risk programme seems to have been provided in this of maintaining a patient on therapy at home is really fifteen-year era of chemotherapy. An additional quite low. Indeed, the chances are that this risk is ethical justification exists-and it is one not to be no greater than the risk that the family of a patient discounted-namely, that by the use of domiciliary with an arrested tuberculous lesion constantly therapy it is possible to maintain so many more endures. For, as we all know, in any patient who patients under therapy than would otherwise have has once had infectious tuberculosis, no matter how been the case.

CHOICE OF CHEMOTHERAPY FOR PREVIOUSLY UNTREATED PATIENTS

In terms of the initial tuberculosis chemotherapy of drug dosage are considered in detail in a sub- of either the hospitalized or the home-living patient, sequent section. Unless otherwise specified, a daily there are really only four regimens for our considera- isoniazid dosage of 6-8 mg per kg of body-weight tion. These are: isoniazid and streptomycin daily, and a daily PAS dosage of 10-12 g per adult patient isoniazid and p-aminosalicylic acid (PAS) daily, and are taken as the basis of the discussion in this section. isoniazid alone or isoniazid and streptomycin, with It is possible to rank these four drug regimens the latter administered two or three times weekly. crudely on a relative basis and the evidence is clear There is one other regimen, pyrazinamide-isoniazid, that, of these four regimens, isoniazid and daily which probably represents more effective therapy streptomycin represent the most effective therapy per than any of the above. Unfortunately, however, unit of time. Closely behind it in degree of effec- pyrazinamide has far too great a toxicity for wide- tiveness is isoniazid-PAS. Whether isoniazid with spread general usage. All other existing therapies twice or thrice weekly streptomycin is superior to are both less effective and too toxic for general usage. isoniazid alone is highly debatable. The chances are All will agree that when the circumstances are great that these two regimens are approximately favourable, a multiple-drug regimen is distinctly equivalent and occupy a place below, but not too far preferable. Triple-drug regimens have little place, below, isoniazid-PAS. Without question, with any as judged both on theoretical grounds and from ex- of these regimens it is the isoniazid that provides the perience in actual trials (Mount & Ferebee, 1954), major antituberculous action. What is really being two-drug regimens being almost invariably prefer- ranked here, therefore, is the relative effectiveness of able. There is little disagreement concerning the daily streptomycin, daily PAS, and non-daily usefulness of isoniazid alone in certain restricted streptomycin as companion drugs for isoniazid. situations, such as in chemoprophylaxis. Whether Let us consider the available evidence for the the use of isoniazid alone can be extended beyond its above statements, the first of which has to do with use in chemoprophylaxis is considered a debatable the superiority ofisoniazid-streptomycin to isoniazid- matter and is discussed separately below. Questions PAS when all drugs are given daily. 432 W. MCDERMOTT

ISONIAZID AND DAILY STREPTOMYCIN VERSUS (Crofton, 1958) and Middlebrook and his associates ISONIAZID-PAS in Denver, Colo., USA (Russell et al., 1959). Both Unfortunately, it is not possible to present as clear- groups have treated patients with pulmonary tuber- cut an answer as one might like on the question of culosis with isoniazid and streptomycin. In the isoniazid-streptomycin versus isoniazid-PAS, be- Edinburgh series the isoniazid dosage was only cause the large-scale control studies on this point 200 mg per day. In the Denver series the isoniazid have not been conducted in comparable fashion. The dosage was even higher than that generally used in three groups that have carried out most of the large- the USA, ranging from 7 to 10 mg per kg per day. scale trials on the comparative effectiveness of Among the 80 Edinburgh and 153 Denver patients various regimens have been the United States Public treated with isoniazid-streptomycin not one patient Health Service (USPHS), the United States Veterans has so far been encountered who continued to Administration-Armed Forces Group, and the discharge tubercle bacilli in the sputum despite the Medical Research Council of Great Britain, operat- therapy.' This is certainly an impressive record. It ing both alone and in association with the Indian is not likely that this regimen will invariably meet Council of Medical Research at the Tuberculosis with such success, for both series are comparatively Chemotherapy Centre,. Madras. The British in- small. Nevertheless, the results are sufficiently vestigators, who have tended to use streptomycin impressive to constitute additional support for the daily, have at the same time used relatively low doses ranking of daily streptomycin over PAS as a com- of isoniazid, i.e., around 200 mg per patient per day. panion drug for isoniazid. Contrariwise, the United States investigators have Thus, if the initial treatment is to be in hospital, used larger doses of isoniazid, but have tended to the most effective therapy per unit of time would be give the streptomycin only twice or thrice weekly. isoniazid-streptomycin, with both drugs admi- Nevertheless, there is now a fair body of evidence in nistered daily. The difficulty with this particular support of the statement that isoniazid-streptomycin regimen is the fact that streptomycin must be given is superior. First, in the laboratory it can be shown by intramuscular administration. In practice, this in an animal model that permits evaluation of two- tends to limit isoniazid-streptomycin therapy to drug therapy that when streptomycin and isoniazid in-patients. The administration of streptomycin are administered daily together, the reduction in the twice or thrice weekly over a period of many months population of tubercle bacilli is slightly, but definite- can sometimes be managed on an out-patient basis, ly, better than when isoniazid is used alone (McCune but the administration of streptomycin daily on an & Tompsett, 1956). Secondly, there is some evidence out-patient basis is only rarely practicable. In several on the point from the large-scale clinical trials. The clinics around the world patients are instructed in the USPHS group have conducted no investigation into technique of intramuscular administration of strep- this particular question of the use of daily strepto- tomycin, just as diabetics are taught to administer mycin with isoniazid, and in the Veterans Admi- insulin themselves. It does not seem likely, however, nistration-Armed Forces trials (Tucker, 1955a, that such an educational procedure would have a 1955b, 1958; Tucker & Livings, 1955) the evidence very widespread application. Moreover, unlike the that daily streptomycin was superior to the twice or situation with diabetes, effective therapies that do thrice weekly streptomycin in association with not involve parenteral administration are available. isoniazid was not particularly striking (in these trials As it stands therefore, the most effective therapy per the daily isoniazid dosage was 300400 mg). In the unit of time-namely, daily streptomycin and MRC trials (Great Britain, Medical Research isoniazid-means hospitalization of the patient Council, 1955), when used as a companion drug for throughout the period of therapy. isoniazid, streptomycin was more effective when ad- ministered daily than when administered less ISONIAZID-PAS frequently. In these trials, however, the isoniazid dosage was low (200 mg daily), which might tend to What is the situation with respect to isoniazid- magnify the effectiveness of the companion drug. PAS, a therapy that can be easily administered out- More impressive evidence of the superiority of side the hospital? From the available evidence, this isoniazid-streptomycin comes from the studies of regimen appears almost as effective as daily strepto- two individual groups of investigators-Crofton and his associates at the University of Edinburgh I Surgery was also used. ANTIMCROBIAL THERAPY OF PULMONARY TUBERCULOSIS 433 mycin and isoniazid. Here again, there is the diffi- are virtually non-existent and to streptomycin are culty that in the British studies the isoniazid dosage relatively rare. is low and in the United States studies there are very What the situation amounts to is that, for the few groups with daily streptomycin with which to majority of people-namely, those who can take make comparisons. From the United States Veterans PAS in sufficiently large doses-PAS with isoniazid Administration-Armed Forces studies, however, it represents the most satisfactory all-purpose form of was found that isoniazid-PAS compared very multiple-drug therapy. For those who are unable to favourably with daily streptomycin-isoniazid' tolerate the PAS, either owing to the " minor " (Tucker, 1955a, 1955b, 1958; Tucker& Livings, 1955). gastric intolerance or to more serious toxic mani- In the MRC studies, in which the isoniazid dosage festations, the choice has to be made between iso- was low and, in one subgroup, the PAS dosage was niazid and streptomycin twice weekly or isoniazid considerably higher than that used in the USA, alone. If any other therapy is to be substituted isoniazid-PAS was slightly less effective than daily (including isoniazid and daily streptomycin), it is streptomycin-isoniazid at the three months' point, necessary to admit the patient to hospital and keep but reversal of infectiousness was approximately him there until the substituted chemotherapy has 75 % with both regimens. been completed. In terms of the widespread usefulness, however, isoniazid-PAS represents the multiple-drug therapy PAS dosage of choice and its effectiveness is so closely similar to It is possible that very large doses of PAS may not that of isoniazid and daily streptomycin that the be necessary if the dose of isoniazid is sufficiently margin of difference is probably of little consequence. large. In the British studies, for example, with The difficulty with the isoniazid-PAS regimen lies in streptomycin and PAS, it was found that it was the toxicity of the PAS. necessary to take 20 g of PAS to get full effectiveness with this particular pair of drugs. In the USA, PAS toxicity the 20-g dosage has never been employed on any Of the three antituberculous drugs in widespread considerable scale and, in general, 9-12 g is the use, PAS has the greatest toxicity. The most com- recommended dosage. In practice, it is probable mon toxic symptom-gastro-intestinal intolerance- that many patients in the USA take considerably less is not in itself potentially dangerous, but the gastritis than the recommended dosage, perhaps consuming and looseness of the stools caused by PAS do exert about 5 or 6 g daily. With the isoniazid dosages an important influence in that they repel the patient employed in the USA, however, the 5-6 g daily from his therapy. As a consequence, in domiciliary dosage of PAS may be sufficient. In a subsequent programmes in which the patient supervises his own MRC study with isoniazid-PAS it appeared that treatment, it is a commonplace experience to find the 10 g of PAS daily were as effective as 20 g. patients apparently taking their isoniazid, as judged by their request for further supplies, whereas the PAS ISONLAZID ALONE VERSUS ISONIAZID AND TWICE- is sadly neglected. Consequently, if multiple-drug WEEKLY STREPTOMYCIN therapy is desired at all costs, it is necessary to The third and fourth regimens available to the administer the PAS along with the isoniazid in the patient, therefore, consist of isoniazid-streptomycin, same preparation, as is done with the cachets used with the latter given two to three times weekly, and in the Madras study. It is not wholly appreciated, isoniazid alone. There has been only one large-scale however, that gastro-intestinal intolerance is not study in which these two regimens were compared, the only form of PAS toxicity. In fact, more instances that conducted by the USPHS (Mount & Ferebee, of serious toxicity probably occur with PAS than 1953a, 1953b; Mount, Jenkins & Ferebee, 1953). with either streptomycin or isoniazid. Certain of After nine months of therapy, substantial roent- these other toxic manifestations-notably, the genographic improvement was observed in 59% of hypersensitivity phenomenon with the syndrome of the group on isoniazid-streptomycin, compared with infectious mononucleosis-may be quite disquieting 50.6% for the group on isoniazid alone, and 50.4% and, indeed, a few fatalities have occurred. By for the group on streptomycin-PAS. Some 583 contrast, hypersensitivity phenomena to isoniazid patients were included in the study and were approxi- mately equally distributed among the three regimens. 1 In fact, the two regimens gave identical results, except in cases with large cavities, i.e., 4 cm or greater. The reversal of infectiousness was likewise superior

2 434 W. MCDERMOTT on the isoniazid-streptomycin regimen. From this arose because experience with streptomycin so group at the 40-week observation point, tubercle conditioned thinking that laboratory findings, bacilli could be cultured from 16%, in contrast to which with isoniazid are of extremely varied signifi- 32% of those who received streptomycin-PAS and cance, were allowed to dominate decisions to the 29% of those treated with isoniazid alone. The virtual exclusion of what was actually happening frequency of roentgenographic worsening at the in the patients. As a result a climate of opinion nine-month point (40 weeks) was 4.3 % on isoniazid- was rapidly created that has made it impossible streptomycin, 7.7% on isoniazid alone, and 6.8% for almost a decade to study this question, which on streptomycin-PAS. is the one with the greatest practical significance. In this carefully conducted study, which is the Partial studies of the question have been carried only study that has been made of the subject, out-for example, the nine months' study of isoniazid with twice-weekly streptomycin showed a isoniazid alone conducted by the USPHS in 1952- 13 % greater effectiveness than isoniazid alone in 1953 and the recent United States Veterans Admi- the reversal of infectiousness and a 9 % greater nistration-Armed Forces study of isoniazid alone effectiveness in roentgenographic improvement. The versus isoniazid-PAS. The only reason why the latter difference, although definite, is not great in latter study has to be considered only partial is view of the 5 % differences seen in these studies that the patients included were limited to those among patients on virtually identical regimens. with moderately advanced non-cavitary pulmonary Thus it appears that isoniazid with non-daily disease. In all cases, however, tubercle bacilli streptomycin is slightly more effective than iso- could be cultured from the sputum. At the time of niazid alone, but the margin is small. Moreover, writing, therefore, the USPHS study is the only there are good theoretical reasons (discussed later) reasonably long-term study of the use of isoniazid for believing that to administer a companion drug alone and the Veterans Administration-Armed intermittently may be to throw away most, if not Forces study is absolutely the only study of isoniazid all, of the advantages of two-drug therapy. When alone versus isoniazid-PAS in concurrently treated these points are considered against the background patients. Present evaluation of this question, there- of the additional efforts involved in administering fore, must be based on: these two studies; studies the streptomycin intramuscularly, the procedure by a few individual investigators on the use of iso- hardly seems worth while. Consequently, if it is niazid alone (Clark et al., 1952; Deuschle et al., not possible to administer streptomycin daily as a 1954; Vargas-Jimenez, 1956; Jordahl et al., 1958); companion drug for isoniazid and it is not possible and studies in laboratory animals. In the past to use PAS, there is probably little benefit to be few years, however, a concurrent comparative derived from twice-weekly streptomycin and one study of isoniazid alone and isoniazid-PAS in might as well simply administer isoniazid alone. pulmonary tuberculosis, including cavitary cases, has been set up as part of the carefully conducted research programme of the Tuberculosis Chemo- ISONIAZID-PAS VERSUS ISONIAZID ALONE therapy Centre, Madras. The results of this study For all practical purposes, the choice of therapy should settle the question.' It is believed that the for a tuberculous patient outside the hospital comes general outcome of the Madras study is predictable, to a decision between isoniazid-PAS and isoniazid however, from evaluation of the available material alone. The question of the margin of difference cited above. The following predictions only concern between isoniazid and isoniazid-PAS is thus the the Madras patients who received 300 mg or more most important question of all in the chemotherapy of isoniazid daily, as the studies by the USPHS, by of tuberculosis today. Nevertheless, it is sad to the Veterans Administration-Armed Forces and report that this most important question has never by our own group at Cornell University Medical been satisfactorily studied in terms of a large-scale College, New York, have all used that dosage comparison of the two regimens in two randomly without accompanying pyridoxine. selected comparable groups of patients treated I At the time of writing, the report from the Tuberculosis concurrently. This is the case despite all the elabo- Chemotherapy Centre which appears on page 535 of this rately organized large-scale trials conducted in issue was not available to the author, nor was the report various parts of the world the various of a similar study which has just been carried out in East by groups Africa (East African/British Medical Research Council involved in such studies. In my opinion, this situation Isoniazid Investigation, 1960). - ED. ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 435

In the isoniazid-PAS and the isoniazid-alone groups of 47 patients or one-third of the group followed for the on that dosage in the Madras study, the incidence of whole year. It should be noted that 22 of the 47 patients substantial roentgenographic improvement will be had received streptomycin prior to the start of the iso- approximately the same and will range between 55% niazid therapy and in 13 cases the streptcmy_in had and 60% after one year of treatment. been abandoned as unsatisfactory therapy more than The incidence ofcavity closure will likewise be approxi- three months before the start of isoniazid. mately the same in both the isoniazid-PAS and the In the second study (Jordahl et al., 1958), 32 pre- isoniazid-alone groups and will occur in about 50% of viously untreated patients with moderately advanced the patients with cavities at the start of treatment. and advanced pulmonary tuberculosis were treated with Reversal of infectiousness (assessed by culture) will osoniazid alone for the one-year period. In two-third be higher in the isoniazid-PAS than in the isoniazid- if this group the therapeutic objectives were obtaineds alone group by about 10-20%, probably by about 15%. without the need of additional medical or surgical Strains of tubercle bacilli resistant in vitro to isoniazid therapy. Reversal of infectiousness occurred in 23 of concentrations of 1,ug per ml will be isolated from some the 29 patients who had had tubercle bacilli in the sputum patients in both groups. Such isoniazid-resistant strains when treatment was started. Cavity closure occurred will be found in the majority, but not in all, of those in 19 of the 30 patients with cavitation at the start of members of each group who are discharging tubercle therapy. These results in the second series were distinctly bacilli one year after the start of therapy. more successful than those observed in the first series, and presumably reflect the less favourable type of Let us review the evidence that forms the basis disease that had to be treated in the first series. for these predictions. At the 40-week observation Of the 11 cases in which additional therapy was insti- point in the USPHS study of isoniazid alone, tuted, there were six which were not treatment failures substantial roentgenographic improvement had in the usual sense. In four of these patients, a considerable occurred in 50.6% and tubercle bacilli could be degree of improvement had been observed before sur- cultured from 29% of the patients. The Cornell gical treatment was recommended. In these six patients studies consist of one-year observations of two excellent results were obtained from excisional therapy. small groups, totalling 79 consecutively treated Additional drugs were used during the surgical period, but only because of the routine local practice at the patients (Deuschle et al., 1954; Jordahl et al., 1958). hospital where the surgery was performed. Of the In the first study, an isoniazid dosage of approxi- remaining five patients, two did well on additional mately 300 mg daily was used (5 mg per kg); in the chemotherapy and in three the final result was not second study, a dosage of 10 mg per kg was used satisfactory. during the initial three weeks, followed by 5 mg per Of the two instances of roentgenographic progression kg daily thereafter. listed, one merely represented an increase in density without an increase in the size of the diseased area or In the first study (Deuschle et al., 1954), 47 patients in the extent of cavitation. Surgery was performed at with pulmonary tuberculosis moderately advanced or an early date in this patient, principally because of the far advanced in extent, were started on isoniazid therapy possible presence of a complicating bronchogenic car- with the expectation that it would be continued for at cinoma. The other patient is the only one of the entire least one year. Any patient whose therapy was altered group in whom an unequivocal spread of disease took in any way during the year, either by a change in drugs place while she was receiving isoniazid therapy. It or by the use of collapse or excisional therapy, was should be emphasized, however, that this apparently eliminated from the study at that time. Thirty-two of new area of disease cleared entirely without change in the 47 patients completed one year of such therapy and the single-drug isoniazid therapy. another three presumably could have remained in that group were it not for the fact that on transfer to other hos- pitals their chemotherapy was changed in conformance The only other reported study in which isoniazid with local practice. At some time during the year, 29 alone has been employed for nine months or more of the 47 patients were classified as having shown sub- is the one reported by Vargas-Jimenez (1956) from stantial roentgenographic improvement and six were South America. In this study of 40 patients with classified as having shown roentgenographic worsening. pulmonary tuberculosis he found substantial roent- In no instance did the roentgenographic worsening re- genographic improvement in 70% and reversal of present a major spread of the disease. Cavity closure (all cavities per patient) occurred in 15 of the 44 patients infectiousness in 77% at one year. All of these with cavitary disease and occurred without the employ- patients had moderately advanced or far advanced ment of collapse or excisional therapy. At the end of disease and none had received previous antimicrobial the therapeutic year, tubercle bacilli could be cultured therapy. In contrast to the Cornell studies, which from approximately one-fourth of the original group were conducted on hospitalized patients, the studies 436 W. MCDERMO1T in South America were conducted almost exclusively emerge in patients despite the fact that they are on ambulatory patients. receiving isoniazid-PAS. Thus the question is not Taking all these studies together, therefore, it is whether isoniazid-resistant tubercle bacilli can be clear that in the treatment of unselected moderately cultured from patients treated with isoniazid alone, advanced or far advanced pulmonary tuberculosis but how much more frequently they are met with with isoniazid alone in a daily dosage of 300 mg in such patients than in patients receiving PAS as or more, one can expect a reversal of infectiousness well. For in both groups of patients, isoniazid- in approximately 57% of the cases, substantial resistant tubercle bacilli can be isolated. roentgenographic improvement in at least 50-60% As indicated earlier, the limitation of this compa- and cavity closure of all cavities in a little more than rison of isoniazid and isoniazid-PAS lies in the fact half without any additional therapy. The question that cavitary disease was not included. For it is in then arises as to how satisfactory these results are cavitary disease, particularly in cavities with a in comparison with what might have been obtained diameter of more than 2 cm, that the companion had isoniazid-PAS been used. This brings us to drug, in this case PAS, is most needed. There is the above-mentioned study of randomly selected every reason to believe that, in cavitary disease, and concurrently treated groups by the United the reversal of infectiousness with isoniazid-PAS States Veterans Administration-Armed Forces, would be substantially greater- 10-20%-than with recently reported by Phillips (1959). isoniazid alone. The results reported by Phillips In that study of isoniazid alone versus isoniazid- (1959) are of very considerable importance, however, PAS, only patients who were discharging tubercle not only for their comparative value, but bezause bacilli were included, but the cases were limited to they afford ethical justification for the use ofisoniazid instances of minimal or moderately advanced alone in patients whose cavities have closed on disease with no demonstrable cavitary component. multiple-drug therapy. By chance selection, two groups were formed that This raises the important question of how much appeared to be comparable in all important parti- antimicrobial action is necessary once the initial culars. Approximately 80 patients were included in maximal effects have been produced. It has been each group.' The dosages of isoniazid and PAS suggested (Muschenheim et al., 1954) that it is are those in standard use in the USA as described probable that the major part of what can be accom- above. plished in terms of incapacitating tubercle bacilli is At the five to eight months' observation point actually accomplished within the initial weeks of there was no difference between the two groups therapy and that the chief useful purpose served in terms of either roentgenographic improvement or by therapy thereafter is to ensure the continued reversal of infectiousness. Cavity closure was not " physiologic imprisonment " of surviving micro- ta issue, since no patients with demonstrable organisms-i.e., to prevent reactivation of the healing cavities were included. The disappearance of disease. If this concept is true, the advantages of tubercle bacilli from the sputum occurred in appro- isoniazid-streptomycin and isoniazid-PAS over iso- ximately 80% of both groups and substantial niazid alone might be considerably different in the roentgenographic improvement occurred on 55%. early and in the late phases of therapy. Thus, the The results of the drug-susceptibility studies are ideal therapy would be to treat all patients initially of particular interest. At the four-month observation with isoniazid-streptomycin (daily) and those in point, there were only three patients who were whom cavity closure and reversal of infectiousness excreting drug-resistant organisms; two of these had occurred could be treated with isoniazid alone patients were from the isoniazid-PAS group and thereafter. one was from the isoniazid-alone group. At the The situation with respect to isoniazid-PAS versus five to eight months' observation point there were isoniazid alone was well summarized three years also three patients excreting drug-resistant bacilli ago in the following statement by the WHO Study and on this occasion two were from the isoniazid- Group on Chemotherapy and Chemoprophylaxis alone group and one from the isoniazid-PAS group. in Tuberculosis Control (1957): This emphasizes a point all too often ignored- namely, that isoniazid-resistant tubercle bacilli will " 7. The preferable regimen would consist of daily administration of both INH and a companion drug. 1 At the time of writing, there are more than 150 patients In ambulatory and domiciliary patients it is advisable in each group and the findings are unchanged. to use PAS as the companion drug. ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 437

8. If a local situation exists in which it is not practicable a considerable restriction of the programme, as to use the above drug regimen, the use of INH alone is mentioned above in the report of the WHO Study justifiable (see Annex). The Study Group agrees that Group; on present knowledge its use cannot be recommended with the same assurance as the use of INH-PAS. Never- (b) in patients with cavitary pulmonary tuber- theless, if a local situation exists in which the alternatives culosis in whom the prospect of cavitary closure faced by the public health administrators are the institu- on chemotherapy appears good, but who are tion of a programme with INH alone or no programme unable to take PAS and for whom daily strepto- at all - or one drastically smaller in scope - the Study mycin is not a feasible alternative. Group agrees that a programme with INH alone would constitute an acceptable practice today and until definite When the patient with moderately advanced or far further evidence to the contrary should be forthcoming." advanced pulmonary tuberculosis is treated on any one of the four regimens outlined above, the course From all of the above information, therefore, it of the disease follows one of the following three can be concluded that in the use of isoniazid alone patterns: in a total daily dosage of 300-500 mg in an adult, the clinician has a regimen inferior to isoniazid- 1. There is a considerable regression of the pul- PAS in terms of reversal of infectiousness, but monary infiltration, closure of the cavities, and generally very little inferior to isoniazid-streptomycin attainment of the non-infectious state. This ob- when the latter drug is not given daily. What then viously occurs in the majority of the cases treated. would seem to be the reasonable indications for the 2. There is a considerable regression of the in- use of isoniazid alone today? It seems to me that filtration, failure to close the cavity, but attainment the indications would be the following: of the non-infectious state nevertheless. This 1. As initial treatment in disease prophylaxis, the happens in perhaps 15-20% of the cases treated and prophylaxis of the person who is a tuberculin reactor is the so-called " open negative " syndrome. but has no other evidence of tuberculous disease. 3. There is a greater or lesser regression of the 2. As the initial treatment in non-cavitary pulmo- infiltration, but no impressive reduction in cavity size nary tuberculosis. and the discharge of tubercle bacilli in the sputum 3. As the follow-up treatment once reversal of continues. This happens in about 15% of the cases infectiousness and cavity closure have been obtained treated-i.e., approximately as frequently as the in cavitary pulmonary disease. open-negative syndrome. 4. As the initial treatment in cavitary pulmonary The management of the last two patterns, both uberculosis only in certain circumstances, such as: with persistent cavities, is considerably different. It (a) in village programmes and areas of high pre- is the third pattern-persistent cavitation with valence in which the additional expense and persistent infectiousness-that represents chemo- problems created by the use of PAS would mean therapeutic failure and will be discussed at this point.

MANAGEMENT OF PATIENTS WITH AN UNSATISFACTORY RESULT FROM PREVIOUS CHEMOTHERAPY

In addition to the persistent cavitation and the There is some tendency to take an oversimplified presence of tubercle bacilli in the sputum, the strains view of what is happening in such a case and to isolated from these patients are usually resistant in regard it merely as a case in which, for unknown vitro to one or more of the drugs previously received. reasons (for the failure to use " the proper drugs "), In my opinion, this finding should weigh less in the drug-resistant strains of bacilli have emerged and are decisions as to the management than the facts of the the cause of the persistent cavitation and the thera- history of the previous treatment and the amount peutic failure. Obviously to some extent this is true, and type of disease present at this point, which is but such a view of the probable events is so grossly usually some time in the second half of the first year oversimplified as to be dangerous in terms of appre- of chemotherapy. ciation of the proper management of the situation. 438 W. MCDERMOTT

For, in view of the many factors involved in a chronic failure. The mere finding in the former case of a destructive disease such as cavitary tuberculosis, it is few bacilli that are drug-resistant in vitro does not extremely unlikely that failure of cavitary closure is render collapse or excisional therapy highly desirable merely a simple matter of failure of the drug- or a change in chemotherapy imperative, as is the microbe relationship. In other words, factors case in the clearly recognized therapeutic failure. presumably exist that may determine whether or not For the above reasons, the management of the a particular cavity closes that have nothing to do with patient who has received considerable chemotherapy, the drug-microbe reaction. And an unhealed cavity yet whose disease still continues to be active, is a subjected to continuous antimicrobial therapy problem that ideally should be handled in hospital. sooner or later inevitably leads to a situation in Certainly the most effective way of dealing with which drug-resistant microbes emerge. Indeed, the the situation is to institute collapse or excisional caseous material lining the cavity wall and in direct therapy right away. If possible, therefore, the first access to the atmosphere represents the finest step to be taken in the therapeutic failure case is to possible medium for the proliferation of bacilli and make arrangements for collapse or excision of the for the emergence of the drug-resistant strain. In principal lesions. A change in chemotherapy is also such a situation, therefore, the cavity itself becomes called for and if, for one reason or another, collapse a cause of the drug-resistance, so there is really a or excisional therapy is not possible, must in any vicious circle as to causation. This fact has impor- case be made. tant therapeutic implications, because it means that The first decision that has to be taken is whether whatever factors were present that caused the lesion to continue the isoniazid that the patient has almost to fall into the 15% failure group with standard certainly been receiving in the past. The scientific chemotherapy are still operative and may continue to evidence on this point is scanty and is somewhat represent formidable impediments to thefull effective- conflicting. It has been shown by McCune and ness of any other chemotherapy. This represents Tompsett (unpublished -observations, 1954) that, one side of the therapeutic coin. in laboratory animals, certain strains of tubercle Representing the other side of the coin are four bacilli that are isoniazid-resistant seem to attain drugs that are now available for such cases-cyclo- slightly higher populations in animals that are serine, pyrazinamide, a-ethyl-thioamide, and vio- receiving isoniazid than in those that are not. mycin. These are all drugs that in general can McCune, Dineen & Batten (1956) also noted, with a be administered for only relatively short periods, variety of other drugs and infections other than e.g., 3-4 months, owing to their toxicity. From the those with tubercle bacilli, a phenomenon whereby therapeutic standpoint, therefore, the clinician is when two drugs are given together in an infection attempting to achieve in about 3-4 months with new caused by a strain resistant to one, the second drugs a result that it was not possible to obtain with drug, in its initial stages at least, does not seem drugs that could be administered for much longer to be so effective as when it is given alone. In periods. short, there are reactions taking place within the It is because of these two factors (the particular microbial cell that interfere with the full effectiveness tissue changes present and the limitations on the use of the drug to which the microbe is demonstrably of the drugs now available) that it is so very impor- susceptible. These are fascinating phenomena, but tant in such cases to obliterate or remove the cavity it would be dangerous to make too much of them by collapse or excisional therapy. To some extent, in terms of the situation with the patient. For therefore, this is a " now or never " proposition and there are other observations that point in quite it must be recognized in its full dimensions in proper the opposite direction with respect to the wisdom of time. Moreover, in so recognizing therapeutic continuing the isoniazid. The first is the fact that failure it is important not to confuse it with the most drug-resistant organisms contain some drug- second pattern-that of a persistent cavity with a susceptible cells. The continued administration of healing tendency as evidenced by the disappearance isoniazid therefore might work at that " protective of tubercle bacilli from the sputum. A very great level" for the as yet uninvolved lung mentioned difference exists between the situation of the patient previously. Secondly, it is quite clear that isoniazid- whose last remaining important lesion is a cavity resistant tubercle bacilli differ in their biological from which only a few bacilli are obtained and that properties from isoniazid-susceptible strains and that of the patient whose case represents a therapeutic these differences in the drug-resistant strains show a ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 439 variety of patterns. One of these patterns, but not the effective agents against tubercle bacilli when used only one, is a diminished pathogenicity for various alone, none of them can, as a rule, be administered animal species, including rhesus monkeys, as shown effectively for more than about three or four months. by Schmidt (1956). The continued administration of Consequently, they must be used as part of a two- isoniazid might tend to favour the continued pre- drug regimen with a companion drug to which, sence of these drug-resistant, but essentially non- from the history of the treatment and the drug- pathogenic, tubercle bacilli. Finally in this con- susceptibility tests, it is reasonable to assume the nexion, there is the more direct observation that has patient's infection would be susceptible. Most of just been reported by Dr Emmanuel Wolinsky from the clinical experience with these three drugs thus Western Reserve University in Cleveland, Ohio. far has been with either streptomycin or isoniazid Dr Wolinsky studied a group of 30 patients with as the companion drug. This is unfortunate, be- the therapeutic failure syndrome outlined above. cause the situation in which these drugs have their He divided the group into two equal subgroups: in greatest potential usefulness is in the treatment of one of the subgroups, isoniazid administration was disease that failed to respond satisfactorily to iso- continued; in the other subgroup it was not. In niazid and probably also to streptomycin. If strepto- both groups the strains of tubercle bacilli isolated mycin has not yet been given and the therapeutic from the patients were highly resistant to isoniazid failure has occurred solely on isoniazid-PAS, then in vitro. In this particular experiment, the continued the situation from the standpoint of therapy with administration of isoniazid appeared to protect the one of the newer drugs is considerably more hope- patients despite the fact that the strains of tubercle ful. This aspect of the subject will be discussed bacilli were highly resistant to the isoniazid in vitro. below in connexion with the recent USPHS studies Although the isoniazid appeared to protect them and of pyrazinamide and streptomycin. hold the infection in check, there was no evidence The clinician is usually faced with the situation, that any more positive therapeutic benefits were however, in which two of these three drugs must being obtained in that there was no very striking be given together, although knowledge as to which improvement in the status of these incompletely combination would serve best is simply non-existent. healed tuberculous lesions. We must begin, therefore, by considering the advan- From these observations, therefore, especially the tages and disavantages of the drugs as individual studies of Wolinsky which were presented at the compounds. May 1960 annual meeting of the American Trudeau Cycloserine appears to be a highly effective drug Society in Los Angeles, Calif., it seems wise to when used as a companion drug with isoniazid. continue to administer isoniazid in the patient with In general, cycloserine does not appear to be espe- persistently active cavitary disease, despite the fact cially active in vitro. This probably reflects our that the tubercle bacilli cultured therefrom are inability to create in vitro the set of circumstances highly resistant to isoniazid in vitro. In addition to in which the drug operates within the tuberculous continuing the isoniazid, however, it is essential, lesion. In any case, as a companion drug to isonia- irrespective of whether surgery is to be carried out, zid, cycloserine administered in two doses each to administer drugs which have a greater prospect of day of 250 mg or a total daily dose of 0.5 g appears operating effectively against the infection. Where sur- to be as effective a companion drug as streptomycin gery is not possible, such drugs must be used in an at- administered daily, or a-ethyl-thioamide and per- tempt to attain disease arrest by chemotherapy alone. haps pyrazinamide. As mentioned earlier, four drugs-cycloserine, The only difficulty with cycloserine lies in its pyrazinamide, a-ethyl-thioamide, and viomycin are toxicity, which is of a potentially serious sort because available for use in such a situation. Viomycin is it leads to epileptiform seizures. From all the probably less valuable than the other three, but experience thus far, this neurotoxicity does not does have usefulness in highly specialized circum- occur when the drug is carefully administered in stances. The other three drugs are all administered individual doses of 250 mg twice each day. The by mouth, and from this standpoint would be neurotoxicity will occur, however, if the same suitable for non-hospital administration, but their total daily dose of 0.5 g is given all at the same time toxicity is such as virtually to exclude them for or if the individual doses of 250 mg are given more non-hospital administration, especially on any often than twice a day. It may be seen, therefore, widespread basis. Although all three drugs are that the margin of safety with respect to the neuro- 440 W. MCDERMOTT toxicity of cycloserine is uncomfortably small. tolerated by approximately 60% of the patients. The safety margin is certainly sufficient so that it In the other 40%, however, gastro-intestinal into- is a perfectly proper procedure to administer the lerance of some sort was present and in 30% of all drug in a hospital, where if a seizure should occur, of the patients this intolerance was severe. Indeed, proper therapeutic steps could be taken to relieve Brouet states that although the patients were well the patient. If the drug were to be used on a self- aware that their situation was not favourable from administered basis at home, however, there definitely a therapeutic standpoint, it was only with the great- would be instances with the larger doses, and per- est of difficulty that they could be persuaded to haps also with the recommended doses, in which take the drug regularly for a period of ninety days. an epileptiform seizure might occur and might In 10% of the patients it was not possible to do so, progress to fatal status epilepticus before proper and the drug had to be discontinued. help could be summoned. For this reason, the use- There was less definite evidence of another type fulness of cycloserine is at present largely limited of toxicity-namely, a cumulative effect with iso- to hospital situations. It is possible that with greater niazid in the production of peripheral neuritis. experience with the recommended dosage the neuro- The findings on this point, though not definite, toxicity might prove either to be minimal or not would make it essential, ifisoniazid is to be continued to occur at all. Ifthis should prove to be the case, then as recommended above, for a more careful watch cycloserine would rapidlyjoin isoniazid, streptomycin to be kept for the development of peripheral neuritis and PAS as a major antituberculous drug, for it has than would otherwise be necessary. no other important disadvantages. It has been Attempts have been made to reduce the gastric stated that pyridoxide prevents the neurotoxicity toxicity of a-ethyl-thioamide by the use of enteric of cycloserine, but it is not known whether this is coated tablets or by administering the drug as a accomplished at the expense of its antituberculous rectal suppository. While it is true that the frequency effectiveness. of drug-induced nausea and vomiting has been The compound a-ethyl-thioamide is the newest reduced by these means, there is good reason to derivative of a series that has been studied in animals believe that this is accomplished by interfering with and man for the past five or six years. The other the absorption ofthe drug and hence is self-defeating. derivatives of the series have all shown themselves In terms of the type of therapeutic situation highly effective in animals, but have been poorly under discussion, therefore the use of a-ethyl- tolerated by man because of serious nausea and thioamide alone with, say, cycloserine might be vomiting. The a-ethyl derivative was shown by quite an effective short-term therapy in those pa- Rist, Grumbach & Libermann (1959) in animals to tients (Brouet estimates 60%) who are able to have greater effectiveness than its predecessors. tolerate the drug. Consequently, it is certainly Clinical trials with this substance were first conducted worthy of a trial in such situations. by Brouet and his associates (1959) in France and Pyrazinamide is another drug whose effectiveness have subsequently been carried out by other groups is limited when used alone, but is a drug of great in Great Britain, Canada and the USA. The investi- effectiveness in association with isoniazid or strep- gation by Brouet was most extensive, involving over tomycin. It is probable that the pyrazinamide- 100 patients. In a group treated with the drug alone, containing regimens are the most effective of all an appreciable degree of antituberculous effective- and the drug causes no gastro-intestinal reactions ness was observed, but it was limited in time to several (McDermott et al., 1954). Unfortunately, however, months by the emergence ofdrug-resistant infections. the one form of toxicity associated with pyrazina- Consequently, most of the experience was acquired mide-hepatitis-has serious potentialities. Hepa- with the use ofthe a-ethyl-thioamide as a companion titis with jaundice occurs in about 3% of patients drug to isoniazid. From a therapeutic standpoint, treated with pyrazinamide. As with any form of as a companion to isoniazid, the a-ethyl-thioamide hepatitis there is a great variation in the severity appeared quite satisfactory. In general, the results of individual cases. As a consequence, the clinically were as good as those seen with PAS, streptomycin, inexperienced physician who has seen only a few or cycloserine. mild cases finds it difficult to appreciate the full The difficulty with a-ethyl-thioamide also lies in potential of this reaction and in a number of cases, its toxicity, notably, its production of nausea and perhaps 1 % of those treated with the drug, the vomiting. In the Brouet series the drug was well hepatitis proves fatal. For this reason, pyrazinamide ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 441 should only be employed in special circumstances reaction took the form of abnormal values for liver when the risks of the disease clearly outweigh the function tests and no deaths or serious cases of toxic potential of the drug. hepatitis were encountered. It is believed, how- The USPHS group has recently reported the ever, that from the knowledge of the widely variable results of the clinical investigation of pyrazinamide behaviour of hepatitis in general, an incidence of and other drugs as companion drugs (United 2-3 %, even without encountering serious forms, in States, Public Health Service, Tuberculosis Chemo- no way changes the position set forth above con- therapy Trials, 1959). cerning the great limitations imposed on the use- The basic experimental procedure was to study fulness of pyrazinamide. four two-drug regimens in a large group of patients, The suggestion that streptomycin should be with- the regimens being given sequentially in groups held for use as a companion drug in the minority of two. Thus a particular group of patients would of cases that are unsuccessfully treated with iso- receive regimen A for a period of 16 weeks and niazid-PAS has great merit. Obviously, however, regimen B for an additional 16 weeks, while the it would not be accepted by investigators such as control group would receive a 32-week regimen of Crofton, who believes that all patients should be isoniazid-PAS. treated with daily streptomycin along with isoniazid. All of the regimens studied were highly effective. It should be pointed out, though, that Crofton, in The one that was slightly more effective than the Edinburgh, is dealing almost exclusively with others was pyrazinamide and streptomycin, with the hospitalized patients in an urban environment, and streptomycin administered daily for 16 weeks and his recommendations are specifically directed to isoniazid-PAS thereafter. that type of situation. When it is considered, how- Approximately 1800 patients were included in ever, that isoniazid-PAS is sufficiently close in this 32-week study. The value of the pyrazinamide- effectiveness to isoniazid plus daily streptomycin to streptomycin regimen in this type of situation was be a practicable substitute, the withholding of revealed so clearly that the investigators suggested streptomycin does seem to be a wise procedure. that this regimen, followed by isoniazid-PAS, Finally, it cannot be too strongly emphasized that should be used in far advanced cavitary disease. therapy with the secondary trio of drugs, particu- In effect, they considered that for the primary larly when accompanied by abandonment of iso- treatment of most cases of pulmonary tuberculosis, niazid, should never be instituted solely on the isoniazid-PAS would be the regimen of choice, basis of drug-resistance tests. On the contrary, but that the cases most likely to show a poor there must be evidence of persistent cavitation des- response to such primary treatment-those with far pite a reasonably long-continued period of therapy advanced cavitary disease-should be given pyra- with the major drugs, e.g., 4-6 months. Moreover, zinamide with streptomycin for 12 weeks, followed it must likewise be clear that the trend of the disease by isoniazid-PAS. is unfavourable. Unless these two important factors The principle involved is an important one and -the history of the chemotherapy and the status goes beyond the question of the use of pyrazinamide. of the lesion at a given point in time thereafter-are Obviously, if the practice recommended by the carefully evaluated, the patient may be exposed to USPHS were followed with respect to streptomycin, a greater risk from the toxicity of the secondary it would mean that this drug would also be available drugs than he would run if his disease were allowed for administration as a companion drug with a-ethyl- to remain even essentially untreated. In other thioamide or with cycloserine. The reason for the words, the use of pyrazinamide or cycloserine or choice of streptomycin rather than PAS for the perhaps even a-ethyl-thioamide may represent a far companion drug to be held in reserve is the obvious greater danger to the patient than the continued one that PAS-isoniazid is an " all purpose " regimen, activity ofhis pulmonary tuberculosis. Consequently, suitable for use in home or in hospital, whereas these secondary drugs should be resorted to only isoniazid-streptomycin is for use principally in on sufficient evidence of treatment failure and not hospital. And the three secondary drugs, as men- simply on the ground that tubercle bacilli cultured tioned above, are of necessity limited to hospital use. from the patients' sputum happen to be resistant In these large-scale USPHS studies hepatic to isoniazid in vitro. manifestations of pyrazinamide toxicity occurred in To summarize the situation at this point. Iso- 3% of the cases. In all instances, however, the niazid with daily streptomycin is probably the most 442 W. MCDERMOTT effective therapy per unit of time that is available Consequently, if one were to look for an all- today, with the exception of isoniazid-pyrazinamide, purpose antituberculosis therapy, the most flexible which is too toxic for general use. The isoniazid- one would be isoniazid-PAS daily for a six-month streptomycin regimen, however, has the limitation period, or until it is clear that therapeutic failure that its use is largely feasible only in hospitalized has occurred. Then, excisional or collapse therapy patients. As many patients today have to be treated should be attempted, with the use of streptomycin outside hospitals if they are to be treated at all, and either cycloserine, a-ethyl-thioamide, or pyra- it is essential to have a regimen useful both in home zinamide, in that order of choice. The order of and in hospital. The two-drug regimen of isoniazid- choice is dictated by the relative risks of serious PAS is almost as effective per unit of time as iso- toxic effects from the three drugs. If the patient niazid and daily streptomycin and lends itself, happens to be one of the 40% who would be unable apart from the difficulties occasionally encountered to take a-ethyl-thioamide, pyrazinamide would with PAS, to widespread usage on a domiciliary become the second or even the first choice for use basis. With both regimens and, indeed, even when along with the streptomycin. all three drugs are administered together, there will So much for an all-purpose, general type of be a portion of the patients who will continue to recommendation. What about the patient who is have cavitary disease and infectious sputum.' severely ill " ith an acute process such as an extensive In general, this minority will represent approxi- tuberculous pneumonia? In all probability the mately 15 % of the patients with moderately advanced therapy outlined above would prove to be perfectly or far advanced cavitary disease who have received effective in such a situation. Nevertheless, the chemotherapy for six months or more. Resectional evidence that isoniazid plus daily streptomycin therapy is clearly indicated for this group, but some represents the most effective therapy per unit of additional antimicrobial therapy is required before time is sufficiently convincing for one to believe it can be done with reasonable safety. Moreover, that such cases should be individualized, hospita- in some of these cases, either because of bilateral lized, and treated with isoniazid-streptomycin daily disease or because surgical facilities are not avail- until the process has subsided and non-infectious able, collapse or excisional therapy will not be status has been achieved. At this point, which practicable. In any case, a modification of the would be obtained, say, between four and eight chemotherapy is necessary for the minority group months after the start of therapy, it would probably of failures. be most advisable to continue the therapy thereafter There are two points to be mentioned in con- with isoniazid alone. nexion with this modification of the chemotherapy. The use of isoniazid alone has other indications, First, it is advisable to continue the isoniazid even set forth in detail above, but would probably never though the patient's strain of tubercle bacilli is be the most desirable therapy for patients with demonstrably resistant to isoniazid in vitro. Secondly, cavities 2 cm in diameter or greater. If, as is so it is necessary to administer an additional two-drug frequently the case, the patient has already received regimen, using either a combination of two of the streptomycin for three or four months before the three secondary drugs (cycloserine, a-ethyl-thio- therapeutic failure can be established, the only amide and pyrazinamide) or a combination of one recourse is to use two of the three secondary drugs of these drugs with streptomycin. What is to be together for so long a period as appears safe from expected from administering any two of the secon- the standpoint of drug toxicity. dary drugs together is not yet known. The results Viomycin and the neomycin series. Viomycin and of using any of the three with streptomycin are the neomycin series, which includes kanamycin, promising, and in the case of the pair that has been merit only very brief discussion. These compounds most frequently studied-i.e., streptomycin and have the same pattern of toxicity as the streptomycin pyrazinamide-they are very promising indeed. series, but are more toxic and appreciably less effec- 1 The author realizes that Crofton (see Crofton, 1958) tive than streptomycin. Viomycin and neomycin would not accept this statement, nor perhaps would Middle- are two distinct antimicrobial drugs, as is evidenced brook, Russell and their associates (see Russell et al., 1959). Nevertheless, the combined experience of these two investiga- by the fact that cross-resistance does not occur tors with their recommended regimen amounts only to about with them, i.e., tubercle bacilli resistant to one drug 250 cases, and it is virtually certain that when dealing with thousands of cases an impressive number of failures will are susceptible to the other. To what extent vio- occur even on the isoniazid with daily streptomycin regimen. mycin is less toxic than neomycin can only be ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 443 guessed, because the two drugs have not been three times weekly, should be 20 mg per kg, studied in comparable dosage in humans. When and the toxic manifestations to be feared are, viomycin toxicity was first observed (Werner et al., principally, deafness and, to some extent, renal 1951), a charge was promptly made from giving damage. the drug daily to giving it twice or three times Neomycin has been judged to be too toxic for weekly, which is the United States practice with use on a systemic basis in humans, but the com- streptomycin. In these circumstances, viomycin pound enjoys a considerable usefulness as a local toxicity was considerably reduced, presumably, ointment and as a non-absorbable drug for prepara- though, with corresponding loss of therapeutic tion of the bowel in abdominal surgery. It cannot effectiveness. This reduction from daily to twice or be too strongly emphasized that what applies to thrice weekly administration was never done in neomycin likewise applies to kanamycin. Kanamycin the case of neomycin and the drug was judged too is as closely related to neomycin as the various tetra- toxic for systemic use in humans on the basis of cyclines, the various sulfonamides, and the various daily administration (Carr et al., 1951). Because of streptomycins are related to each other. This is the inadvisability of giving any antituberculous drug evidenced not only by the chemical similarities of less frequently than daily as part of a two-drug the two compounds, but by the far more sensitive combination (see action on two-drug therapy below) index that tubercle bacilli resistant to neomycin are and the availability of the three drugs, pyrazinamide, resistant to kanamycin and vice versa. It has been a-ethyl-thioamide, and cycloserine, there seems to be claimed on the basis of rather sketchy evidence in a relatively small place for viomycin in antituber- animal studies that kanamycin is a less toxic com- culous therapy today. Nevertheless, such a place pound than neomycin. In actual trial in humans, does exist-namely, in a patient with severe laryn- however, the drug clearly has a high toxicity, and geal disease or some other form of disease in which an appreciable number of instances of deafness a temporary period of perhaps ninety days of some have been encountered from its use in patients with chemotherapeutic effectiveness would be highly pulmonary tuberculosis (Organick, 1960). There desirable, while managing the situation more defini- would seem to be no reason, therefore, for using tively by excisional or collapse therapy. The dosage either kanamycin or neomycin in the treatment of of viomycin, whether the drug is given daily or tuberculosis.

MANAGEMENT OF PATIENTS WITH THE " OPEN-NEGATIVE " SYNDROME

The second of the three patterns of response to the examination of the tissues removed in such chemotherapy outlined above is characterized by situations, we are no longer so quick to excise the considerable resolution of the pulmonary infiltration, lesion. The reason for this is the fact that, in some reversal of infectiousness, and persistent cavitation. of them, it is quite clear that so-called " open In many instances of this type of case, all of the healing " of the lesion has occurred. density surrounding the cavity will have disappeared Auerbach et al. (1953) have shown that in most in four to eight months and the sole remaining cases without chemotherapy a tuberculous cavity roentgenographic abnormality will be a bleb. The heals by closure of its bronchial connexion and by bronchopulmonary secretions may have been ne- inspissation of the cavity contents. With antituber- gative for tubercle bacilli since the third or fourth culous chemotherapy, however-and particularly month of therapy. This type of situation presents with the most effective drug, isoniazid-the lesion at very real problems in clinical judgement, and the the bronchocavitary junction heals quite rapidly and pattern is encountered in approximately half of the allows the bronchial communication to remain patients with persistent cavities after six months of patent. This creates an entirely different set of cir- therapy. A few years ago it was customary to excise cumstances with respect to the cavity. As the caseous all such lesions, despite the fact that there might material is discharged from the cavity through the have been no tubercle bacilli demonstrable in the open bronchus, epithelium can grow over the granul- sputum for a period of as long as a year before the ating surface from the bronchocavitary junction and surgery. As experience has been accumulated with eventually encompass the whole surface of the cavity. 444 W. MCDERMOTT

To all intents and purposes, therefore, the patient is About all that can be said, therefore, is that in left with a small, non-tuberculous cyst in the lung. cases in which tubercle bacilli have been absent from Such cyst-like healing was observed rarely in the the sputum for six months or more, there is at least days before chemotherapy, but was mentioned by one chance in five that excision of the lesion will Pinner (1945). With antimicrobial therapy such cases reveal that the lesion was completely healed. By are being seen with increasing frequency. the same token, in the other four or five cases, the The problem facing the clinician is how to distin- potential for relapse to the tuberculous disease is guish such cases of " open healing" from the larger still present. group of cases in which the healing is incomplete. In view of the lack of precise information to guide When a number of persistent cavitary lesions are us in this type of case, all we can do is to treat each examined pathologically at various intervals after the case on its merits and to do so with the realization roentgenographic resolution of the surrounding infil- that surgery may not be absolutely necessary. To a tration and the reversal of infectiousness, it is found considerable extent the indications for surgery here that, in the early stages at least, the majority of are economic, the employability of the patient being them fail to show complete open healing. By this a deciding factor. For example, a young physician is meant that although the cavity lining may be or a dentist who presented such an " open healed " clean, and indeed completely epithelialized, a cavity would probably be well advised to have it number of sections through the cavity wall will excised, even though his sputum continues to be non- reveal microscopic areas of tuberculous disease. infectious on continued chemotherapy. Contrari- When such lesions are examined at later stages after wise, a middle-aged or older person whose way of life the disappearance of tubercle bacilli from the was such that he would not constitute too great a sputum, as would be anticipated, the number of public health menace to small children or associates cases of complete healing rises appreciably. As a might well dispense with surgery, but should con- rough estimate at the present time, it might be tinue to receive antimicrobial drugs. stated that six months after the regression of the Fortunately, the MRC is conducting a long-term pulmonary infiltration and the disappearance of study of such cases, and it is only in this way that tubercle bacilli from the sputum, approximately our estimates of the risk of relapse can finally be 20 % of such cases will show complete open healing, established. At present, one must treat these and the other 80 % will show various grades of cases individually, fully appreciating that many of persistently active tuberculous disease. To what them will represent persistently active disease, extent this figure of 20% would be increased by but being slow to institute surgery unless the another six months or a year ofantimicrobial therapy patients' circumstances make relatively early sur- cannot be stated at this time. gery advisable.

DURATION AND DOSAGE OF CHEMOTHERAPY

DURATION OF THERAPY IN PULMONARY TUBERCULOSIS mals it can be observed that final healing of the des- tructive tuberculous lesion may require many months. In tuberculosis, unlike in the other destructive When a microscopic tubercle is produced in a pulmonary infections, the process of sutolysis rabbit ear and followed by direct microscopy in an becomes arrested, so to speak, and we have the form ear chamber during therapy with isoniazid, it may of solid necrosis known as caseation. In other be seen that within a few days of the start of isoniazid words, the tissue is destroyed as it is in a strepto- therapy, all of the surrounding induration and coccal or staphylococcal infection, but instead of cellular activity of the lesion starts to resolve and going on to complete autolysis, the process is that this process is complete within about two " frozen " in this non-liquid stage. It is this that weeks. For a long period, thereafter, however, makes the tuberculous healing process such a perhaps for so long as nine or ten months, the actual protracted one and it is a commonplace experience necrotic area remains incompletely healed. in studying excised lesions to find the disease partially From experience with miliary tuberculosis in active during the second half of the first year of humans, it appears that once the surrounding in- therapy. In addition, in studies with laboratory ani- flammation has subsided in a few weeks, the lesions ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 445 are no longer roentgenographically demonstrable; the host as a direct consequence of the chemotherapy nevertheless, they are still present. at any time and are most certainly not eradicated In the case of the lesions excised from the human within the first half-year of therapy. Consequently, lung after many months of chemotherapy, tubercle the practical wisdom of continuing the chemo- bacilli may be demonstrable by microscopy but therapy well past the period during which most cannot be cultured. Presumably they are alive, but of the healing takes place is obvious. are obviously at a low level of metabolic activity. Whether any viable bacilli are present cannot DOSAGE therefore be stated with certainty, although judging by experiences with dormant and latent infections, Streptomycin the presumption is that a few are still present. The pharmacology of streptomycin was well Because final healing may be so long postponed, defined in the elegant studies of Boxer et al. (1948) therefore, it has become the common practice to using chemical methods of determination. It is administer chemotherapy in pulmonary tuberculosis clear that at a dosage of 20 mg per kg per day, which for very long periods, usually at least 18 to 24 is usually one gram in the average sized adult, deaf- months. It must be appreciated that, in all prob- ness need not be anticipated and the degree of vesti- ability, for most of this period the chemotherapy is bular dysfunction that occurs is relatively slight and exerting only a protective or suppressive action, is manageable in terms of subsequent adaptations by rather than the actual therapeutic action it exerts in the patient. It is probable that such a dosage is not the early months of therapy. the maximal effective dosage of streptomycin, so Expressed differently, there are many reasons for that in the early weeks of therapy, particularly in believing that the principal action of the therapy is situations such as acute tuberculous pneumonia in exerted in the early weeks of its administration and which streptomycin is to be used along with iso- that its action thereafter is simply to prevent re- niazid, it would probably be wise to use 30 or 40 mg activation of the drug-suppressed infection. This per kg per day for a short period, say, two to three would be particularly the case in instances in which weeks. It must be appreciated, however, that if a pulmonary lesion, whether cavitary or not, receded this is done there will be a considerable risk of to the point of cavity closure and reversal of in- vestibular toxicity. Indeed, if a streptomycin dosage fectiousness. From this point on, it can be presumed of 60 mg per kg, or 3 g, a day is given for so long that the bacilli represent a diminishing population as 21 days, vestibular dysfunction occurs almost that is at a relatively low level of metabolic activity uniformly. and are not being increasingly incapacitated by the In most instances, the patient is able to compen- further administration of the drug. This is in sate for the vestibular dysfunction once he is again contrast to the early weeks of infection, in which very ambulatory. In the older age-groups, however-e.g., large number of bacilli are operating at a high level over 60 years adaptation is not always so easy. of metabolic activity and are being incapacitated in Consequently, in cases of either advanced age or large numbers by the drugs. Consequently, it is renal insufficiency (which results in an accumulation conceivable that even very short periods of chemo- of drugs), the dosage of streptomycin must be kept therapy might really be all that is necessary and that low and, indeed, should seldom exceed the generally the host could deal with the problem satisfactorily applicable 20 mg per kg daily dose. from that point on. There is some clinical evidence that this might PAS be the case-notably, the study of what happens The precise PAS dosage for maximal therapeutic to people with pleural effusion of tuberculous effect is difficult to determine because, as mentioned etiology who have received only three or four months previously, to a considerable extent the matter of chemotherapy. The sequelae in terms of sub- depends on the dosage of the companion drug that sequent appearance of parenchymal disease are very is employed. With streptomycin in the MRC much less frequent among such people than among studies, it was believed that as much as 20 g of patients with pleural effusions who received no PAS per day were necessary for full effectiveness. therapy at all. With isoniazid, there is reason to believe that the Despite these theoretical considerations, however, dosage may be considerably lower, but how much it is also clear that the bacilli are not eradicated from lower has not yet been established. Moreover, this 446 W. MCDERMOTT

point obviously depends on the dosage of isoniazid isoniazid per day, if, indeed, it were possible at all. usually employed, which in British practice is quite In short, pulmonary tuberculosis in the adult low in comparison with United States practice. It human is too variable a model to permit compara- seems probable, but can only be guessed, that when tive studies of even fairly wide differences in iso- 300 mg or more of isoniazid are given daily, the niazid dosage. This point has been discussed in proper dosage of PAS would lie somewhere between detail elsewhere (McDermott et al., 1954). 6 and 10 g per patient. With respect to the published studies of high and low dosage, the principal ones have failed to show Isoniazid any detectable difference, as would be expected It has been possible to demonstrate unequivocally for the reason just mentioned. For example, the (see, for example, McCune et al., 1957) that a dose- USPHS conducted a large-scale study with two response curve exists for isoniazid in tuberculous isoniazid dosages, both used in association with infections in laboratory animals. For example, in streptomycin. The differences in roentgenographic the mouse system employed by McCune and his improvement and reversal of infeztiousne3s were co-workers, an isoniazid dosage of 5 mg per kg essentially the same for the two groups. Berte & produced very definite effects, but increasing the Dunnington (1960) at the Valley Forge Hospital in dose to 20 mg per kg produced even greater effects. Pennsylvania, USA, have likewise conducted studies When the dose was increased fivefold beyond that, and were unable to detect any differences between a however, there was no increase in therapeutic 5 and a 10 mg per kg dosage. This does not mean effectiveness. Obviously, one cannot apply these data that therapeutic differences do not exist, but simply to man beyond inferring that, if a dosage-response that they are not detectable in so variable a model as curve exists for animals, it also exists for man. For the pulmonary lesions of tuberculosis in the human. all practical purposes, this means that the ideal In 1954, Schmidt and his associates in Cincinnati, dosage in man is the maximal tolerated dosage. Ohio, USA, published elegant chemical studies of From the considerable experience with isoniazid the pharmacology of isoniazid and showed that it administration now available, it appears that the is acetylated, and hence inactivated, to a variable maximal tolerated dosage-i.e., the dosage that degree by different subjects (Hughes et al., 1954). will cause no or very few toxic reactions in a large In the present writer's opinion, these excellent group of people-lies somewhere between 5 and 8 studies by Schmidt have been given (not by him mg per kg per day. Certainly, as one approaches or his associates, but by others) a far greater im- 8 mg per kg per day, one is getting into the toxic portance than the phenomenon deserves in terms range, although in individual cases such a dosage of the clinical management of tuberculosis. can usually be maintained without difficulty for a The fact is that all drugs are inactivated to a period of several weeks. Nevertheless, it is within greater or lesser extent by various mechanisms the toxic range, as evidenced by the appearance of within the body. Acetylation and glucoronidation peripheral neuritis or the toxic encephalopathy are two of the common mechanisms used for manifested by epileptiform seizures. To stay well inactivating the sulfonamide3 and chloramphenicol; within the relatively safe range, therefore, it is binding to protein is another mechanism and, in necessary to use a total daily dose of between 300 the case of penicillin, the speed of renal excretion and 450 mg per adult patient per day, depending represents yet another. Moreover, all of these to some extent upon the size of the patient. "neutralizations " of drug activity usually show It cannot be too strongly emphasized that this considerable variation among different subjects. choice of a dosage range of 300-450 mg is based Thus the fact that isoniazid is acetylated, and hence largely on reasoning by analogy from the fact that neutralized, to a variable degree makes the thera- a dose-response curve can be demonstrated in peutic situation fundamentally no different with animals, rather than on direct observations in this than with any other antimicrobial drug. Ob- humans with tuberculosis. The reason for this is viously, if it could be shown that very large numbers that individual cases of pulmonary tuberculosis of patients acetylated the drug very rapidly and to present so many variables that an extremely large a very considerable extent, the position would be series of patients (probably thousands) would have different. But all the evidence indicates that the to be treated before it would be possible to detect number of very high acetylators is quite small, the difference between, say, 300 mg and 600 mg of probably less than 15%, and even in these cases ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 447

the drug is present in its active form within the body The principal objection to the procedure is the for several hours before the acetylation becomes fact that there is good reason to believe that pyri- excessive. And there is every reason to believe doxine in its metabolically active form produces its that it is only a matter of a few hours before an toxicity-reducing action at the expense of isoniazid antimicrobial drug is exerting its maximal activity effectiveness. In short, the studies of Boone et al. for each level of dosage. Indeed, many of the un- (1957), McCune, Lee, Deuschle & McDermott published clinical studies on the subject show that (1957), Manthei (1957) and McDermott (1957) have unaltered isoniazid is excreted in the urine in the indicated that the action of the pyridoxine is to same quantity in the rapid as in the slow acetylators. form an easily reversible hydrazone with the isoniazid Obviously, therefore, the same amount of active and deviate it from its antimicrobial activity against drug must have been present within the bodies of the invading organism. In the reported clinical the patients for essentially the same period of time. studies with high isoniazid dosage and pyridoxine, The notion that PAS or compounds of similar the observation that " full isoniazid effectiveness " is chemical structure could interfere with the acetyla- observed is meaningless, because, as mentioned tion of isoniazid within the body and, hence, provide above, a reduction from, say, 15 mg per kg to 5 mg higher concentrations of the drug for longer periods per kg per day would simply not be detectable in so has not stood the test of careful scrutiny with che- variable an experimental model as the patient with mical methods of determination of the various pulmonary tuberculosis. The same applies to the breakdown products of the isoniazid. concentrations of drug in the blood. For here, too, What the fact that isoniazid is acetylated does the dynamics are so rapid that the fact that a par- mean, however-and it is the same point indicated ticular concentration of microbially active drug is by the presence of the dosage-response curve in present despite the administration of pyridoxine is animals is that it is highly advisable to give as meaningless. large a dose as possible within the safe limits. It From the studies in vitro and in animals, which is in this way that, with all antimicrobial drugs, we clearly indicate a direct reaction between pyridoxine protect the relatively unusual individual from and isoniazid, it would seem that the case for using excessive neutralization of his drug, while protecting pyridoxine with isoniazid clearly depends on proof the majority against excessive toxicity. Thus if one that such a procedure is of value. Thus far, no value is operating close to the lower level of effectiveness, has been convincingly established from the thera- as, for example, would probably be the case with peutic standpoint. The fact that pyridoxine will pre- a total daily dose of 200 mg, in the few individuals vent the peripheral neuritis caused by large dosages who were rapid acetylators, underdosage would pro- of isoniazid is unquestionable. Strangely enough, bably occur. If these same people were given 400 mg however, it will not protect the patient against the per kg per day, they would be receiving better protec- toxic encephalopathy that will occur in some people tion against the various neutralizing mechanisms. on high dosage and manifests itself in the form of The question arises whether it is a sensible pro- clinical psychosis. cedure to give more than the maximally tolerated For these reasons, therefore, it is far more sensible dosage of 5-8 mg per kg per day and to protect the to attempt to use the maximal safe dosage of patient against neurotoxicity by the concurrent ad- isoniazid without pyridoxine than to administer ministration of pyridoxine. This practice has become larger amounts that, for all we know, are subject to quite fashionable, but in the writer's opinion rests considerable reduction by the concurrently admi- on a very unsubstantial foundation. nistered pyridoxine.

USE OF STEROID HORMONES IN ASSOCIATION WITH ANTIMICROBIAL THERAPY At one time all steroid hormones were universally effects, however, it is well to examine the available considered " bad" for pulmonary tuberculosis, but evidence. the pendulum has now swung to the opposite From the outset, in studies with laboratory extreme and some clinicians advocate their use animals (Batten & McCune, 1957a, 1957b), it almost as a routine measure. Before recommending became clear that the administration of steroid this therapy, that has a capacity for unpleasant side- hormones does someth ing to the tissues whereby 448 W. MCDERMOTT populations of tubercle bacilli will multiply in them roentgenographic improvement was greater in the to a far greater extent than in unaltered tissues. steroid group, but the reversal of infectiousness, Whether the action here consists in protecting the although comparable at 20 weeks, was appreciably tissues against the toxicity ofthe bacilli, thus allowing less in the hormone-treated group than in the the animal to survive despite the higher microbial control group at the 12-week observation point population, or whether some definite defence (37%4 still infectious as compared with 25%). mechanism of the host is abolished by the hormone Although the differences in the reversal of infectious- cannot be stated. What can be stated quite definitely, ness were not marked, they were in the direction of however, is that antimicrobial drugs have the same a lessened total therapeutic response in the patients (but no greater) effectiveness in the presence as in maintained on the hormone. Certainly, the results the absence of steroid hormone administration. provide no support for the use of the hormone as a The hope expressed by some people that the routine practice in the chemotherapy of pulmonary enhanced proliferation of the bacilli made possible tuberculosis. by steroid hormone administration could make them A situation does exist in pulmonary tuberculosis, more susceptible to the chemotherapy by virtue of however, in which the hormone therapy might be of their presumably enhanced metabolic activity has value-namely, in the comparatively rare case of a not been realized, at least in experiments in animals. person with extensive acute tuberculous pneumonia. For example, in the Batten & McCune studies, the In this type of situation the immediate effectiveness reduction in the population of tubercle bacilli of antimicrobial drugs might not be sufficient to proceeded no faster and to no greater extent in prevent continued destruction of the lung as the animals maintained on steroid hormones than in process comes under control. Moreover, in extreme animals not subjected to the influence of hormones. examples, the disease itself might cause the death of Thus one possible indication for the use of hor- the patient before incapacitation of the tubercle mones-namely, the stepping-up of microbial bacilli could be accomplished on a sufficient scale. activity for greater drug effectiveness-would not In such a situation, the use of steroid hormones for seem to be well founded, at least as judged by the the first two or three weeks of therapy would seem available experimental data. to be a reasonable procedure. But it is a procedure From the clinical standpoint, a very careful, that must be followed with the full realization that chance-selection control study has just been reported there is really no scientific evidence at the present by the USPHS (United States, Public Health time as to its value. Other than this relatively rarely Service, Tuberculosis Therapy Trials, 1960). In this encountered type of situation, there is no satisfactory study, patients with pulmonary tuberculosis were evidence in favour of the use of the hormones. And treated with isoniazid and PAS, but by random as the side-effects of steroid hormone administration selection were divided into two groups, of which one are so well known, whenever it can be avoided it is received prednisolone and the other did not. The preferable to do so.

LOCUS OF ACTION OF TWO-DRUG THERAPY

The usually invoked explanation of the way in rience in which there is convincing evidence that certain which two-drug therapy postpones or retards the drug pairings produce results superior to those attainable emergence of drug-resistant micro-organisms has when the more powerful of the two drugs is used alone. recently been challenged by the present writer in a With certain other infections, notably those produced by brucella or staphylococci, there is some evidence of discussion of the mechanism of action of multiple- superior two-drug effectiveness in certain circumstances drug therapy. For the full discussion the reader is in laboratory animals, but the same type of drug effective- referred to the original publication (McDermott, ness in humans has not yet been demonstrated. When 1958). To quote briefly from that work: the evidence available both from studies in laboratory animals and man is reviewed, certain inferences seem " The situation with respect to the use of two or more to be reasonable: (1) The superiority of the drug pairing antimicrobial drugs together can be summed up thus: to one of its members is a phenomenon with considerable Infections with enterococci and tubercle bacilli represent specificity in terms of the drugs and microbial species the only examples available from present clinical expe- involved; hence, superior drug pairings are relatively ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 449 rare and are not to be expected with any pairing in any drugs is exerted on the microbial cells susceptible to drug-susceptible parasite. (2) The superior effectiveness both drugs does not imply that emergence to pre- of the pairing appears to depend principally on the dominance of drug-resistant genotypes would action of both drugs on the microbes susceptible to both necessarily remain unaffected. On the contrary, drugs, and hence in large measure consists of both drugs acting on the same microbial cell. (3) The influence of there should be impressive reductions in the re- multiple drug regimens on the emergence to predomi- lapses that occur during treatment owing to the nance of drug-resistant microbes is indirect and is a emergence of drug-resistant organisms. For the consequence of this greater inhibitory action produced enhanced influence on the doubly susceptible micro- in the microbes susceptible to both drugs. It is doubtful bial cells produced by the two drugs together should that an action of one drug on the microbes genotypi- result in a greater degree of incapacitation of the cally resistant to the other drug plays an important role majority of the infecting population. The resulting in the process. (4) Even with the few microbial species reduction in microbial proliferation would lessen the for which multiple drug action has been established as chances of the birth of drug-resistant genotypes. superior, no combination of drugs has yet been found which would uniformly eliminate all of the drug- Moreover, the greater control of infection should susceptible microbes from the infected tissues of the host." considerably facilitate the processes of healing and hence help to modify the tissue environment to one The point at issue, although mainly concerned less conducive to the emergence of drug-resistant with the mechanisms of chemotherapy, has never- organisms in large numbers. theless certain clinical implications. For, if the The most important point is that, whether the conclusion stated above is correct and the major retardation of significant drug-resistance occurs by action of a multiple-drug regimen is exerted on the the mechanism postulated above or by the orthodox cells susceptible to both drugs-and the process genetic mechanism, the fact remains that with all the seems to be one of considerable specificity (pre- two-drug combinations thus far studied, some strains sumably due to the way the individual drugs work of tubercle bacilli resistant to one or both of the in the particular environmental conditions of the drugs employed eventually emerge. In other words, lesion)-there are obvious implications with respect the use of multiple-drug therapy, although definitely to the " secondary drugs ". For example, of the three beneficial, is not an absolute guarantee against the secondary drugs now available, one pairing might be emergence ofdrug-resistant infections. Indeed, in the considerably superior to another. This merely em- specific case of isoniazid-PAS versus isoniazid alone, phasizes the importance of establishing, by clinical the evidence from the studies of Phillips (1959) is to trial and suitable studies in laboratory animals, which the effect that the emergence of isoniazid-resistant of the various pairings of the three secondary drugs strains occurs to the same extent in both circum- (and streptomycin) represent the most effective multi- stances. Consequently, we cannot have confidence ple-drug regimens. It should further be emphasized that drug-resistant tubercle bacilli will not emerge that the concept that the principal action of a pair of simply because multiple-drug therapy is employed.

IMPLICATIONS OF DRUG-RESISTANCE

It may be seen from the statement immediately our minds, in the long run it is the epidemiological above as well as from the discussion on the manage- implications that have the greater significance. ment of therapeutic failure that the present writer It is my contention that this highly important believes that the emergence of drug-resistant tubercle question of drug-resistance has been almost totally bacilli represents a problem. Moreover, it is a prob- obscured by uncritical interpretations of drug- lem that has to be looked at from two different susceptibility tests, which of necessity have to be aspects: (a) from the point of view of the reduction performed in vitro. Such tests are of unquestioned in therapeutic effectiveness of the drugs given to an value from the epidemiological standpoint-namely individual patient and (b) from the point of view of for the identification of patients whose infection the epidemiological implications of the spread of was originally produced by a drug-resistant strain drug-resistant infections among a community. of tubercle bacilli. They are of considerably less Although the individual patient is always more in value, however, in the management of the therapy

3 450 W. MCDERMOTT

of an individual patient. Indeed, they are of so little today's drugs, including isoniazid, we may find value that at times it almost seems as if their employ- ourselves a decade or so from now in a serious ment does more harm than good to the patient in situation from the standpoint of resistance. The that the physician is misled by these crude tests writer presented his thoughts on all the implications into using fcrms of therapy that are not necessary. of drug-resistance, both for the individual patient With respect to the second aspect of the question- and for the community, in a paper submitted three namely, the emergence of drug-resistant strains as years ago at the annual meeting of the International a threat to the community-thus far there is little Union against Tuberculosis in New Delhi, India. indication in the case of isoniazid that this is occur- But it seems advisable to recapitulate them in ring on any scale that is at all significant. For abbreviated form at this point. example, in the recent studies by Debre and his The major biological problem concerning iso- associates (1959), only four strains of isoniazid- niazid-resistant tubercle bacilli is the fact that we resistant tubercle bacilli were isolated from children are almost wholly ignorant of their significance for with primary infections over a five-year period. And man. One aspect of this problem is the identification it is in primary infections in children that the first and evaluation of the numbers of drug-susceptible effects of widespread drug-resistant infections would and drug-resistant bacilli present in any population be noticeable. Interestingly enough, one of these of tubercle bacilli infecting man. This in itself is a four strains was of bovine origin and two of the complex matter, but the problem is further com- other three were resistant to streptomycin as well plicated by the fact that the general term " isoniazid- as to isoniazid. The finding, in these other studies, resistant tubercle bacilli " embraces individual of tubercle bacilli resistant to both isoniazid and cells and strains with widely different capacities for streptomycin is of interest in connexion with the producing progressive disease in a number of animal effectiveness of multiple drug therapy in preventing hosts. These differences in pathogenic potential the emergence of drug-resistant strains. For the presumably also exist, to an undetermined extent, inference is either that the patient received these with respect to man. We are faced, therefore, with drugs sequentially, which seems highly unlikely, a twofold problem: first, to determine how many or that strains resistant to both drugs emerged drug-resistant tubercle bacilli represent a significant despite the multiple-drug administration. Other number in terms of drug neutralization; and, studies of the prevalence of primary infection with secondly, to determine which kinds of drug-resistant drug-resistant tubercle bacilli have been conducted bacilli are present among those demonstrably re- by Chaves et al. (1956) in New York, by Cummings sistant to isoniazid in vitro. & Livings (1958) of the United States Armed Forces It is important to recognize at the outset that the -Veterans Administration and by the MRC in situation with respect to isoniazid-resistant tubercle Great Britain (Sutherland, 1958). All of them show bacilli is very considerably different from that pre- a relatively low incidence of isoniazid-resistant sented by streptomycin-resistant tubercle bacilli. infections. A questionnaire-type study has recently Indeed, from the first clinical use of isoniazid in been reported by Lincoln & Vera Cruz (1960) but tuberculosis it was clear that the experience gained the material is not really interpretable because, in with streptomycin-resistant infections was only the circumstances, there was no opportunity to applicable in the broadest sense to the problems check on the individual susceptibility tests conducted presented by isoniazid-resistant infections. by the various laboratories and no information was With streptomycin, drug-resistant bacilli had been obtained on what drugs had been received. shown to be present in infections previously un- What can be said, therefore, is that at the moment treated with the drug, but such initially drug- the prevalence of isoniazid-resistant tubercle bacilli resistant bacilli were quite few in number and, in various communities does not appear to represent indeed, were not usually demonstrable by the a threat. At the same time, by all biological prece- standard procedures. By contrast, it was shown dents, even any prevalence of drug-resistant strains in the very early days of isoniazid therapy that is a threat if our circumstances do not change with tubercle bacilli resistant to isoniazid in vitro could respect to new drugs in the next decade or so. In be isolated with ease from the sputum of patients other words, although there seems to be no definite who had received no isoniazid (Hobby & Lenert, danger at the present time, unless we can effect a 1952). Although the ease with which such isoniazid- reduction of the total case load of tuberculosis with resistant tubercle bacilli could be isolated from ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 451

untreated patients was surprising, the basic prin- sputum with respect to relating this finding to the ciple that drug-susceptible infections contained some patient's present or future isoniazid therapy. In drug-resistant bacilli was not unexpected because brief, what is the relationship between " isoniazid- of the streptomycin experience. In effect, our minds resistant tubercle bacilli" considered broadly and were prepared to accept this phenomenon, even an isoniazid-resistant infection in an individual though the ease with which it could be demonstrated patient. I submit that our situation is not a very was disquieting. What we were not prepared for, satisfactory one in terms of our present ability to however, was the fact that so many isoniazid- relate the two phenomena. Perhaps the best ap- resistant tubercle bacilli were so obviously different proach, therefore, is to deal with the matter by in their biological properties from their isoniazid- considering a series of questions. susceptible brethren. It was in this particular that The first question to consider is whether under any the comparisons made by analogy with the strepto- circumstances the presence of tubercle bacilli resistant mycin experience broke down so completely. to any drug in any patient means that the benefits For, with streptomycin, it had been clearly of that drug in that patient are seriously compro- demonstrated that a drug-resistant tubercle bacillus mised. Convincing evidence exists that the answer was otherwise completely indistinguishable from a to this question is in the affirmative. The single bit drug-susceptible tubercle bacillus; the only problem of evidence in this connexion which was most had been to determine how many drug-resistant convincing to me was our own experience in 1946 tubercie bacilli in a given population represented a with patients with acute miliary tuberculosis who significant number in terms of neutralization of were treated with large daily doses of streptomycin drug activity. With isoniazid, however, there was (McDermott et al., 1947). With this naturally not only the question of how many drug-resistant occurring experimental model, five patients expe- tubercle bacilli represented a significant number, rienced a complete disappearance of all evidence but also the far more difficult question of which of miliary tuberculosis only to have the disease kinds of isoniazid-resistant tubercle bacilli were return in fatal form while they were still receiving present and what did their presence mean. large doses of streptomycin. As the fatal relapses Thus, there was no problem involved in the during the therapy coincided in time with the isola- demonstration that isoniazid-resistant tubercle bacilli tion of streptomycin-resistant tubercle bacilli in were being excreted by a patient. The problems large numbers, it is reasonable to conclude that the arose when we attempted to evaluate this finding two phenomena bore a direct relationship to each in terms of the chemotherapeutic prospects of that other. Indeed, in three of the five patients, tubercle patient and the infectiousness ofhis disease for others. bacilli could be cultured from the circulating blood Both of these problems are of importance, but in despite the daily administration of three grams of the long run it is the infectiousness of the disease streptomycin in divided doses. In this situation, for others which has the greater significance. The therefore, in which the susceptibility of the infection reason for this is the fact that, with our multiple to its therapy bears a direct relationship to the therapies, both chemical and surgical, the important occurrence of relapse, the appearance of large question with respect to an individual patient is not numbers of streptomycin-resistant tubercle bacilli whether he is excreting isoniazid-resistant tubercle was accompanied in every instance by fatal relapse, bacilli, but whether he is excreting any tubercle despite the continued administration of the strepto- bacilli after, let us say, four to six months of anti- mycin. Thus the fact that, in some circumstances, microbial therapy. Nevertheless, although the the presence of a high proportion of drug-resistant question of individual patients' chemotherapeutic tubercle bacilli in the sputum or other exudates prospects is less important in the long run than the means that the major portion of the infection is, broad question of their infectiousness for others, to all intents and purposes, going untreated seems the chemotherapeutic prospects will be considered to be well established. first. This procedure is followed because certain of The next question that arises is whether there are our fragments of available information derived from any circumstances in which the presence of isoniazid- studies of the individual patient have a bearing on resistant tubercle bacilli in the sputum or other the more important epidemiological problem. exudates means that the major portion of that How, then, do we stand when faced with the infection is untreatable with isoniazid. On this finding of isoniazid-resistant tubercle bacilli in the question the amount of direct evidence, i.e., evidence 452 W. MCDERMOT7

based on the actual course of the infection in tuberculosis, direct relationships between loss of humans, is far from satisfying. Hence, we must drug-susceptibility and loss of drug effectiveness are attempt to construct the situation from the indirect extremely difficult to demonstrate in a clear-cut evidence provided by the many studies of tubercle way. There are many problems involved in using bacilli derived from treated patients. Based on the changes in cavity size, or even transient roent- evaluation of all the fragments of evidence, the genographic densities which disappear without indirect as well as the direct, the answer is probably change of therapy, as indices of loss of drug effec- affirmative and to the effect that in certain circum- tiveness. stances, otherwise undefined, the isolation of iso- When the climate of opinion was that isoniazid niazid-resistant tubercle bacilli from a patient lost a large part of its effectiveness after ninety days means that his infection is going largely untreated or so of administration, any change in cavity size or in so far as concerns isoniazid. Clear-cut proof of appearance of a new density was regarded as just this in man, such as would be provided by the cause for an immediate change of therapy. The case relapsing of miliary tuberculosis during treatment, then went into the records as a relapse during has not been forthcoming, because thus far there isoniazid therapy caused by drug-resistance and if have been no reports of patients with acute miliary the new density then promptly disappeared, it was tuberculosis treated solely with isoniazid who have attributed to the effects of the new therapy. We now experienced a relapse during therapy. know that, in some of these cases at least, the out- Other observations have been made in patients come would have been the same even if no change of which have been interpreted as showing a direct therapy had been made. Indeed, the problem of relationship between the finding of the isoniazid- evaluating such questions in pulmonary tuberculosis resistant bacilli and the inadequacy of therapy. is so complicated that even the fact that a patient Except for a USPHS study of sequential regimens, dies while receiving a particular drug is no longer an however, the evidence in man remains unconvincing. indication that drug-resistance was responsible. For The fundamental reason for this lack of direct most deaths from pulmonary tuberculosis today are evidence is the fact that pulmonary tuberculosis by in large measure the consequences of pulmonary its very nature does not lend itself to evaluation of insufficiency from the previous lung destruction and rapid changes of the infection from a state of drug- are not the consequences of the toxicity of the susceptibility to one of drug-resistance. In some rapidly progressing infection of " galloping con- of the earlier isoniazid studies the point was made sumption ". that after 90 or 120 days of therapy there was a The indirect evidence on this question of whether correlation between unsatisfactory healing of the in any circumstances isoniazid-resistant tubercle lesions and the presence of isoniazid-resistant bacilli present in sufficient numbers means the lack bacilli in the sputum. Obviously, this could mean of effectiveness of isoniazid as a drug is considerably the neutralization of drug effectiveness by a change more convincing than the evidence from the direct in the drug-susceptibility of the infection. It is studies in humans. The studies of Carlson, Mit- important to realize, however, that this is not chison, and Tompsett and their respective asso- necessarily the case. For, from our present know- ciates (Karlson & Ikemi, 1952; Barnett, Bushby & ledge of the antimicrobial therapy of tuberculosis, it Mitchison, 1953a, 1953b; Mitchison, 1954; Tomp- is recognized that lesions which persist unhealed in sett & McCune, unpublished data) have clearly drug-treated patients sooner or later become a rich shown that the course of tuberculous infection in source of drug-resistant bacilli. Thus, to say that mice is to a very large extent uninfluenced by iso- lesions which remained unhealed at a certain ob- niazid when the infecting population comprises servation point are a good source of drug-resistant predominantly isoniazid-resistant tubercle bacilli. bacilli is not quite the same thing as to say that the The studies of Tompsett & McCune, which were lesions remained unhealed because of the presence of conducted with precise quantitative techniques are the drug-resistant bacilli. In short, the patients particularly illuminating in this connexion. For they whose pulmonary lesions remain unhealed for one were able to demonstrate that infections initially reason or another despite continued chemotherapy made up almost wholly of isoniazid-resistant cells represent a selected group, selected not necessarily obtained higher population levels when isoniazid entirely in terms of loss of drug effectiveness. This was administered than in the untreated controls. is but another way of stating that, in pulmonary They further showed that, depending on the pro- ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 453

portion of isoniazid-resistant cells present in the The third question which immediately arises is infected population, the curve of the microbial how frequently does this situation occur. On this population during treatment could resemble that question there is a considerable body of observations, obtained with streptomycin, a considerably weaker all of which tend to support the crude approximation drug in this experimental system. In short, when that impairment of drug effectiveness in humans by the infecting population contained more than 40% of the presence in predominance of isoniazid-resistant tubercle bacilli resistant to isoniazid concentrations tubercle bacilli occurs no more frequently and to no of 10 y per ml in vitro, the effectiveness of isoniazid greater extent than is the case, for example, with in reducing the numbers of tubercle bacilli in the streptomycin and PAS. The supporting evidence mouse tissues was appreciably altered. In the comes from observations in humans as well as from particular instance cited, the comparative effec- observations in vitro and in animals with tubercle tiveness of the drug was approximately that of bacilli derived from isoniazid-treated humans. streptomycin in the same circumstances. As with streptomycin, the most convincing direct When a larger proportion of the microbial popula- evidence from observations in humans came from tion was isoniazid-resistant, the demonstrable loss the early studies of miliary tuberculosis. It had been of drug effectiveness was considerably more pro- expected that if loss of drug effectiveness due to nounced. In other studies it was shown that after emergence of isoniazid-resistant infections were to an initial isoniazid effect of a marked lowering of the occur frequently, it would, as with streptomycin, be microbial population, the emergence of isoniazid- observed in the patients with acute miliary tuber- resistant cells to predominance was accompanied culosis. In actuality, however, such was not the by a sharp upsurge of the population to the pre- case. It was noted in the early studies of isoniazid treatment level. The extremely complicated nature in acute miliary tuberculosis (Clark et al., 1952) of this problem can be seen, however, from the fact that relapse did not occur in patients treated solely that both in the isoniazid-tubercle-bacillus system with isoniazid during the administration of the and in various drugs with staphylococci, it has also chemotherapy. Thus, in the most likely situation in been noted in our laboratory that the emergence to which to detect the loss of drug effectiveness due to predominance of drug-resistant micro-organisms isoniazid-resistant tubercle bacilli, such a loss of is not invariably followed by resurgence of the effectiveness was not demonstrated. Moreover, in microbial population. In short, in some circumstan- patients with pulmonary tuberculosis (Deuschle ces, which are not at all clear, the small minority of et al., 1954) treated for long periods of time with organisms which survive the initial impact of the isoniazid alone, it was noteworthy that the develop- chemotherapy may persist at a low level in the tissues ment of progressive disease in a previously unin- for many months, despite the fact that their descen- volved area of lung remote from the original lesion dants when tested in vitro are drug-resistant in the was quite a rare phenomenon. To be sure, changes orthodox sense. This phenomenon is to be distin- in cavity size were observed frequently, as were local guished from the phenomenon of true "microbial extensions of a lesion present prior to chemotherapy. persistence ", in which otherwise drug-susceptible But the development of a totally new area of disease organisms persist in the tissues indefinitely despite during isoniazid therapy was quite rare, despite the continued administration of the appropriate anti- continued presence of tubercle bacilli in the sputum microbial drugs. Without question, however, from the other lesions. A possible exception to this tubercle bacilli derived from isoniazid-treated phenomenon was that, in some patients, a transient patients, and resistant in high proportion to isoniazid lesion was observed to occur in a new portion of in vitro, can produce a tuberculous infection in the lung. In these circumstances, a shadow would mice which is not controlled and may even be suddenly appear on a roentgenogram, remain for a slightly increased by the administration of isoniazid. week or two, and then regress without any alteration Thus, the indirect evidence plus the "change in in the antimicrobial therapy. This phenomenon, regimen " studies provide reasonably convincing which was noted in the treatment of patients with proof that, in some circumstances at least, the pulmonary tuberculosis with isoniazid alone, was presence of isoniazid-resistant tubercle bacilli in seen with much greater frequency in a series treated the human represents a situation in which the with pyrazinamide and isoniazid together (Muschen- infection will be essentially uninfluenced by the heim et al., 1955). Moreover, in the initial studies of administration of isoniazid. miliary tuberculosis as well as in other forms of the 454 W. MCDERMOTT disease, it was noted that lymph-nodes would cation that not all catalase-negative strains of occasionally enlarge during isoniazid therapy but tubercle bacilli are completely without pathogenicity would eventually recede without there being any for guinea-pigs, the central facts of the Middlebrook relapse of the miliary infection itself. observations are thoroughly accepted by all- Thus we had a situation in which isoniazid- namely, that tubercle bacilli derived from isoniazid- resistant tubercle bacilli were known to be present treated patients and uninhibited by isoniazid in before treatment, and in which the numbers of these vitro usually show lowered pathogenicity for guinea- bacilli appeared to increase so long as tubercle pigs. In further studies, working collaboratively in bacilli persisted in the sputum during treatment. two separate laboratories, the Middlebrook group Yet the over-all results of the treatment were and the Schmidt group in Cincinnati (Schmidt, 1956) very considerably better than would have been were able to show that rhesus monkeys infected expected. intratracheally with enormous numbers of these With respect to the number of isoniazid-resistant catalase-negative tubercle bacilli developed a non- tubercle bacilli present in a culture of sputum, destructive transient pneumonia which disappeared Tompsett (1954) was able to show by careful quan- completely in a matter of a few weeks. This was in titative studies that the customary isoniazid-resist- striking contrast to the destructive and fatally pro- ance tests, which are semi-quantitative, could be gressive type of tuberculosis produced in the same quite misleading. His observations were made on animal species by a far smaller inoculum of iso- specimens derived from a group of patients who niazid-susceptible tubercle bacilli. received isoniazid as the sole antimicrobial agent. To a certain extent, therefore, the story could be In some cases, a high proportion of the bacilli were perceived in outline. The incidence of the emergence highly resistant to the drug after only short periods of drug-resistant bacilli, in numbers meaningful from of therapy. In other cases, the great majority of the the standpoint of loss of drug effectiveness, was bacilli were drug-susceptible even after many months obviously not great as determined from the studies of therapy. Yet in both situations, the results of of miliary tuberculosis. The remarkably low the customary semi-quantitative drug-susceptibility incidence of new areas of disease, even in un- tests had indicated that the culture was highly successfully treated patients with pulmonary tuber- resistant to isoniazid. culosis, might conceivably be explained in some With respect to qualitative changes, it was part by the fact that some of the strains of iso- recognized in the earliest microbiological studies of niazid-resistant tubercle bacilli showed remarkably tubercle bacilli from isoniazid-treated patients that different properties and diminished pathogenicity these bacilli changed in many other particulars than for two animal species-namely, guinea-pigs and their degree of susceptibility to isoniazid. It re- monkeys. By the same token, the studies in mice mained for Middlebrook and his associates (Middle- indicated that not all isoniazid-resistant tubercle brook & Cohn, 1953; Cohn et al., 1954), however, bacilli could be regarded as necessarily non-patho- to show: first, that many of the strains of isoniazid- genic. Moreover, the studies of Rist (1956) and of resistant tubercle bacilli had a markedly lower Barry et al. (1955) indicated that even the strains pathogenicity for guinea-pigs; and, secondly, that, containing catalase-negative bacilli might, with to a very considerable degree, this loss of patho- the passage of time, produce progressive disease in genicity could be correlated with another biological the guinea-pig. property of the bacilli-namely, their ability to What the position comes down to is that our form the enzyme, catalase. These observations have usual tests of the isoniazid-susceptibility of bacilli been confirmed and extended in many laboratories derived from the patient provide no solid informa- throughout the world and are familiar to us all. To tion either as to the number of isoniazid-resistant be sure, with a wider experience it has been found that bacilli present in relation to the total number of the loss of pathogenicity of these bacilli for guinea- bacilli present or as to the nature of these isoniazid- pigs is in a sense relative in some circumstances. resistant bacilli with respect to their pathogenicity. For example, Conalty and co-workers (Barry et al., We know that some have and some have not main- 1955; Rist, 1956) have shown that in animals in tained their full pathogenic potential, but in practical whom the infection is allowed to remain for many terms we have no real way of knowing how many, months, progressive disease in some circumstances or of what type, are the bacilli which the patient may finally occur. Nevertheless, despite the qualifi- continues to excrete. ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 455

The situation can be epitomized by saying that change in chemotherapy and a consideration of we know something of the types and the nature of excisional or collapse therapy are clearly indicated. the changes which can take place within the infecting Contrariwise, if by the fifth or sixth month the population in an individual patient, but we are isoniazid-treated patient has shown satisfactory almost completely without methods of detecting roentgenographic improvement (including absence when these various types of change have taken place. of cavitation) and tubercle bacilli can no longer be We do know from the studies of isoniazid in miliary isolated, the clinician can rest assured that continued tuberculosis and the few studies of its long-term isoniazid therapy will almost certainly not lose its use singly in pulmonary tuberculosis that, on the effectiveness in the future by virtue of the emergence whole, the frequency with which isoniazid seems to of a drug-resistant infection. lose its effectiveness on the grounds of drug-resis- The " borderline " result of roentgenographic tance appears to be no greater than is the case with clearing, but with evidence of cavitation persisting streptomycin-PAS. in association with the reversal of infectiousness, Therefore, the answer to the third question-how represents a special problem in the short run. In frequently does loss of drug effectiveness due to some patients this situation can probably be as well isoniazid-resistant bacilli occur ?-is: " not very handled as when the evidence of cavitation is often, but often enough to merit consideration in lacking, but our methods for detecting which of the management of an individual patient who these patients will remain well in the long run are persistently discharges tubercle bacilli after the first not yet sufficiently developed to permit a satisfactory three or four months of isoniazid therapy ". prognosis. What practical conclusion can be drawn from this To sum up this aspect of the discussion, it can be collection of information that can provide the said that the diagnostic and the bacteriological pro- clinician with a basis for guidance in the management blems of isoniazid-resistant tubercle bacilli all of an individual patient? In my opinion he should really boil down to the one problem of the signifi- proceed from the premise that, except for the de- cance of such bacilli for man. The demonstration, monstration of the presence or absence of tubercle by the semi-quantitative methods customarily bacilli in the sputum or gastric washings, there is used in clinical laboratories, that isoniazid-resistant no laboratory test which will provide him with the tubercle bacilli are present in the sputum of an information necessary for a rational initial choice or individual patient has very little meaning or signifi- change of chemotherapy. Thus in the treatment of cance with respzct to the effectiveness of isoniazid pulmonary tuberculosis with isoniazid, as in the therapy for that patient. Because of the extremely treatment of other infections with other drugs, he complicated nature of the situation with isoniazid, must proceed on the basis of his knowledge of the the effectiveness of the therapy must be determined possibilities involved and of the crude approxima- by other means, including observation of the course tions of the probabilities involved. With specific of the infection under the isoniazid therapy. reference to isoniazid, he knows that if the patient As mentioned earlier, the more important of the has received no previous treatment, the chances are two aspects of this problem is the significance of overwhelming that the infection will be drug- isoniazid-resistant tubercle bacilli for the associates susceptible. He also can be assured that the prospects of the infectious patient who is receiving isoniazid. that the isoniazid will lose its effectiveness over the To be sure, this problem also arose in the case of next six to nine months in that patient are on the streptomycin. But far greater numbers of patients whole no greater than is the case with the non- are receiving isoniazid-containing chemotherapies isoniazid chemotherapies, such as streptomycin-PAS. than the other chemotherapies in circumstances in He also knows, however, that though the possibility which the problems of their contagiousness go is much more remote than was once popularly sup- essentially unsupervised. posed there is some risk with isoniazid, as with all It should be clearly recognized that the problem other chemotherapies, that loss of drug effectiveness is to all intents and purposes the same whether one due to drug-resistant bacilli will eventually occur. is considering patients who receive isoniazid alone Hence, if an appropriate degree of roentgenographic or patients who receive a companion drug such as improvement is not occurring and tubercle bacilli PAS along with the isoniazid. In either case it is can be isolated after five or six months of isoniazid the isoniazid which is the major component of the therapy, the clinician should know that both a chemotherapy. And, if an associate of a drug- 456 W. MCDERMOTT treated patient contracts a tuberculous infection and the development of frank pulmonary disease which is completely resistant to isoniazid, it makes with the discharge of tubercle bacilli in the sputum: no difference whether the patient who was the Hence isoniazid-resistant tubercle bacilli could original source of the infection was receiving single- be infecting new hosts at a significantly high attack or multiple-drug therapy. To be sure, the problem rate and yet the problem would not become apparent might have somewhat less wide implications in so as such until several years later. Before the problem far as PAS or another companion drug might be became recognizable in the form of many cases of able to lower the total number of infectious patients. isoniazid-resistant pulmonary tuberculosis, about Nevertheless, in absolute terms on a nation-wide the only other way it would become evident would basis, the problem would still loom large, unless be through a substantial increase in the number of some isoniazid-containing chemotherapy were forth- infants or young children with miliary or meningeal coming in which reversal of infectiousness could be infections which were isoniazid-resistant from the anticipated in almost every patient. beginning of treatment. The lack of any such It seems to me, therefore, that we simply have to upswing in acute miliary and meningeal infections face the situation that with today's chemotherapy is in itself not too comforting, however, because of many infectious patients are going to receive the fact that the prevalence of these forms of tuber- isoniazid outside hospital. In some of these patients, culosis is at its lowest in the very areas of the globe fortunately a minority, even with the additional in which isoniazid was most readily available in the use of companion drugs, the discharge of tubercle first year of its general use. bacilli to the surroundings will continue. Sooner In the geographical areas in which the sulfona- or later, in these circumstances, the majority of mides and penicillin were most readily available these tubercle bacilli will be isoniazid-resistant, as for use, there was no reason to withhold their tested in vitro and in the mouse. At least some of administration, and the widespread use to the these bacilli will presumably be capable of infecting maximum probably occurred very soon after the man and, if they do so, they presumably also would introduction of these drugs for general use. It was be uninfluenced by the administration of isoniazid. in these circumstances that a five-year period sufficed This, then, is the nature of our problem, but to define the magnitude of the drug-resistance pro- what is its magnitude? On this question, we are blem in crude outline. With tuberculosis, on the almost totally without meaningful information, and other hand, the localities in which the drug was must fall back on our general knowledge of the most readily available eight years ago were the very epidemiology of tuberculosis. localities in which the prevalence of tuberculosis was At the outset, in considering this question, it is probably the lowest. And, even in these localities, well to inquire whether the use of isoniazid has been because of the fear engendered by the ready isolation widespread for a sufficient period to let us derive of isoniazid-resistant tubercle bacilli, there was a any feeling of security from the lack of obvious fairly generalized conscious effort to withhold the epidemics with isoniazid-resistant tubercle bacilli. use of isoniazid in patients whose daily activities At the time of writing (May 1960) isoniazid has been were unsupervised. In addition, in these same in reasonably widespread use for considerably areas the prevalence of tuberculosis is low, but longer than had been the case with streptomycin at both the mortality and the morbidity have also the time isoniazid was introduced. In the case of been steadily falling at a fairly steep pace. Hence, the acute bacterial infections-for example, those even if isoniazid-resistant tubercle bacilli represented caused by gonococci, pneumococci, or staphylococci neither a greater nor a lesser threat than their iso- -by the end of the five-year period after the intro- niazid-susceptible brethren, their presence in new duction of a new drug, the extent to which drug- infections in the community would not be so readily resistant infections were developing as new infections apparent. It is for this reason that we cannot derive was reasonably clear. At least in these circumstances complete comfort from detailed studies such as that some outline of the magnitude of the problem in- reported from New York City (Chaves et al., 1956), volved could be relatively well perceived. With tu- in which it was found that during 1955 the incidence berculosis, however, except for the acute miliary and of patients with strains of tubercle bacilli apparently meningeal infections of infants and young children, significantly resistant to isoniazid when first dis- there is frequently a latent period of one or two, to covered was less than 0.8%4. Such a study does show as many as five, years between initiation of infection us that in a community with a falling morbidity ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 457 and mortality rate and an already low prevalence rent in areas of high and in areas of low tech- to start with, new infections with isoniazid-resistant nological development. tubercle bacilli have only gone from the point of It so happens that for the past nine years I have primary infection to clinical recognition in small been working simultaneously in an area of high and numbers. It does not necessarily follow, however, in an area of low technological development. In the that in areas with a high prevalence of infection and course of this sometimes rapidly shifting experience a high morbidity the widespread use of isoniazid I have become very much impressed with the fact without companion drugs might not be associated that, solely in terms of management, tuberculosis in with a somewhat higher attack rate of isoniazid- the former area represents almost a different disease resistant first infections. from that presented in the latter area. Without Thus from our knowledge of the epidemiology of labouring this point here, I would like to point tuberculosis and from our knowledge of anti- out that a clinician working in an area of high microbial therapy in general, we cannot derive com- technological development can be much freer from plete comfort from the fact that new infections due fears of the epidemiological problems of isoniazid- to isoniazid-resistant tubercle bacilli have not yet resistant tubercle bacilli than his colleague working appeared in appreciable numbers. in an area of low technological development. In A major question to be considered is whether there New York City, the area of high technological is any evidence that isoniazid-resistant tubercle development in which I work, the tuberculosis bacilli using the designation broadly-represent morbidity has been steadily declining, so that now any greater or any lesser danger from the standpoint only 13% of our 15-year-old schoolchildren are of contagion than that presented by tubercle bacilli positive cutaneous reactors to tuberculin. This is which are not resistant to isoniazid. As seen above, despite the fact that the city has always been re- the absence of obvious tiny "epidemics " at this ceiving a large number of inunigrants from other time really provides us with no information on this parts of our own country and from other countries. point. The fact that many isoniazid-resistant tu- In effect, the great tuberculosis epidemic of the bercle bacilli have altered pathogenicity for some nineteenth century seems to be finally leaving New animal species is a somewhat favourable sign in this York City. In these circumstances, even if the iso- connexion, but certainly cannot be taken to mean niazid-resistant tubercle bacilli excreted by a patient that sputum containing isoniazid-resistant tubercle represented a considerable menace to others, the end bacilli does not represent a danger to non-tubercu- result would not be a problem of great magnitude. lous persons. About all that can be said on this In contrast, in the area of low technological develop- question is that there is no particular reason to ment-the Navajo Indian Reservation in Arizona- believe that isoniazid-resistant tubercle bacilli have where the tuberculosis morbidity was high, the pre- any increased pathogenicity for man, but neither is sence of a number of adults excreting isoniazid- there adequate information to the effect that resistant tubercle bacilli in crowded homes with many their pathogenicity for man is generally dimi- small children might well have resulted in a problem nished. of considerably larger proportions. To what extent should our obvious ignorance of What should be our course in these two sets of the significance of isoniazid-resistant tubercle bacilli, circumstances and particularly in the latter? Should in terms of the spread of tuberculosis to others, we withhold the undoubted benefits of chemo- prevent us from using isoniazid, with or without a therapy because of a danger the reality of which has companion drug, on a wide scale in the treatment of not yet been completely substantiated? It seems to tuberculosis outside hospital? To some extent this me that the case for going ahead with the widespread question is a philosophical one, yet it has very prac- use of isoniazid, with or without a companion drug, tical implications. As I see it, our present state of considerably outweighs the case for not going ignorance should cause us to be cautious, and to ahead. modify and qualify our practices, but it should not The case in favour of going ahead is based on the be used as justification for failing to take advantage fact that with isoniazid, alone or with a companion of the obvious benefits of isoniazid to the fullest drug, one has a practicable means of delivering extent possible. Among the modifications and powerful antituberculous influences to patients who qualifications which I believe should be considered would otherwise not receive any treatment at all. is the fact that the situation is in some respects diffe- From our total experience in tuberculosis chemo- 458 W. MCDERMOTT therapy, we all recognize that considerably more than group (approximately 75-80 %) who could be half of such patients will attain a satisfactory result, started on the domiciliary chemotherapy, each in terms of regression of their lesions and reversal of patient should be periodically evaluated from the infectiousness, if they are treated with isoniazid with standpoint of his progress. If after four to six or without a companion drug. In short, the majority months of chemotherapy, tubercle bacilli are still of patients will be rendered non-infectious by the present in the sputum, the patient should be removed treatment. In some of those whose infectiousness from the larger group under chemotherapy and persists, many of the isoniazid-resistant tubercle subjected to collapse or excisional therapy. In bacilli may not have full pathogenicity for other this way the dispensary or hospital facilities for persons. The interruption of infectiousness in one collapse or excisional therapy could be used more member of a large family all living together might realistically for the relatively small proportion of reduce small family epidemics. Moreover, as there patients who clearly need such therapy. As it is is no reason to believe that isoniazid-resistant this group in which the continued excretion of tubercle bacilli have any increased pathogenicity isoniazid-resistant tubercle bacilli is most likely to for man, the considerable degree of resistance be quantitatively high, their conversion to the non- generally possessed by man might limit the conse- infectious state by surgery should be the most quences of a single drug-resistant strain to a number effective means of stemming the spread of the iso- of primary infections which do not develop into niazid-resistant tubercle bacilli. progressive disease. In short, if a goal be set of treating all patients In a situation in which crowded living quarters with chemotherapy, but separating off those who and substandard diet are frequently present, the continue to be infectious after five or six months best assurance against the theoretical dangers of of such chemotherapy, then the chances that the isoniazid-resistant tubercle bacilli would be to benefits of the programme will be nullified in time administer chemotherapy to ambulant tuberculous by the spread of isoniazid-resistant tubercle bacilli patients on a selective basis. By this I mean that seem very low. the great majority of patients with tuberculosis Finally, in this connexion, I am convinced that could be started on chemotherapy outside hospital, since the introduction of isoniazid far more people while a minority, perhaps 20%, should at the outset have died because they did not receive the drug be given some form of collapse or excisional therapy than have been seriously affected, one way or along with the chemotherapy. Of the majority another, by isoniazid-resistant tubercle bacilli.

COLLAPSE AND EXCISIONAL THERAPY

Strictly speaking, the question of collapse and would be to eliminate cavities to the extent that it is excisional therapy does not lie within the province possible. For many reasons, it is not always advi- of this paper. There is one aspect of this matter, sable to do this by surgical excision, and, indeed, however, that is related directly to questions of it is seldom advisable to use surgery in the early drug-resistance and antimicrobial therapy-namely, months of antimicrobial therapy. It seems to me, the virtual abandonment of pneumothorax and however, that we have been wrong in our aban- pneumoperitoneum as forms of therapy for tuber- donment of pneumothorax and pneumoperito- culosis. As mentioned above, the conditions of an neum. open cavity are absolutely ideal for the proliferation The reason for the unpopularity of these proce- of tubercle bacilli and, hence, for the emergence to dures is quite understandable, but is based on the predominance of the drug-resistant variants. There facts as they obtained in another day. During the comes a time, therefore, when the cavity itself can 'twenties and 'thirties-indeed, until 1946-pneumo- be regarded as a cause of drug resistance, rather than thorax, along with extensive thoracoplasty, was vir- its consequence. Obviously, therefore, an important tually the only therapy, except bed rest, available measure that could be taken to avoid drug-resistance for the patient with pulmonary tuberculosis. Because ANTIMICROBIAL THERAPY OF PULMONARY TUBERCULOSIS 459 thoracoplasty in those pre-penicillin days was a 2-4 cm in diameter and considerable pulmonary infil- rather heroic procedure, it was understandably tration in whom a satisfactory pneumothorax could avoided whenever possible. By the same token, be established in association with the chemotherapy pneumothorax, which was relatively easy to institute, regimens outlined above. If this were done, we was employed for all sorts of lesions. It was well should have far fewer cases in which the pulmonary realized that the procedure was a dangerous one in infiltration itself recedes satisfactorily during the certain types of situations and that it was parti- chemotherapy, but the patient is left with an open cularly dangerous when adhesions prevented satisfac- cavity which eventually gives rise to the problems tory collapse of the cavity. Nevertheless, as it re- of drug-resistance and therapeutic failure. Above presented essentially the only available therapy, the all, what we are interested in today is bringing under temptation to employ it beyond its real usefulness therapy the vast numbers of persons with pulmonary was irresistible and it was so employed. As a tuberculosis for whom hospitalization is difficult and, consequence, as we all know, large numbers of even when practicable, cannot always provide pleural effusions became infected as tuberculous appropriate facilities for excisional surgery. In empyemas and this complication itself had a case- these circumstances, the procedure ofpneumothorax, fatality rate of about 50%. which can be very well done by any practitioner It seems to me that it is remembrance of these with only a few weeks of training, would seem to things as they were, rather than appreciation of represent a highly satisfactory additional measure what they would be today, that has led us to to our chemotherapy of pulmonary tuberculosis. abandon this procedure, which might be most The procedure lends itself well to ambulatory treat- valuable in association with antimicrobial therapy. ment, requires only periodic visits (sometimes only For example, today the problem of pleural effusion every three weeks or so, once pneumothorax is and tuberculous and non-tuberculous empyema well established) and permits reasonable physical could presumably be easily handled with our avail- activity on the part of the person treated. In view able antimicrobial drugs. Moreover, with our of our present knowledge of the role of the cavity ability today to do excisional surgery that was not in chemotherapeutic failure, of our presumed abil- possible in the 'thirties, the patient with intrapleural ities to control the once serious complications of adhesions would not represent a temptation to pneumothorax, and of the great need for tuberculosis continue the pneumothorax to the danger point, therapy in areas in which excisional surgery might but instead could be handled by excisional therapy. not be so easily provided, a definite move should be Apart from this type of case, however, there are a made to reinvestigate the value of pneumothorax substantial number of patients with cavities of in the care of patients with pulmonary tuberculosis.

RftSUMIL

Les decouvertes des 15 dernieres annees ont radicale- premiere therapie, pour des raisons multiples et com- ment change les conceptions relatives au traitement de la plexes que l'auteur examine; traitement des malades tuberculose, devenue une maladie susceptible de ceder rendus non bacillaires par les medicaments, mais dont a la chimiotherapie. Celle de l'isoniazide, administr6e les lesions ne cicatrisent pas ou cicatrisent de fagon par voie orale, qui date d'environ neuf ans, a redonne anormale (kyste non tuberculeux du poumon); la duree et un espoir aux milliers de malades qui, dans de nom- la posologie de l'administration medicamenteuse; asso- breuses parties du monde, ne recevaient aucun traite- ciation des hormones st6roides aux medicaments anti- ment. Cet avantage n'a pas encore ete exploite comme il tuberculeux; mecanisme de l'activite des medicaments; devrait l'etre, et du temps a ete perdu aL redecouvrir des resistance des bacilles tuberculeux aux medicaments. faits connus pour d'autres maladies. Ayant consacre une grande partie de cet article a l'etude Partant de ces affirmations, l'auteur examine la situa- du probleme de la resistance des bacilles, l'auteur conclut tion actuelle: les avantages respectifs du traitement que les avantages de l'emploi de l'isoniazide surpassent chimiotherapique hospitalier et domestique; le choix de beaucoup ses d6savantages, et que, malgre les dangers des medicaments (isoniazide et streptomycine, selon d'apparition de cette resistance, qu'il ne faut pas sous- diverses posologies, isoniazide et PAS), toutes autres estimer, il n'y a actuellement aucune raison de ne pas therapies etant moins efficaces et trop toxiques pour etre faire un large usage de cette arme efficace dans la lutte generalisees; traitement des malades refractaires a une contre la tuberculose. 460 W. MCDERMOTT

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