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Cycloserine treatment of pulmonary tuberculosis in Asian patients
Tubercle, Lond., (x958), 39, 2x3
Cycloserine Treatment of Pulmonary Tuberculosis in Asian Patients By R. J. G R O V E - W H I T E andJ. M . J . S U P R A M A N I A M from Tan To& Seng's Hospital, Singapore T h e toxic effects of cycloserine in the treatment of pulmonary tuberculosis were first reported in the United Kingdom by Walker and Murdoch (x957). These authors reviewed the literature and reported in detail on io patients who had signs of cycloserine toxicity out of a total of thirteen treated. This present paper reports the effects of the drug on Asian patients. .. ~. In M a y I957 14 in-patients of T a n Tock Seng's Hospital, Singapore, were selected for trial. All other methods of treatment h a d failed to produce satisfactory results; and in all of them, either by virtue of resistance to streptomycin, PAS or isoniazid as revealed by culture (4 cases) or by failure to respond to further treatment with any combination of these drugs, (I o cases), resistance to the three drugs could be reasonably assumed. This latter alternative had to be accepted because of tl~e restricted culture facilities pending the opening of the Central Tuberculosis Laboratory in i958. All patients had sputum positive on direct smear.
Type o f Patient Tile 14 patients who were selected had ceased to improve with conventional chemotherapy and were deemed unsuitable for, or. had refused to undergo, surgical treatment. Thirteen had far advanced or moderately advanced bilateral cavitated disease (by International Union Against Tuberculosis classification). T h e fourteenth was one who had persistent tuberculous endobronchitis in the left lower lobe bronchus which developed after she had undergone left upper lobectomy and thoracoplasty for left upper lobe cavitated disease. This patient had refused further surgical treatment, the organisms were resistant to streptomycin, PAS and isoniazid oll culture and a course of viomycin had not resulted in any improvement. Twelve of the patients were Chinese , 9 male and 3 female. There was I male Eurasian and I female Sikh patient. Ages varied between 2 5 and 6 4 years, averaged 4t ),ears for the men and 3 ° for the women. All these patients had been under treatment in hospital or as out-patients for periods that varied from seven years to five months. T h e patient with the shortest period of observation was allergic to streptomycin and had made no clinical improvement on PAS and isoniazid. All the others had been under treatment for over one year and the average period was almost four years. Dosage and Duration o f Treatment I n view of the lighter build of Asian patients generally it was decided to keep to a low dosage ofcycloserine. T h e dose varied therefore betx~:een 0. 5 g. and 0.75 g. daily, which approximated to 8 - i 2 rag. per kilo body weight per day. T h e drug was combined with isoniazid, 300 mg. daily in all cases and PAS IOg. was given as well in 2 cases where it was thought that the organism might possibly be still sensitive to
o~ 4
TUBERCLE
that drug. In 5 cases, in addition to bed rest, the patient was placed in position for postural retention treatment in the hope of assisting cavity closure. Nine patients had the drug for more than IOO days. O f the 5 who had less than IOO days, 3 took their discharge against advice and ~ had the drug stopped for severe toxic reactions which persisted despite reduction of the dose. T h e r a p e u t i c Effects o f C y c l o s e r l n e All these patients had had considerable periods of conventional chemotherapy with streptomycin, isoniazid and PAS, the one exception having had only five months' chemotherapy with PAS and isoniazid. No case had shown any improvement during the five months prior to commencement of treatment with cyeloserine. It is fair to assume, therefore, that with one possible exception the improvement noted in the cases in the trial can be attributed to the therapeutic effect of cycloserine. Nine sho\ved increase in weight, averaging 1o. 7 lb. and varying between 4 and no lb.; in the other 5 cases the weight remained unchanged. Eight showed a Gall in ESR, averaging 2I mm. per hour, the range varying between 2-45 mm. One case strawed an increase, the E S R rising from ~o2 to 75 mm. In 4 cases the sputum changed from being positive to negative on concentration examination and in ~ of these the culture was also negative. In I of the latter cases the bacilli at the commencement of the trial were only partially resistant to isouiazid. Four showed definite radiographic improvement. In I case a cavity closed but reopened later. T h e persistent tuberculous endo-bronchitis in the One post-operative patient cleared up under cycloserine, though some non-specific endo-bronchitis remained. The sputum became negative on both concentrate and cuhure examination. Five patients claimed an improved sense of well-being, but in 3 of them this followed transient toxic effects. T o x i c Effects O f the 14 patients selected, only 4 had no signs of toxicity which would normally have been attributed to cycloserine. One of these patients, however, who had made considerable clinical and radiographic improvement, became worried about certain family affairs just as he approached the end of his course of cycloserine. Four days before completing five mouths' treatment he took his life by jumping from a sixth floor window. In view of the large number of relatively minor psychological upsets encountered with the other patients in the series, 4 of whom had definite psychotic symptoms, the possibility that the drug m a y have provided the critical imbalance which led hun to take this drastic action cannot be excluded. Furthermore, 3 patients, who had entered the trial willingly and who had at first been quite co-operative, later became increasingly difficult and left the ward at their own request. This proportion is very much higher than would have been expected from ordinary experience and these also might reasonabIy be numbered a m o n g those with minor toxic effects. O f the remaining I o cases the following were the toxic manifestations seen in order of the frequency in which they were encountered : psychoses - 4 (3 with delusions of persecution) ; drowsiness - 3 ; anorexia - 3; lethargy - 2 ; vertigo - 2 ; malaise - ~ ; paraesthesia and numbness of e x t r e m i t i e s - 2 ; p y r e x i a - 2; t i n n i t u s - I ; twitching of m u s c l e s - I ; congestive cardiac f a i l u r e - r. In all but 4 cases the toxic effects were transitory and the drug was continued until the end of the prescribed course (except in the 4 p a t i e n t s w h o took their discharge from hospital at their own request). In the 4 psychotic patients the drng had to be discontinued and i of these developed congestive cardiac failure which proved very difficult in m a n a g e m e n t despite the cessation of the drug. In all 4, the psychotic symptoms cleared up when cycloserine was stopped.
CYCLOSERINE
215
Discussion While cycloserine has been shown to have definite anti-tuberculous activity (Epstein and others, I955, x956, I955-56; Livings, i956 ) its potential toxicity was also recognized in its early clinical trials (Murray, i956 ). Both the therapeutic value and toxicity were observed in this series and though Io patients showed some benefit from cyeloserine therapy the toxic effects were seen i n a high proportion despite the relatively low dosage employed. I n fact, if the drug were in part responsible for the difficult and unsettled behaviour which resulted in the 4 patients taking their d,ischarge against advice and in influencing the worried m a n to take his life, then the toxic effects seen in this group were in even greater proportion than that seen in the series reported by Walker and Murdoch; and in fact only 2 of the 14 patients were clearly free from toxic symptoms of any kind. Minor mental disturbance and psychotic symptoms would appear to be the most frequent manifestation of toxicity and should be watched for carefully. T h e fact that in a mixed racial community such as that in Singapore, the doctors and nurses are often not fluent in the dialects or languages of their patients adds greatly to the difficulty in detecting early deviations from normal. Walker and Murdoch (I957) brought to light the possible association of congestive cardiac failure as a toxic manifestation of cycloserine. One case, a well-nourished Chinese woman of 29 years of age who h a d no evidence of cardiac disease at the start of the trial, developed what appeared to be a toxic myocarditis with tachycardia and congestive failure on the thirty-third day of treatment. This condition persisted for three months after the cessation of Cycloserine therapy before showing improvement. Summary Fourteen Asian patients, 13 with moderately advanced or far advanced pulmonary tuberculosis and I with endo-bronchial tuberculosis, in all of whom the strains of tubercle bacilli were either known to be resistant to conventional forrfis of chemotherapy or were presumed to be so from lack of clinical improvement, were treated with cycloserine. Ten patients showed some. benefit. Although the dosage was low and did not exceed 0.75 g. per day in any case, Io had definite toxic effects in the form of psychotic symptoms, drowsiness, a n d anorexia. One patient developed congestive cardiac failure. T w o others had personality changes which m a y have been due to the effects of cycloserine. The trial indicates that the toxicity in Asian patients is no less than in the groups previously described and that the drug should only be used under the closest hospital supervision and then only to patients who are unsuitable for established methods of chemotherapy. We acknowledge with thanks the help of Messrs Hoffman La Roche (Basle) who supplied file cycloserine and thank Dr M. Doraisingham, Director of Medical Sen-ices, Singapore, for permission to publish. References Epstein, I. G., Nair, K. G. S., and Boyd, L.J. (1955) Antibiotic Med., x, 80. Epstein, I. G., Nair, K. G. S., and Boyd, L.J. (1956) Dis. Chest., 29, 24x. Epstein, I. G., Nair, K. G. S., and Boyd, L.J. (x955-56) Antibiotics Annual, 14x. Livings, D. G. (x956) Transactions of the x5flxConference on the Chemotherapy of Tuberculosis, p. 372, Veterans Admin., U.S.A. Murray, F.J. (x956) Transactions of the 15th Conference on the Chemotherapy of Tuberculosis, P.333, Veterans Admin., U.S.A. Walker, W. C., and Murdoch, J. McC. (1957) Tubercle, Loud., 38, 297.
Cycloserine Treatment of Pulmonary Tuberculosis in Asian Patients By R. J. G R O V E - W H I T E andJ. M . J . S U P R A M A N I A M from Tan To& Seng's Hospital, Singapore T h e toxic effects of cycloserine in the treatment of pulmonary tuberculosis were first reported in the United Kingdom by Walker and Murdoch (x957). These authors reviewed the literature and reported in detail on io patients who had signs of cycloserine toxicity out of a total of thirteen treated. This present paper reports the effects of the drug on Asian patients. .. ~. In M a y I957 14 in-patients of T a n Tock Seng's Hospital, Singapore, were selected for trial. All other methods of treatment h a d failed to produce satisfactory results; and in all of them, either by virtue of resistance to streptomycin, PAS or isoniazid as revealed by culture (4 cases) or by failure to respond to further treatment with any combination of these drugs, (I o cases), resistance to the three drugs could be reasonably assumed. This latter alternative had to be accepted because of tl~e restricted culture facilities pending the opening of the Central Tuberculosis Laboratory in i958. All patients had sputum positive on direct smear.
Type o f Patient Tile 14 patients who were selected had ceased to improve with conventional chemotherapy and were deemed unsuitable for, or. had refused to undergo, surgical treatment. Thirteen had far advanced or moderately advanced bilateral cavitated disease (by International Union Against Tuberculosis classification). T h e fourteenth was one who had persistent tuberculous endobronchitis in the left lower lobe bronchus which developed after she had undergone left upper lobectomy and thoracoplasty for left upper lobe cavitated disease. This patient had refused further surgical treatment, the organisms were resistant to streptomycin, PAS and isoniazid oll culture and a course of viomycin had not resulted in any improvement. Twelve of the patients were Chinese , 9 male and 3 female. There was I male Eurasian and I female Sikh patient. Ages varied between 2 5 and 6 4 years, averaged 4t ),ears for the men and 3 ° for the women. All these patients had been under treatment in hospital or as out-patients for periods that varied from seven years to five months. T h e patient with the shortest period of observation was allergic to streptomycin and had made no clinical improvement on PAS and isoniazid. All the others had been under treatment for over one year and the average period was almost four years. Dosage and Duration o f Treatment I n view of the lighter build of Asian patients generally it was decided to keep to a low dosage ofcycloserine. T h e dose varied therefore betx~:een 0. 5 g. and 0.75 g. daily, which approximated to 8 - i 2 rag. per kilo body weight per day. T h e drug was combined with isoniazid, 300 mg. daily in all cases and PAS IOg. was given as well in 2 cases where it was thought that the organism might possibly be still sensitive to
o~ 4
TUBERCLE
that drug. In 5 cases, in addition to bed rest, the patient was placed in position for postural retention treatment in the hope of assisting cavity closure. Nine patients had the drug for more than IOO days. O f the 5 who had less than IOO days, 3 took their discharge against advice and ~ had the drug stopped for severe toxic reactions which persisted despite reduction of the dose. T h e r a p e u t i c Effects o f C y c l o s e r l n e All these patients had had considerable periods of conventional chemotherapy with streptomycin, isoniazid and PAS, the one exception having had only five months' chemotherapy with PAS and isoniazid. No case had shown any improvement during the five months prior to commencement of treatment with cyeloserine. It is fair to assume, therefore, that with one possible exception the improvement noted in the cases in the trial can be attributed to the therapeutic effect of cycloserine. Nine sho\ved increase in weight, averaging 1o. 7 lb. and varying between 4 and no lb.; in the other 5 cases the weight remained unchanged. Eight showed a Gall in ESR, averaging 2I mm. per hour, the range varying between 2-45 mm. One case strawed an increase, the E S R rising from ~o2 to 75 mm. In 4 cases the sputum changed from being positive to negative on concentration examination and in ~ of these the culture was also negative. In I of the latter cases the bacilli at the commencement of the trial were only partially resistant to isouiazid. Four showed definite radiographic improvement. In I case a cavity closed but reopened later. T h e persistent tuberculous endo-bronchitis in the One post-operative patient cleared up under cycloserine, though some non-specific endo-bronchitis remained. The sputum became negative on both concentrate and cuhure examination. Five patients claimed an improved sense of well-being, but in 3 of them this followed transient toxic effects. T o x i c Effects O f the 14 patients selected, only 4 had no signs of toxicity which would normally have been attributed to cycloserine. One of these patients, however, who had made considerable clinical and radiographic improvement, became worried about certain family affairs just as he approached the end of his course of cycloserine. Four days before completing five mouths' treatment he took his life by jumping from a sixth floor window. In view of the large number of relatively minor psychological upsets encountered with the other patients in the series, 4 of whom had definite psychotic symptoms, the possibility that the drug m a y have provided the critical imbalance which led hun to take this drastic action cannot be excluded. Furthermore, 3 patients, who had entered the trial willingly and who had at first been quite co-operative, later became increasingly difficult and left the ward at their own request. This proportion is very much higher than would have been expected from ordinary experience and these also might reasonabIy be numbered a m o n g those with minor toxic effects. O f the remaining I o cases the following were the toxic manifestations seen in order of the frequency in which they were encountered : psychoses - 4 (3 with delusions of persecution) ; drowsiness - 3 ; anorexia - 3; lethargy - 2 ; vertigo - 2 ; malaise - ~ ; paraesthesia and numbness of e x t r e m i t i e s - 2 ; p y r e x i a - 2; t i n n i t u s - I ; twitching of m u s c l e s - I ; congestive cardiac f a i l u r e - r. In all but 4 cases the toxic effects were transitory and the drug was continued until the end of the prescribed course (except in the 4 p a t i e n t s w h o took their discharge from hospital at their own request). In the 4 psychotic patients the drng had to be discontinued and i of these developed congestive cardiac failure which proved very difficult in m a n a g e m e n t despite the cessation of the drug. In all 4, the psychotic symptoms cleared up when cycloserine was stopped.
CYCLOSERINE
215
Discussion While cycloserine has been shown to have definite anti-tuberculous activity (Epstein and others, I955, x956, I955-56; Livings, i956 ) its potential toxicity was also recognized in its early clinical trials (Murray, i956 ). Both the therapeutic value and toxicity were observed in this series and though Io patients showed some benefit from cyeloserine therapy the toxic effects were seen i n a high proportion despite the relatively low dosage employed. I n fact, if the drug were in part responsible for the difficult and unsettled behaviour which resulted in the 4 patients taking their d,ischarge against advice and in influencing the worried m a n to take his life, then the toxic effects seen in this group were in even greater proportion than that seen in the series reported by Walker and Murdoch; and in fact only 2 of the 14 patients were clearly free from toxic symptoms of any kind. Minor mental disturbance and psychotic symptoms would appear to be the most frequent manifestation of toxicity and should be watched for carefully. T h e fact that in a mixed racial community such as that in Singapore, the doctors and nurses are often not fluent in the dialects or languages of their patients adds greatly to the difficulty in detecting early deviations from normal. Walker and Murdoch (I957) brought to light the possible association of congestive cardiac failure as a toxic manifestation of cycloserine. One case, a well-nourished Chinese woman of 29 years of age who h a d no evidence of cardiac disease at the start of the trial, developed what appeared to be a toxic myocarditis with tachycardia and congestive failure on the thirty-third day of treatment. This condition persisted for three months after the cessation of Cycloserine therapy before showing improvement. Summary Fourteen Asian patients, 13 with moderately advanced or far advanced pulmonary tuberculosis and I with endo-bronchial tuberculosis, in all of whom the strains of tubercle bacilli were either known to be resistant to conventional forrfis of chemotherapy or were presumed to be so from lack of clinical improvement, were treated with cycloserine. Ten patients showed some. benefit. Although the dosage was low and did not exceed 0.75 g. per day in any case, Io had definite toxic effects in the form of psychotic symptoms, drowsiness, a n d anorexia. One patient developed congestive cardiac failure. T w o others had personality changes which m a y have been due to the effects of cycloserine. The trial indicates that the toxicity in Asian patients is no less than in the groups previously described and that the drug should only be used under the closest hospital supervision and then only to patients who are unsuitable for established methods of chemotherapy. We acknowledge with thanks the help of Messrs Hoffman La Roche (Basle) who supplied file cycloserine and thank Dr M. Doraisingham, Director of Medical Sen-ices, Singapore, for permission to publish. References Epstein, I. G., Nair, K. G. S., and Boyd, L.J. (1955) Antibiotic Med., x, 80. Epstein, I. G., Nair, K. G. S., and Boyd, L.J. (1956) Dis. Chest., 29, 24x. Epstein, I. G., Nair, K. G. S., and Boyd, L.J. (x955-56) Antibiotics Annual, 14x. Livings, D. G. (x956) Transactions of the x5flxConference on the Chemotherapy of Tuberculosis, p. 372, Veterans Admin., U.S.A. Murray, F.J. (x956) Transactions of the 15th Conference on the Chemotherapy of Tuberculosis, P.333, Veterans Admin., U.S.A. Walker, W. C., and Murdoch, J. McC. (1957) Tubercle, Loud., 38, 297.