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Streptomycin twice a week with daily PAS in the treatment of pulmonary tuberculosis
x82
Tubercle, Lond., (I957) , 38, I82
Streptomycin Twice a Week with Daily PAS in the Treatment of Pulmonary Tuberculosis By T. W. L L O Y D from St. IVulstan's Hospital, Mah,ern I n the last five years the routine use of streptomycin on two or three days of the week with PAS daily has been widely practised. T e m p e l and others (195x) were among, the first to report on this combination of drugs, which they found clinically as effective over a period of I2o days as any regime of streptomycin alone and very m u c h more effective bacteriologically. Recently the intermittent use of streptomycin in combination either with daily PAS or daily isoniazid has been sharply criticized (Crofton, i956) on the grounds that it is less effective than daily streptomycin, especially in the suppression of resistant bacilli; but though it is true that the use of intermittent'streptomycin and daily isoniazid has been shown to be inferior in this respect to daily streptomycin and isoniazid (Medical Research Council, I955) , there is no published evidence suggesting that intermittent Streptomycin with daily PAS is also inferior to the two drugs daily. When the intermittent use of streptomycin was begun at this hospital it was c o m bined with 3 g- sodium-PAS four times daily. T h e results were not found wholly satisfactory in that in some cases resistant bacilli were seen to develop, and when the Medical Research Council (M.R.C.) published the results of its second trial of daily streptomycin with PAS (Medical Research Council, I952) it was noted that, though there was little clinical difference, the use of sodium-PAS 5 g. four times daily was definitely superior to both 2.5 g- and I-25 g. four times daily in suppressing streptomycin resistance. These results have g e n e r a l l y b e e n interpreted as mealaing that 20 g. a day is better than I o g . or 5 g- a d~ty. I t s e e m e d possible, however, t ~ t in fact the correct deduction was that the peak blood leveI attained with a d6ge of 5 gsodium-PAS was more effective than that obtained with smaller doses. In August I952 , therefore, it was planned to use as a routine treatment streptomycin sulphate I g. twice a week with sodium-PAS 5 g. twice dMly in the hope that the bacterial results would be more satisfactory.
Plan o f the Investigation For three and a half years, except for one period of six months, the regime was used in nearly every case in which chemotherapy was indicated. T h e results are here reported of the treatment of 2oo sputum-positive patients for minimum periods of twenty-four weeks without interruption, except as indicated below, and without surgical treatment of any kind, major or minor, during this initial period. This is a selected group only in that all patients sputum-negative on admission and all whose treatment was interrupted by surgery or was not continued on this regime for as long as twenty-four weeks have been excluded, as also have a few cases of fulminating
I N T E R M I T T E N T STREPTOMYCIN
t83
disease in which daily streptomycin, generally with isoniazid, was used and those patients whose bacilli were found on admission to be resistant to any drug.* Treatment was continuous except in 12 patients who developed allergic drug reactions after three or four weeks. In only one of these did this break last more than three weeks before chemotherapy was resumed in full dosage. The as'erage period of treatment was thirty-seven weeks and varied from twenty-four to ninety weeks. This figure does not necessarily indicate the total duration of chemotherapy given since this has often been extended in other forms and in some cases continues on the original regime. In the years ~95~-54 it was rather exceptional to admit patients who had received no chemotherapy at all. Among these 200, 32 were 'retreatment' cases and 74 had been given treatment for a n average of eight weeks while awaiting admission. It is impossible to make accurate allowance for this in estimating progress. I n the figures below some allowance has been made by correcting the observed date of sputum conversion to include the sum of chemotherapy given. The results at six months are not affected. There were I I6 men and 84 women. Their ages ranged from x6 to 61 but the age distribution was in no way remarkable. The ~oo patients were classified after the method of Foster Carter and others (I95~). (Class I - unilateral disease, only one zone involved; Class II - unilateral or bilateral disease having 2 or 3 zones affected; Class I I I - 4 or more zones affected.) There were 54 in Class I, 99 in Class II and 47 in Class III. X-ray films were taken at two-month inter~-ais and sputum was examined by smear and culture on two or three successive days each month. When sputum was absent 2 laryngeal swabs were cultured each month. Sensitivity tests to streptomycin and PAS were set up at three-month intervals on positive cultures. The tests were carried out by the method described by the Medical Research Council (1953a). The organism was considered to have become resistant to streptomycin if it grew in Dubos medium containing x t~g.[ml, of the drug. This concentration is nearer four than eight times that normally required to inhibit H37Rv in our laboratory and is therefore at least as strict as the Medical Research Council's definition of resistance (Medical Research Council., x95o ). Sputum conversion was not claimed until all smears and cultures for a minimum of three montKs had proved negative. Streptomycin was given on the same days each week and PAS was given in solution half a n hour after breakfast and supper.
Results
RadiographicChange R a d i o g r a p h i c c h a n g e w a s assessed b y t h e a u t h o r o n r e p e a t e d s c r u t i n y o f t h e films o f e a c h case. T h i r t y - s e v e n cases s h o w e d l i t t l e o r n o c h a n g e , x x x m o d e r a t e i m p r o v e m e n t a n d 52 w e l l - m a r k e d o r s p e c t a c u l a r i m p r o v e m e n t . C a v i t i e s i c m . o r m o r e i n diameter were visible at the time of admission on straight postero-anterior film in x33 cases. T h e s e w e r e classified b y m e a s u r e m e n t . F o r t y - t w o w e r e b e t w e e n I a n d c m . i n d i a m e t e r , 58 m e a s u r e d f r o m 2 to 4 c m . a n d 33 w e r e l a r g e r . C a v i t y c l o s u r e w a s o b t a i n e d w i t h i n six m o n t h s i n 35 o u t o f 42 s m a l l c a v i t i e s , 33 o u t o f 5 8 m e a s u r i n g 2 - 4 c m . , a n d i n x6 o f t h e 33 v e r y l a r g e c a v i t i e s .
SputumExamination S p u t u m c o n v e r s i o n o c c u r r e d i n i 5 9 (79"5 p e r c e n t ) cases w i t h i n six m o n t h s ( T a b l e I ) . F o r t y - o n e p a t i e n t s w e r e f o u n d still t o h a v e p o s i t i v e s p u t u m a t six m o n t h s or later. Before discussing these I must add that, on further prolongation of chemot t i e r a p y b e y o n d t h e s e v e n t h m o n t h i n 32 o f t h e s e 4 I, s p u t u m c o n v e r s i o n t o o k p l a c e i n 8 m o r e cases. M a j o r s u r g i c a l t r e a t m e n t w a s u s e d a f t e r six m o n t h s i n 7 ° a n d A P o r *Resistant bacilli occurring in an untreated case are still rare. Among 436 consecutive sputumpositive patients, sensitivity .tests on admission to this hospital showed resistance of some kind in 43 (xo.2 per cent). Multiple resxstance was seen in t2 cases; isoniazid resistance in 22 (in 16 of these the bacilli grew on more than 5 tag./ml.) ; PAS resistance was seen in 2 x instances and streptomycin resistance in 20 (in 12 of these the bacilli grew in 5 #g./ml.). There was a n entirely satisfactory explanation in the past history of their chemotherapy in all but 6 patients, either much chemotherapy or single drugs having been given. Of these 6 who had never been given the drug in question before, in I case streptomycin resistance was present to x/~g./ml.; in ~ resistance to isoniazid (x #g./ml. or 5 tzg./ml.) was found and in 3 PAS resistance of tiffs order was also found. PAS sensitivity tests are well known for unreliability in the x to 5 #g./ml. range and they require confirmation before acceptance. This was possible in only t of these 3.
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TABLE I . - RESULTS OF STREPTOMYCIN SENSITIVITY TESTS
Patients culture positive with sensitivity tests Total Culture Culture Total with negative: positive: results Resistant Resistant no test no test available Sensitive to to Total trealment culture (months) examined possible available I tLg.[ml. 5 t~g.[ m!. resistaut
Duration
of
3 I86 6 2oo 9 (approx.)56 I2 15
I42 166 42 8
7 2 3 --
37 32 Ir 7
35 25 8 3
2 5 I x
-2 2 3
2 7 3 4
PP in Io cases. I n 17 surgical t r e a t m e n t was given while the p a t i e n t was still s p u t u m positive; a n d in one sputum-positive case it was refused. I n c l u d i n g patients treated surgically s p u t u m conversion was o b t a i n e d in i8 4 (9 2 per cent). I n tlae absence of a control series it is difficult to d r a w a n y definite conclusion from these results, b u t some a t t e m p t is m a d e below.
Sensitivity Tests T h e chief interest lies in the 41 cases in wlfich s p u t u m was found positive to s m e a r or culture after six m o n t h s ' t r e a t m e n t . These i n c l u d e those which r e m a i n e d continuously positive a n d all in w h o m a n y isolated positive test occurred after the twenty-fourth week.
Streptomych, Sensitivity. - I n 4 cases a single or occasional positive smear was f o u n d d u r i n g the second s i x - m o n t h period a n d c u l t u r e r e m a i n e d negative. I n 3 others o n e isolated positive c u l t u r e was o b t a i n e d a n d the o p p o r t u n i t y of d o i n g a sensitivity test was lost. F r o m the 34 cases r e m a i n i n g , resistant bacilli were recovered at some time in x I cases ( T a b l e I). Successful tests were d o n e at six m o n t h s in 32 cases; 7 of these yielded bacilli resistant to streptomycin. Later tests were done between e i g h t a n d eleven m o n t h s in x I cases; resistant strains were f o u n d i n 3 (in 2 the o r g a n i s m h a d a l r e a d y been found resistant at six months, a n d the third case (A. G.) is reported below). 0 n l y 7 cases still h a d positive s p u t u m at a n d after twelve m o n t h s a n d resistant strains were f o u n d in 4 of these. I n I case this confirmed the same f i n d i n g at six a n d n i n e m o n t h s a n d i n 2 cases the bacilli were n o w found resistant for the first time after a series of sensitive tests. T h e fourth case (F. T.) is reported below. I n 4 cases the bacilli were n e v e r found resistant to 5 pg./ml., that is to say t h a t resistance was p r o b a b l y not absolute. I n 3 cases resistance was present at six m o n t h s to I /zg.]ml. b u t was f o u n d later to have increased. Resistance to 5/zg./ml. was f o u n d at some time in 7 cases. This h a d developed wittfin six m o n t h s i n 2 cases; it was f o u n d at n i n e months i n 2 (of which A. G. was one), a n d at twelve m o n t h s in 3 more (of w h i c h F. T. was one). I n 2 cases particular circumstances d e m a n d mention. A. G., a w o m a n of 4o with extensive bilateral excavated disease de~-eloped a severe a n d persistent allergic reaction to streptomycin in the early weeks; desensitization was delayed b u t even so it took four weeks to complete. T h o u g h this period was covered with full PAS dosage it seems possible that it was this circumstance which encouraged the development of d r u g resistance. As a consequence of this interruption sensitivity tests were unfortunately n o t done till t r e a t m e n t h a d been resumed for a period of six m o n t h s a n d t h e case is
therefore recorded as being tested and found resistant nine months after the beginning of treatfiaent. The other ease, F. T., omitted from the results at six months was an elderly man whose sputum was constantly positive on smear but negative on culture. Several attempts at culture failed and when
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INTERMITTENT STREPTOMYCIN
a reluctant growth o f highly resistant organisms was obtained it was from s p u t u m produced some time after discharge, a n d there is good reason to fear that this patient h a d become tired o f PAS as a regular medicine some weeks before. Tile case is recorded, however, as being resistant to streptomycin at twelve months.
P A S SensitMty. - PAS resistance was f o u n d only in 6 cases. I n 3 a low d e g r e e o f resistance was p r e s e n t a t six m o n t h s ( g r o w t h on I ttg./ml.) a n d in 3 g r o w t h was observed on 5 t~g./ml-, I a t nine m o n t h s (case A. G.) a n d 2 for t h e first t i m e at twelve months. I n 5 o f these cases p a r a l l e l resistance to s t r e p t o m y c i n was present. Evaluation T h e 41 p a t i e n t s w h o tailed to convert t h e i r s p u t u m in six m o n t h s w e r e p r e d o m i n a n t l y those wittl extensive disease. T h e y w e r e d i s t r i b u t e d as follows: Class I : 4, Class I I : i7, Class I I I : 2I. I t is this observation w h i c h makes it necessary to a t t e m p t a n evaluation o f t h e clinical success o f the m e t h o d despite t h e absence o f controls, for it seems possible t h a t the excellent results o b s e r v e d in cases o f lesser severity m a y h a v e .given a false impression o f g e n e r a l satisfaction. C o m p a r i s o n w i t h A m e r i c a n figures IS m a d e difficult b y the r a t h e r different p e r i o d s o f assessment a n d the different t e c h n i q u e used for e s t i m a t i n g resistance. C o m p a r i s o n c a n best b e a t t e m p t e d w i t h the figures o f the M e d i c a l R e s e a r c h C o u n c i l trials in w h i c h t h e c o m b i n a t i o n o f d a i l y s t r e p t o m y c i n w i t h P A S 2o g. was used ( M e d i c a l R e s e a r c h Council, I95O , I952 , 1953b ). I n the first two o f these trials only cases o f a c u t e b i l a t e r a l disease in y o u n g a d u l t s were a d m i t t e d . I n the t h i r d a w i d e r v a r i a t i o n was a d m i t t e d i n c l u d i n g some cases w h i c h h a d received some c h e m o t h e r a p y . I t is w i t h t h e l a t t e r g r o u p of Io2 cases t h a t c o m p a r i s o n m a y most r e a s o n a b l y be m a d e . U n f o r t u n a t e l y t h e M . R . C . trials w e r e b a s e d on results after t h r e e m o n t h s ' t r e a t m e n t only a n d a n insignificant n u m b e r o f patients c o n t i n u e d c h e m o t h e r a p y w i t h o u t i n t e r r u p t i o n for six m o n t h s ; m o r e o v e r , collapse t h e r a p y was i n t r o d u c e d in a substantial n u m b e r o f cases in the second t h r e e - m o n t h period. I n T a b l e I I t h r e e comparisons a r e m a d e ; first, b e t w e e n the p r e s e n t series after three m o n t h s ' t r e a t m e n t a n d the cases o f the t h i r d M . R . C . t r i a l ; second, b e t w e e n the p r e s e n t series after w i t h d r a w i n g the least extensive class o f disease a n d the s a m e M . R . C . cases; thirdly, the relatively small n u m b e r o f m y cases in Class I I I a r e c o m p a r e d w i t h t h e total TABLE I I . - THE INCIDENCE OF STREPTOMYCIN-RESISTANT ORGANISMS IN TIIE PRESENT SERIES COMPARED x,VITII TIIAT AMONG PATIENTS IN T I I R E E ~ { . R . C .
TRIALS HAVING
DAILY STREPTOMYCIN AND PAS (20 o.)
Present series: all c a s e s . . Present series: Classes I I and III . . . . M . R . C . T r i a l , I953 .. Present series: Class I I I cases • • • G r o u p I eases, ]VI.R.C~ Trials, I95O, z952, I953
Total patients with culture examined
Wo. with positive culture available at 3 months (a)
Resistant
I86
37
2
--
136 IO2
33 17
2 2
43
20
i
II 4
58
2
Con~loderate: siderable : resistance resistance ratio ratio 8-99 > zoo
Total No.
Total as % of (a)
2
5
--
2
2
4
6 23
--
I
5
3
5
i
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n u m b e r of Group z M.R.C. cases (acute bilateral disease)admitted to the three trials. F r o m these figures it appears that even after withdrawal of those patients having least extensive disease the incidence of drug resistance in this series is noticeably less than a m o n g the most varied group admitted to the M.R.C. trials; and that compari'.'on between the M.R.C. Group I cases and the most extensive class of disease in this series shows no evidence whatever that the regime under discussion is inferior in value. It is perhaps also worth noting that I of the 2 patients found to have resistant organisms after three months of this treatment had in addition had intermittent streptomycin with PAS for ten weeks before admission to hospital. Comparison can also be attempted with a rather more similar series of cases published, with a different emphasis, by Hoyle and others (I955). One hundred a n d eleven sputum-positive patients were treated with chemotherapy of various kinds for nine or more months. T h e initial regime was daily streptomycin with either PAS or isoniazid and treatment was continued with intermittent streptomycin with daily PAS. T h e change was usually m a d e after three or four months' treatment. These authors found that positive sputum persisted at three months in 26 per cent and at six months in i6 per cent of their patients. There is little difference between these figures and the 32 per cent and 2o per cent of the present series. T h e incidence of cavitation, the size of the cavities and the incidence of closure among cavities of various sizes during the first six months of chemotherapy in their series seem also to have been very closely similar to the results here reported. T h e authors also stated that sensitivity tests were done at six months in 8 cases and in 2 of these organisms resistant to streptomycin were found, a proportion very similar to that reported above (22 per cent). F r o m this comparison of what seems to be similar material it is reasonable to deduce that the use of streptomycin daily for the first three months of treatment did not produce results conspicuously superior to those obtained x~ith intermittent streptomycin with daily PAS from the beginning. Discussion T h e detection of isolated resistant strains of bacilli during chemotherapy is not of itselfa secure basis for assuming any drug to have lost its value, but this criterion has been so widely Used as one method of evaluating drug treatment that comparison of different methods cannot be attempted without it. T h e r e is remarkably little literature on the relative merit of daily streptomycin and PAS and intermittent streptomycin with daily PAS. T h e US Public Health Service Cooperative Investigation (I953) compared intermittent streptomycin and daily PAS with the results ofisoniazid alone and with streptomycin and isoniazid treatment and found it inferior in value to the latter combination. Tile major work in which the two regimes are compared is the U.S. Veterans' Administrations, A r m y and N a v y co-operative trial, a review of which has lately been written by Tucker (I955). In this trial considerable numbers were involved. After deducting withdrawals approximately 380 patients on intermittent streptomycin and daily PAS are compared with 280 on streptomycin z g. daily with PAS and 290 on streptomycin ~ g. daily with PAS. After exhaustive comparison of the regimes no distinction could be m a d e between the results obtained with them even in the treatment of very advanced and extensively excavated disease, nor did analysis of the development of resistant organisms show any considerable difference (McLean, I954). These findings in so considerable a controlled series are impressive and agree with the tentative conclusion reached from studying m y material that, so far as the results can be measured in terms of routine clinical and pathological observations, the improvement obtained by giving streptomycin twice a week with PAS in doses of 5 g. twice daily is probably as good.as can be obtained with any combination of these two drugs.
I N T E R M I T T E N T STREPTOMYCIN
x87
It is necessary to make only one reservation. T h e bacteriological examination of resected tissue after chemotherapy is a rather refined, but obviously interesting method of estimating its effect, even though such material can be obtained only from a highly selected group. D'Esopo and others (1953) in a small series ofsuch studies failed to grow bacilli from the resected lesions of patients who had received daily streptomycin and PAS for more than eight months, but they did get positive c~:ltures after the same period on twice weekly treatment. T h e material was very scanty and the method had not been perfected (Hobby and others, I954). It is possible that future studies of this kind may reveal a difference between the regimes in this respect, but it is noteworthy that Steele and others (I953) failed to find any difference and other authors were quite unable to correlate findings of this nature with the form and duration of pre-operative treatment (Auerbach and others, I955a , i955b; Canetti, I954). An alternative and less esoteric approach would be to compare the relative incidence.of relapse among these groups of patients, but unfortunately the data are not available. In the U.S. Veterans' Administration trial sodium-PAS was given in 5 g- doses three times daily. Though this dose has found wide acceptance in this co~:ntry many physicians g'~ve less. I believe the individual dose i~ important. T h e Medical Research Council (I952) has proved this in the daily streptomycin and PAS regime, for decidedly inferior results were obtained when the individual PAS dose was halved. In another trial (Medical Research Council, I955) it was proved that PAS 5 g. twice daily was not inferior to PAS 5 g- four times a day when given with isoniazid. T h e series here reported seems to show that this dose is also adequate when streptomycin is given twice a week. I believe also that the method of administration is important. Absorption from the bowel is slow when PAS is given in any form of tablet (Battersby and others, 195 o) and the blood levels of PAS attained by the use of tablets do not compare with those obtained when PAS is given as solution or powder. I believe that the concentration reached in plasma and body fluids must have an important bearing on the value of this drug and I hold therefore that the use of PAS tablets of all kinds is pernicious. M y patients take an orange-flavoured solution with little complaint; if this is not tolerated rice-paper cachets are a convenient and satisfactory alternative, though this usually means a higher (6 g.) single dose. Intermittent streptomycin with daily PAS in this dosage, though it appears to be the equal of both drugs given daily, is not the most effective treatment known. T h e Medical Research Council established the superior value of daily streptomycin and isoniazid. Sputum conversion after six months of the order of 92-IOO per cent was obtained in their trials, both from the use of this combination and of isoniazid and PAS (Medical Research Council, I955). Tucker and Livings (I955) have also shown that streptomycin and PAS in any combination is inferior in value to isoniazid and PAS, though the difference is not very great; and in the very chronic open case it has been suggested that the continuous use of a single combination of drugs may give less good results than a regime involving rotation of several combinations (Joiner and others, x956). Horne and Grant (i956) have emphasized the need to set the most exacting standards of therapeutic success, but the holding of high standards does not demand the application of the most intensive treatment in every case; some indeed are reluctant to adventure the two most potent drugs at one time unnecessarily (Scadding, 1955) ; and the physician can still exercise personal judgment in choosing his treatment from a number of valuable chemotherapeutic combinations. T h e most acute and extensive disease is best treated by a regime which includes isoniazid; and streptomycin and PAS may not be ideal as an initial treatment for those elderly or bronchitic patients to whom surgery can never be applied to convert a persistent positive sputum or make secure a precarious sputum conversion. But the p.rognosis of minor and moderately advanced disease nowadays is good and the regime described is attended by excellent results in such cases.
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TUBERCLE
Summary
200 s p u t u m - p o s i t i v e patients w e r e t r e a t e d for a t least twenty-four weeks w i t h s t r e p t o m y c i n x g. twice a week a n d PAS 5 g- twice daily. S p u t u m conversion was o b t a i n e d in 83. 5 p e r c e n t on c h e m o t h e r a p y a l o n e a n d in 92 p e r cent w i t h tlm a i d o f surgery. S t r e p t o m y c i n - r e s i s t a n t organisms w e r e f o u n d a t s o m e stage in i I cases. I n 7 o f these the o r g a n i s m was resistant to 5 /~g./ml. P A S resistance was e n c o u n t e r e d in 6 instances, in 5 o f w h i c h t h e r e was c o n c o m i t a n t s t r e p t o m y c i n resistance. T h e i m p o r t a n c e o f using P A S in solution o r c a c h e t form a n d o f giving doses o f n o t less t h a n 5 g- e a c h is e m p h a s i z e d . T h e s e results seem to s u p p o r t the view t h a t i n t e r m i t t e n t s t r e p t o m y c i n a n d d a i l y P A S is n o t less v a l u a b l e t h a n b o t h drugs d a i l y . References
Auerbach, O., Hobby, G. L., Small, M.J., Lenert, T. F., and Comer, J. V. (I955 a) 07. thorac. Surg., 29, xo9. Auerbach, O., Hobby, G. L., Small, M.J., Lenert, T. F., and Vaughan, L. H. (I955 b) Amer. Rev. Tnberc., 72) 386. Battersby, J. M., Crulckshank, D. B., Hesling, C., and Hudson, E. H. (x95o) Tubercle, Lond., 3x) ~8~. Canetti, G. (1954) Bull. Un. int. Tuberc., 24, 144. Crofton, J. 0956) Brit. rned..7., i, 345. D'Esopo, N., Bernstein, S., Decker, A. M., Raleigh, J. W., and Steenken, ~V. 0953) Transactions of the I2th Conference on Chemotherapy of Tubcrculosls, U.S. Veterans Administration, Army and Navy, p. 229. Foster-Carter, A. F., Myers, M., Goddard, D. L. H., Young, F. H., and Benjamin, B. (195~) Brombton IIosp. Rep., 2x) x.
Hobby, G. L., Auerbach, O., Lenert, T. F., Small, M.J., and Comer, J. V. (i954) Amer. Re~. ~berc., 7 o, I9I. Horne, J. W., and Grant, I. W. B. (I956) Brit. reed.ft., i, 803. Hoyle, C., Nicholson, H., and Dawson, J. (1955) Lancet, il, i3xo. Joiner, C. L., MacLean, K. S., Marsh, K., Carrol, J. D., and Knox, R. (x956) Lancet, ii, x65. McLean, R. L. (I954) Transactions of the x3th Conference on Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Na~T, p. 43. Medical Research Council 095 o) Brit. reed. 07, ii, m73. Medical Research Council (I952) Brit. :ned. 07, i, x157. Medical Research Council (1953a) Lancet, ii, 2 I3. Medical Research Council (1953b) Brit. reed. jT., i, 521. Medical Research Council (x955) Brit. reed. ft., i, 435. Scadding, J. G. 0955) Lancet, ii, 99. Steele, J. D., Narodick, B. G., and Cadden, A. V. (t953) 07. thorac. Surg., 26) 459Tempel, 13. W., Hughes, F.J., Mardis, R. E., Towbin, M. N., and Dye, W. E. 0 9 5 0 Amer. Rtv. Tuberc., 63, 295. Tucker, W. B. (x955) Amer. Rev. Tuberc., 72, 733. Tucker, W. B., and Livings, D. G. (1955) Amer. Rev. Tuberc., 72, 756. U.S. Public Health Ser~-iceCooperative Investigation (I953) Amtr. Rev. Tuber¢., 67) 553.
Tubercle, Lond., (I957) , 38, I82
Streptomycin Twice a Week with Daily PAS in the Treatment of Pulmonary Tuberculosis By T. W. L L O Y D from St. IVulstan's Hospital, Mah,ern I n the last five years the routine use of streptomycin on two or three days of the week with PAS daily has been widely practised. T e m p e l and others (195x) were among, the first to report on this combination of drugs, which they found clinically as effective over a period of I2o days as any regime of streptomycin alone and very m u c h more effective bacteriologically. Recently the intermittent use of streptomycin in combination either with daily PAS or daily isoniazid has been sharply criticized (Crofton, i956) on the grounds that it is less effective than daily streptomycin, especially in the suppression of resistant bacilli; but though it is true that the use of intermittent'streptomycin and daily isoniazid has been shown to be inferior in this respect to daily streptomycin and isoniazid (Medical Research Council, I955) , there is no published evidence suggesting that intermittent Streptomycin with daily PAS is also inferior to the two drugs daily. When the intermittent use of streptomycin was begun at this hospital it was c o m bined with 3 g- sodium-PAS four times daily. T h e results were not found wholly satisfactory in that in some cases resistant bacilli were seen to develop, and when the Medical Research Council (M.R.C.) published the results of its second trial of daily streptomycin with PAS (Medical Research Council, I952) it was noted that, though there was little clinical difference, the use of sodium-PAS 5 g. four times daily was definitely superior to both 2.5 g- and I-25 g. four times daily in suppressing streptomycin resistance. These results have g e n e r a l l y b e e n interpreted as mealaing that 20 g. a day is better than I o g . or 5 g- a d~ty. I t s e e m e d possible, however, t ~ t in fact the correct deduction was that the peak blood leveI attained with a d6ge of 5 gsodium-PAS was more effective than that obtained with smaller doses. In August I952 , therefore, it was planned to use as a routine treatment streptomycin sulphate I g. twice a week with sodium-PAS 5 g. twice dMly in the hope that the bacterial results would be more satisfactory.
Plan o f the Investigation For three and a half years, except for one period of six months, the regime was used in nearly every case in which chemotherapy was indicated. T h e results are here reported of the treatment of 2oo sputum-positive patients for minimum periods of twenty-four weeks without interruption, except as indicated below, and without surgical treatment of any kind, major or minor, during this initial period. This is a selected group only in that all patients sputum-negative on admission and all whose treatment was interrupted by surgery or was not continued on this regime for as long as twenty-four weeks have been excluded, as also have a few cases of fulminating
I N T E R M I T T E N T STREPTOMYCIN
t83
disease in which daily streptomycin, generally with isoniazid, was used and those patients whose bacilli were found on admission to be resistant to any drug.* Treatment was continuous except in 12 patients who developed allergic drug reactions after three or four weeks. In only one of these did this break last more than three weeks before chemotherapy was resumed in full dosage. The as'erage period of treatment was thirty-seven weeks and varied from twenty-four to ninety weeks. This figure does not necessarily indicate the total duration of chemotherapy given since this has often been extended in other forms and in some cases continues on the original regime. In the years ~95~-54 it was rather exceptional to admit patients who had received no chemotherapy at all. Among these 200, 32 were 'retreatment' cases and 74 had been given treatment for a n average of eight weeks while awaiting admission. It is impossible to make accurate allowance for this in estimating progress. I n the figures below some allowance has been made by correcting the observed date of sputum conversion to include the sum of chemotherapy given. The results at six months are not affected. There were I I6 men and 84 women. Their ages ranged from x6 to 61 but the age distribution was in no way remarkable. The ~oo patients were classified after the method of Foster Carter and others (I95~). (Class I - unilateral disease, only one zone involved; Class II - unilateral or bilateral disease having 2 or 3 zones affected; Class I I I - 4 or more zones affected.) There were 54 in Class I, 99 in Class II and 47 in Class III. X-ray films were taken at two-month inter~-ais and sputum was examined by smear and culture on two or three successive days each month. When sputum was absent 2 laryngeal swabs were cultured each month. Sensitivity tests to streptomycin and PAS were set up at three-month intervals on positive cultures. The tests were carried out by the method described by the Medical Research Council (1953a). The organism was considered to have become resistant to streptomycin if it grew in Dubos medium containing x t~g.[ml, of the drug. This concentration is nearer four than eight times that normally required to inhibit H37Rv in our laboratory and is therefore at least as strict as the Medical Research Council's definition of resistance (Medical Research Council., x95o ). Sputum conversion was not claimed until all smears and cultures for a minimum of three montKs had proved negative. Streptomycin was given on the same days each week and PAS was given in solution half a n hour after breakfast and supper.
Results
RadiographicChange R a d i o g r a p h i c c h a n g e w a s assessed b y t h e a u t h o r o n r e p e a t e d s c r u t i n y o f t h e films o f e a c h case. T h i r t y - s e v e n cases s h o w e d l i t t l e o r n o c h a n g e , x x x m o d e r a t e i m p r o v e m e n t a n d 52 w e l l - m a r k e d o r s p e c t a c u l a r i m p r o v e m e n t . C a v i t i e s i c m . o r m o r e i n diameter were visible at the time of admission on straight postero-anterior film in x33 cases. T h e s e w e r e classified b y m e a s u r e m e n t . F o r t y - t w o w e r e b e t w e e n I a n d c m . i n d i a m e t e r , 58 m e a s u r e d f r o m 2 to 4 c m . a n d 33 w e r e l a r g e r . C a v i t y c l o s u r e w a s o b t a i n e d w i t h i n six m o n t h s i n 35 o u t o f 42 s m a l l c a v i t i e s , 33 o u t o f 5 8 m e a s u r i n g 2 - 4 c m . , a n d i n x6 o f t h e 33 v e r y l a r g e c a v i t i e s .
SputumExamination S p u t u m c o n v e r s i o n o c c u r r e d i n i 5 9 (79"5 p e r c e n t ) cases w i t h i n six m o n t h s ( T a b l e I ) . F o r t y - o n e p a t i e n t s w e r e f o u n d still t o h a v e p o s i t i v e s p u t u m a t six m o n t h s or later. Before discussing these I must add that, on further prolongation of chemot t i e r a p y b e y o n d t h e s e v e n t h m o n t h i n 32 o f t h e s e 4 I, s p u t u m c o n v e r s i o n t o o k p l a c e i n 8 m o r e cases. M a j o r s u r g i c a l t r e a t m e n t w a s u s e d a f t e r six m o n t h s i n 7 ° a n d A P o r *Resistant bacilli occurring in an untreated case are still rare. Among 436 consecutive sputumpositive patients, sensitivity .tests on admission to this hospital showed resistance of some kind in 43 (xo.2 per cent). Multiple resxstance was seen in t2 cases; isoniazid resistance in 22 (in 16 of these the bacilli grew on more than 5 tag./ml.) ; PAS resistance was seen in 2 x instances and streptomycin resistance in 20 (in 12 of these the bacilli grew in 5 #g./ml.). There was a n entirely satisfactory explanation in the past history of their chemotherapy in all but 6 patients, either much chemotherapy or single drugs having been given. Of these 6 who had never been given the drug in question before, in I case streptomycin resistance was present to x/~g./ml.; in ~ resistance to isoniazid (x #g./ml. or 5 tzg./ml.) was found and in 3 PAS resistance of tiffs order was also found. PAS sensitivity tests are well known for unreliability in the x to 5 #g./ml. range and they require confirmation before acceptance. This was possible in only t of these 3.
TUBERCLE
x84
TABLE I . - RESULTS OF STREPTOMYCIN SENSITIVITY TESTS
Patients culture positive with sensitivity tests Total Culture Culture Total with negative: positive: results Resistant Resistant no test no test available Sensitive to to Total trealment culture (months) examined possible available I tLg.[ml. 5 t~g.[ m!. resistaut
Duration
of
3 I86 6 2oo 9 (approx.)56 I2 15
I42 166 42 8
7 2 3 --
37 32 Ir 7
35 25 8 3
2 5 I x
-2 2 3
2 7 3 4
PP in Io cases. I n 17 surgical t r e a t m e n t was given while the p a t i e n t was still s p u t u m positive; a n d in one sputum-positive case it was refused. I n c l u d i n g patients treated surgically s p u t u m conversion was o b t a i n e d in i8 4 (9 2 per cent). I n tlae absence of a control series it is difficult to d r a w a n y definite conclusion from these results, b u t some a t t e m p t is m a d e below.
Sensitivity Tests T h e chief interest lies in the 41 cases in wlfich s p u t u m was found positive to s m e a r or culture after six m o n t h s ' t r e a t m e n t . These i n c l u d e those which r e m a i n e d continuously positive a n d all in w h o m a n y isolated positive test occurred after the twenty-fourth week.
Streptomych, Sensitivity. - I n 4 cases a single or occasional positive smear was f o u n d d u r i n g the second s i x - m o n t h period a n d c u l t u r e r e m a i n e d negative. I n 3 others o n e isolated positive c u l t u r e was o b t a i n e d a n d the o p p o r t u n i t y of d o i n g a sensitivity test was lost. F r o m the 34 cases r e m a i n i n g , resistant bacilli were recovered at some time in x I cases ( T a b l e I). Successful tests were d o n e at six m o n t h s in 32 cases; 7 of these yielded bacilli resistant to streptomycin. Later tests were done between e i g h t a n d eleven m o n t h s in x I cases; resistant strains were f o u n d i n 3 (in 2 the o r g a n i s m h a d a l r e a d y been found resistant at six months, a n d the third case (A. G.) is reported below). 0 n l y 7 cases still h a d positive s p u t u m at a n d after twelve m o n t h s a n d resistant strains were f o u n d in 4 of these. I n I case this confirmed the same f i n d i n g at six a n d n i n e m o n t h s a n d i n 2 cases the bacilli were n o w found resistant for the first time after a series of sensitive tests. T h e fourth case (F. T.) is reported below. I n 4 cases the bacilli were n e v e r found resistant to 5 pg./ml., that is to say t h a t resistance was p r o b a b l y not absolute. I n 3 cases resistance was present at six m o n t h s to I /zg.]ml. b u t was f o u n d later to have increased. Resistance to 5/zg./ml. was f o u n d at some time in 7 cases. This h a d developed wittfin six m o n t h s i n 2 cases; it was f o u n d at n i n e months i n 2 (of which A. G. was one), a n d at twelve m o n t h s in 3 more (of w h i c h F. T. was one). I n 2 cases particular circumstances d e m a n d mention. A. G., a w o m a n of 4o with extensive bilateral excavated disease de~-eloped a severe a n d persistent allergic reaction to streptomycin in the early weeks; desensitization was delayed b u t even so it took four weeks to complete. T h o u g h this period was covered with full PAS dosage it seems possible that it was this circumstance which encouraged the development of d r u g resistance. As a consequence of this interruption sensitivity tests were unfortunately n o t done till t r e a t m e n t h a d been resumed for a period of six m o n t h s a n d t h e case is
therefore recorded as being tested and found resistant nine months after the beginning of treatfiaent. The other ease, F. T., omitted from the results at six months was an elderly man whose sputum was constantly positive on smear but negative on culture. Several attempts at culture failed and when
I85
INTERMITTENT STREPTOMYCIN
a reluctant growth o f highly resistant organisms was obtained it was from s p u t u m produced some time after discharge, a n d there is good reason to fear that this patient h a d become tired o f PAS as a regular medicine some weeks before. Tile case is recorded, however, as being resistant to streptomycin at twelve months.
P A S SensitMty. - PAS resistance was f o u n d only in 6 cases. I n 3 a low d e g r e e o f resistance was p r e s e n t a t six m o n t h s ( g r o w t h on I ttg./ml.) a n d in 3 g r o w t h was observed on 5 t~g./ml-, I a t nine m o n t h s (case A. G.) a n d 2 for t h e first t i m e at twelve months. I n 5 o f these cases p a r a l l e l resistance to s t r e p t o m y c i n was present. Evaluation T h e 41 p a t i e n t s w h o tailed to convert t h e i r s p u t u m in six m o n t h s w e r e p r e d o m i n a n t l y those wittl extensive disease. T h e y w e r e d i s t r i b u t e d as follows: Class I : 4, Class I I : i7, Class I I I : 2I. I t is this observation w h i c h makes it necessary to a t t e m p t a n evaluation o f t h e clinical success o f the m e t h o d despite t h e absence o f controls, for it seems possible t h a t the excellent results o b s e r v e d in cases o f lesser severity m a y h a v e .given a false impression o f g e n e r a l satisfaction. C o m p a r i s o n w i t h A m e r i c a n figures IS m a d e difficult b y the r a t h e r different p e r i o d s o f assessment a n d the different t e c h n i q u e used for e s t i m a t i n g resistance. C o m p a r i s o n c a n best b e a t t e m p t e d w i t h the figures o f the M e d i c a l R e s e a r c h C o u n c i l trials in w h i c h t h e c o m b i n a t i o n o f d a i l y s t r e p t o m y c i n w i t h P A S 2o g. was used ( M e d i c a l R e s e a r c h Council, I95O , I952 , 1953b ). I n the first two o f these trials only cases o f a c u t e b i l a t e r a l disease in y o u n g a d u l t s were a d m i t t e d . I n the t h i r d a w i d e r v a r i a t i o n was a d m i t t e d i n c l u d i n g some cases w h i c h h a d received some c h e m o t h e r a p y . I t is w i t h t h e l a t t e r g r o u p of Io2 cases t h a t c o m p a r i s o n m a y most r e a s o n a b l y be m a d e . U n f o r t u n a t e l y t h e M . R . C . trials w e r e b a s e d on results after t h r e e m o n t h s ' t r e a t m e n t only a n d a n insignificant n u m b e r o f patients c o n t i n u e d c h e m o t h e r a p y w i t h o u t i n t e r r u p t i o n for six m o n t h s ; m o r e o v e r , collapse t h e r a p y was i n t r o d u c e d in a substantial n u m b e r o f cases in the second t h r e e - m o n t h period. I n T a b l e I I t h r e e comparisons a r e m a d e ; first, b e t w e e n the p r e s e n t series after three m o n t h s ' t r e a t m e n t a n d the cases o f the t h i r d M . R . C . t r i a l ; second, b e t w e e n the p r e s e n t series after w i t h d r a w i n g the least extensive class o f disease a n d the s a m e M . R . C . cases; thirdly, the relatively small n u m b e r o f m y cases in Class I I I a r e c o m p a r e d w i t h t h e total TABLE I I . - THE INCIDENCE OF STREPTOMYCIN-RESISTANT ORGANISMS IN TIIE PRESENT SERIES COMPARED x,VITII TIIAT AMONG PATIENTS IN T I I R E E ~ { . R . C .
TRIALS HAVING
DAILY STREPTOMYCIN AND PAS (20 o.)
Present series: all c a s e s . . Present series: Classes I I and III . . . . M . R . C . T r i a l , I953 .. Present series: Class I I I cases • • • G r o u p I eases, ]VI.R.C~ Trials, I95O, z952, I953
Total patients with culture examined
Wo. with positive culture available at 3 months (a)
Resistant
I86
37
2
--
136 IO2
33 17
2 2
43
20
i
II 4
58
2
Con~loderate: siderable : resistance resistance ratio ratio 8-99 > zoo
Total No.
Total as % of (a)
2
5
--
2
2
4
6 23
--
I
5
3
5
i
I86
TUBERCLE
n u m b e r of Group z M.R.C. cases (acute bilateral disease)admitted to the three trials. F r o m these figures it appears that even after withdrawal of those patients having least extensive disease the incidence of drug resistance in this series is noticeably less than a m o n g the most varied group admitted to the M.R.C. trials; and that compari'.'on between the M.R.C. Group I cases and the most extensive class of disease in this series shows no evidence whatever that the regime under discussion is inferior in value. It is perhaps also worth noting that I of the 2 patients found to have resistant organisms after three months of this treatment had in addition had intermittent streptomycin with PAS for ten weeks before admission to hospital. Comparison can also be attempted with a rather more similar series of cases published, with a different emphasis, by Hoyle and others (I955). One hundred a n d eleven sputum-positive patients were treated with chemotherapy of various kinds for nine or more months. T h e initial regime was daily streptomycin with either PAS or isoniazid and treatment was continued with intermittent streptomycin with daily PAS. T h e change was usually m a d e after three or four months' treatment. These authors found that positive sputum persisted at three months in 26 per cent and at six months in i6 per cent of their patients. There is little difference between these figures and the 32 per cent and 2o per cent of the present series. T h e incidence of cavitation, the size of the cavities and the incidence of closure among cavities of various sizes during the first six months of chemotherapy in their series seem also to have been very closely similar to the results here reported. T h e authors also stated that sensitivity tests were done at six months in 8 cases and in 2 of these organisms resistant to streptomycin were found, a proportion very similar to that reported above (22 per cent). F r o m this comparison of what seems to be similar material it is reasonable to deduce that the use of streptomycin daily for the first three months of treatment did not produce results conspicuously superior to those obtained x~ith intermittent streptomycin with daily PAS from the beginning. Discussion T h e detection of isolated resistant strains of bacilli during chemotherapy is not of itselfa secure basis for assuming any drug to have lost its value, but this criterion has been so widely Used as one method of evaluating drug treatment that comparison of different methods cannot be attempted without it. T h e r e is remarkably little literature on the relative merit of daily streptomycin and PAS and intermittent streptomycin with daily PAS. T h e US Public Health Service Cooperative Investigation (I953) compared intermittent streptomycin and daily PAS with the results ofisoniazid alone and with streptomycin and isoniazid treatment and found it inferior in value to the latter combination. Tile major work in which the two regimes are compared is the U.S. Veterans' Administrations, A r m y and N a v y co-operative trial, a review of which has lately been written by Tucker (I955). In this trial considerable numbers were involved. After deducting withdrawals approximately 380 patients on intermittent streptomycin and daily PAS are compared with 280 on streptomycin z g. daily with PAS and 290 on streptomycin ~ g. daily with PAS. After exhaustive comparison of the regimes no distinction could be m a d e between the results obtained with them even in the treatment of very advanced and extensively excavated disease, nor did analysis of the development of resistant organisms show any considerable difference (McLean, I954). These findings in so considerable a controlled series are impressive and agree with the tentative conclusion reached from studying m y material that, so far as the results can be measured in terms of routine clinical and pathological observations, the improvement obtained by giving streptomycin twice a week with PAS in doses of 5 g. twice daily is probably as good.as can be obtained with any combination of these two drugs.
I N T E R M I T T E N T STREPTOMYCIN
x87
It is necessary to make only one reservation. T h e bacteriological examination of resected tissue after chemotherapy is a rather refined, but obviously interesting method of estimating its effect, even though such material can be obtained only from a highly selected group. D'Esopo and others (1953) in a small series ofsuch studies failed to grow bacilli from the resected lesions of patients who had received daily streptomycin and PAS for more than eight months, but they did get positive c~:ltures after the same period on twice weekly treatment. T h e material was very scanty and the method had not been perfected (Hobby and others, I954). It is possible that future studies of this kind may reveal a difference between the regimes in this respect, but it is noteworthy that Steele and others (I953) failed to find any difference and other authors were quite unable to correlate findings of this nature with the form and duration of pre-operative treatment (Auerbach and others, I955a , i955b; Canetti, I954). An alternative and less esoteric approach would be to compare the relative incidence.of relapse among these groups of patients, but unfortunately the data are not available. In the U.S. Veterans' Administration trial sodium-PAS was given in 5 g- doses three times daily. Though this dose has found wide acceptance in this co~:ntry many physicians g'~ve less. I believe the individual dose i~ important. T h e Medical Research Council (I952) has proved this in the daily streptomycin and PAS regime, for decidedly inferior results were obtained when the individual PAS dose was halved. In another trial (Medical Research Council, I955) it was proved that PAS 5 g. twice daily was not inferior to PAS 5 g- four times a day when given with isoniazid. T h e series here reported seems to show that this dose is also adequate when streptomycin is given twice a week. I believe also that the method of administration is important. Absorption from the bowel is slow when PAS is given in any form of tablet (Battersby and others, 195 o) and the blood levels of PAS attained by the use of tablets do not compare with those obtained when PAS is given as solution or powder. I believe that the concentration reached in plasma and body fluids must have an important bearing on the value of this drug and I hold therefore that the use of PAS tablets of all kinds is pernicious. M y patients take an orange-flavoured solution with little complaint; if this is not tolerated rice-paper cachets are a convenient and satisfactory alternative, though this usually means a higher (6 g.) single dose. Intermittent streptomycin with daily PAS in this dosage, though it appears to be the equal of both drugs given daily, is not the most effective treatment known. T h e Medical Research Council established the superior value of daily streptomycin and isoniazid. Sputum conversion after six months of the order of 92-IOO per cent was obtained in their trials, both from the use of this combination and of isoniazid and PAS (Medical Research Council, I955). Tucker and Livings (I955) have also shown that streptomycin and PAS in any combination is inferior in value to isoniazid and PAS, though the difference is not very great; and in the very chronic open case it has been suggested that the continuous use of a single combination of drugs may give less good results than a regime involving rotation of several combinations (Joiner and others, x956). Horne and Grant (i956) have emphasized the need to set the most exacting standards of therapeutic success, but the holding of high standards does not demand the application of the most intensive treatment in every case; some indeed are reluctant to adventure the two most potent drugs at one time unnecessarily (Scadding, 1955) ; and the physician can still exercise personal judgment in choosing his treatment from a number of valuable chemotherapeutic combinations. T h e most acute and extensive disease is best treated by a regime which includes isoniazid; and streptomycin and PAS may not be ideal as an initial treatment for those elderly or bronchitic patients to whom surgery can never be applied to convert a persistent positive sputum or make secure a precarious sputum conversion. But the p.rognosis of minor and moderately advanced disease nowadays is good and the regime described is attended by excellent results in such cases.
I88
TUBERCLE
Summary
200 s p u t u m - p o s i t i v e patients w e r e t r e a t e d for a t least twenty-four weeks w i t h s t r e p t o m y c i n x g. twice a week a n d PAS 5 g- twice daily. S p u t u m conversion was o b t a i n e d in 83. 5 p e r c e n t on c h e m o t h e r a p y a l o n e a n d in 92 p e r cent w i t h tlm a i d o f surgery. S t r e p t o m y c i n - r e s i s t a n t organisms w e r e f o u n d a t s o m e stage in i I cases. I n 7 o f these the o r g a n i s m was resistant to 5 /~g./ml. P A S resistance was e n c o u n t e r e d in 6 instances, in 5 o f w h i c h t h e r e was c o n c o m i t a n t s t r e p t o m y c i n resistance. T h e i m p o r t a n c e o f using P A S in solution o r c a c h e t form a n d o f giving doses o f n o t less t h a n 5 g- e a c h is e m p h a s i z e d . T h e s e results seem to s u p p o r t the view t h a t i n t e r m i t t e n t s t r e p t o m y c i n a n d d a i l y P A S is n o t less v a l u a b l e t h a n b o t h drugs d a i l y . References
Auerbach, O., Hobby, G. L., Small, M.J., Lenert, T. F., and Comer, J. V. (I955 a) 07. thorac. Surg., 29, xo9. Auerbach, O., Hobby, G. L., Small, M.J., Lenert, T. F., and Vaughan, L. H. (I955 b) Amer. Rev. Tnberc., 72) 386. Battersby, J. M., Crulckshank, D. B., Hesling, C., and Hudson, E. H. (x95o) Tubercle, Lond., 3x) ~8~. Canetti, G. (1954) Bull. Un. int. Tuberc., 24, 144. Crofton, J. 0956) Brit. rned..7., i, 345. D'Esopo, N., Bernstein, S., Decker, A. M., Raleigh, J. W., and Steenken, ~V. 0953) Transactions of the I2th Conference on Chemotherapy of Tubcrculosls, U.S. Veterans Administration, Army and Navy, p. 229. Foster-Carter, A. F., Myers, M., Goddard, D. L. H., Young, F. H., and Benjamin, B. (195~) Brombton IIosp. Rep., 2x) x.
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