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The treatment of amoebiasis: A field study of various methods
400 TRANSACTIONSOF TIlE ROYAL SOCIETYOF TROPICAl. MEDICINE AND HYGIENE. Vol. 56. No. 5. September, 1962.
THE TREATMENT OF AMOEBIASIS: A FIELD STUDY OF VARIOUS METHODS BY
D. M. FORSYTtt*
The Ross Institute, lately Physician Kuwait Oil Co. Ltd. During recent years attempts have been made to compare the relative merit of the many drugs available for the treatment of amoebiasis. Probably the most valuable contributions in this field have come from WOODRUFF, BELL and SCHOFIELD (1956); BELL and WOODRUFF (1960) ; WOODRUFF and BELL (1960). T h e last-named wrote that it was undesirable to assay the efficacy of a particular drug when accurate follow-up is complicated by the possibility of re-infection. T h e point is well taken, but it is submitted that the facts reported below are worthy of notice in that the follow-up of individual cases appears to have been more thorough than that reported by some observers. MATERIAL During the year April, 1960--April, 1961, more than 300 staff and payroll employees of Kuwait Oil Company were treated for amoebiasis, but of these it was possible to follow up only 282 completely. The series reviewed consists of the first 245 unselected payroll employee patients from this group. METHODS
Diagnosis. This was based upon the finding of E. histolytica cysts or trophozoites in the stool. Nearly all cases were discovered following routine physical examination, and only 10 per cent. had symptoms suggesting that a stool examination was desirable. Very few had physical signs indicative of active amoebiasis and in the stools of only two were trophozoites seen. Several patients had a history of amoebic dysentery, trophozoites being demonstrated in their stool during the acute illness. Following the observations of HOARE (1952) no attempt was made to measure the size of the cysts of E. histolytica voided. Before treatment a full history was taken from all patients, followed by full routine physical examination. Sigmoidoscopy. It was intended to sigmoidoscope all in-patients. Some declined. In only one instance were amoebic ulcers seen in the colon, and this was in an asymptomatic cyst-passer. Follow-up. Simple slide preparations of a minimum of nine stools were examined from each patient by a technician having at least 2 years' experience in this speciality. It was hoped to examine three specimens on consecutive days 1 month after treatment had * I am grateful to Mr. M. J. Bagge, Chief Hospital Laboratory Technician, Kuwait Oil Company, for help, and to Sir Alexander Biggam for kind criticism and advice. The paromomycin (ttumatin) tablets were supplied by Dr. H. W. Pearson of Parke, Davis & Company, and the diloxanide furoate (Furamide) by Dr. E. V. B. Morton of Boots Pure Drug Company.
I). M. FORSYTH
401
been completed, three more after 2 months, and a final three at the end of 3 months. ()hen this was not possible, but each patient had nine or more negative stool examinations, and at least three of these were taken at the end of the third month.
R E S U L T S OF" T R F . A T M E N T
Emeline bismuth iodide Twenty-five patients were treated in the ward, using the method advocated by Bm(;AM (1961), except that enteric-coated tablets were used instead of capsules. 0.2 gramme (3 grains) were given each night, followed by a glass of water and preceded by 0.2 gramme (3 grains) sodium amytal, on 12 successive nights. Six (24 per cent.) relapsed. Anorexia, nausea, abdominal discomfort and general malaise were reported by the majority. The cost of treatment per patient was 11 :'-. 1)
Bialamicol kvdrochloride (Camoform). i lere all patients were given 2 tablets (0.5 gramme) thrice daily for 5 days, and this was repeated after an interval of 1 week. a) Twenty patients received the first course in hospital and the repeat as out-patients. ()f these, three (15 per cent.) continued to void cysts. b) l:ifty patients received both courses as out-patients, and there were 19 (38 per cent.) failures eight defaulted from treatment. Of the latter, one patient had severe urticaria. the only occasion that such a reaction has been seen in association with bialamicol hydrochloride medication over a period of many years. The cost of treatment per patient was 50/'-. 2)
Paromomvcin Three regimes were used: a) Twenty-five in-patients were treated, each receiving 30 mg. per kg. body weight daily for 10 days (BELL and WOOORVFF, 1960). Four (16 per cent.) relapsed. The drug was given in divided doses and occasionally caused mild abdominal upset. The cost of treatment per patient was 210/-. b) Fifty in-patients were given 30 rag. per kg. body weight in daily divided doses for 5 days (CMCrl~R, 1959). No untoward symptoms or signs were noted, and only three (6 per cent.) relapses were detected. The cost of treatment per patient was 105/-. c) Fifty out-patients were treated with the same regime except that the entire daily dose was administered by the sister i/c O.P.D. each morning. The course frequently caused diarrhoea and colic, and four patients defaulted. A further four relapsed, a total demonstrable failure rate of 16 per cent. The cost of treatment per patient was 105/-. 3)
Diloxanide .fitroate Twentv-five out-patients were treated, each receiving 20 mg. per kg. body weight daily in divided doses for 10 days. in five (20 per cent.) treatment was shown to be unsuccessful, but it is impossible to estimate how many of this group took the medicine as prescribed. No complaints were made about toxic or side-effects. The cost of treatment per patient was 5/'6d. 4)
402
THE TREATMENT OF AMOEBIASIS: A F I E L D STUDY OF VARIOUS METHODS DISCUSSION
The results reported for treating cases of amoebiasis with emetine bismuth iodide compare unfavourably with those of WOODRUFFet al. (1956) who had only one failure amongst 64 patients treated with the same daily dosage of E.B.I. for 10 days only. In the latter series, the average number of attendances per patient for follow-up was only 1.83. According to DOBELL (1917) the odds are 3:2 against E. histolytica cysts being found in a single examination of a stool from a patient known to be suffering from amoebiasis. With a follow-up of 1.83 examinations, a patient known to be still infected would have only a slightly better than even chance of being proved positive when only simple slide preparations are examined: indeed the authors stated " it is not supposed that the follow-up which has been possible has revealed all the relapses that have occurred." In observing the results obtained by colleagues in Kuwait treating amoebiasis with E.B.I., it appeared that the drug is not as effective as is commonly taught, but the possibility of re-infection of individual patients must always be borne in mind when comparing results with those achieved in a non-tropical environment. The system of follow-up adopted for the present study was not considered to be absolute, though according to SVENSSONand LINDERS (1934) it does give an almost certain chance against the inadequately-treated patient being missed. It is submitted that, as a result of the greater number of stool examinations made per subject, the relapse rate of 24 per cent. found during the present investigation is likely to be more accurate than that reported by WOODRUFFet al. However in view of the small numbers involved much of the difference could be due to chance. The results of treatment with bialamicol hydrochloride, first in in-patients and then in out-patients, are not so good as those claimed by BARRIOS (1954) whose follow-up was inadequate, but are strictly comparable with those of HOEKENOA and BATTERSON (1954) and also with those of WOODRUFF et al. (1956). When out-patient treatment only was given, the results were poor, although the drug was usually well tolerated. The therapeutic effect of paromomycin upon in-patients was most gratifying; there is no significant difference statistically in percentage success between the two in-patient groups (P > 0.05). Toxic or side-effects are insignificant. Gastro-intestinal upset was often conspicuous and troublesome when the drug was given to out-patients, the whole dose being administered each morning. Subsequently, it was found with Western staff volunteers that the regime was well tolerated in out-patients if the paromomycin were given daily in divided doses, but not usually if taken as a single dose each morning. It may well be that the smaller doses as used by ELIAS and OLIV~R-GONZALFZ(1959) are equally effective. Diloxanide furoate was well tolerated by our patients, the relapse rate being comparable with that noted by WOODRUFFand BELL in their preliminary report (1960) and by MARSDEN (1960). It has been argued that apparently healthy persons who are found to be passing the cysts of E. histolytica in their stools do not require treatment, especially when the discovery is made in an area where amoebiasis is prevalent (BoYD, 1960). These views are not held by myself, and I would much prefer to be treated should such a misfortune befall me. It has been the policy of the Medical Department of Kuwait Oil Company to treat all foodhandlers found to have E. histolytica cysts in the stool, and also all persons unlikely to be re-exposed to infection in the near future, and it is thought that this view is sound. It appears that diloxanide furoate and paromomycin are at least as effective in the treatment of amoebiasis as is E.B.I. The first has the advantage of being cheaper and much
D. IM. FORSYTE1
403
better tolerated. It is eminently suitable for administration to intelligent and co-operative out-patients. Paromomycin is much more expensive than either E.B.I. or diloxanide furoate, but a course of treatment occupies only 5 days. It appears, therefore, to be the drug of choice for the less co-operative patient who cannot be depended upon to take the medicine as prescribed and therefore requires in-patient treatment. Here the amount saved in occupying a hospital bed for the shorter period far outweighs the relatively high cost of the drug. Bialarnicol hydrochloridc is a useful alternative, but less effective when used for out-patients than is diloxanide furoate. With combined in-patient and out-patient courses, the results achieved are comparable to those obtained with the paromomycin 5-dav in-patient regime. T h e second or repeat course is a complication to be aw)ided, and does not offset the slight saving in drug costs. T o evaluate accurately the efficacy of the various methods of treatment of amoebiasis discussed here and elsewhere, it is necessary to have a much larger and more carefully controlled series of cases than has yet been reported, thus allowing accurate statistical analysis of the results obtained. In retrospect, six stool examinations on successive days, using the concentration technique of RIDLFY and HAW(;OOD (1956), 6 weeks after treatment was completed would be more effective and less time-consuming than the method used in the present study (Bm(;AM, 1961, pers. commun.) SUMMARY
An account is given of the results of treating non-dysenteric intestinal amoebiasis with some of the newer drugs and the results compared with those achieved by using E.B.I. It is thought that E.B.I., diloxanide furoate and paromomycin are all extremely effective and of approximately equal merit from a therapeutic standpoint. Diloxanide furoate is the cheapest and best tolerated and should be used to treat co-operative ambulant out-patients. T h e paromomycin course is the shortest and so should be used for the less co-operative person who requires in-patient treatment. REFERENCES BARRIOS, HI. (1954). Gastroenterology, 27, 81. [JELL, S. & WOODRUFF, A. W. (1960). Amer. J. trop. ~Vled. Hyg., 9, 155. BI(;(;AM, A. G. (1961). Textbook of ~Vledical Treatment, Davidson, Dunlop & Alstead. 8th Ed., Edinburgh: E. & S. Livingstone. BOYD, J. S. K. (1960). Trans. R. Soc. trop. ~1ed. Iqyg., 54, 505. CARTER,C. H. (1959). Antibiotic Med., 6, 586. DO,ELf, C. (1917). 5'pec. Rep. Ser. reed. Res. Comm. Lond., No. 4. DooxFn, H. P. (1960). Antibiotic. ~Ied., 7, 486. ELIAS, F. I~. & OI,IVER-(]ONZALEZ, J. (1959). Ibid., 6, 584. fIOAR~, C. A. (1952). Exp. Parasit., 1, 411. [~OEKEN(;A, ~I. ~F. & BATTERSON,D. I~. (1946). Amer. J. trop. ~/led. Hyg., 3, 849. MAnSD~X, P. D. (1960). Trans. R. Soc. trop. filed, tlyg., 54, 396. RIDI.EY, D. S. & HAW(;ool), B. C. (1956). J. clin. Path., 9, 74. SVENSSON, R. & LINDERS, F. J. (1934). Acta 3lied. Scan&, 81, 267. WOODnUr:F, A. W., BELL, S. & SCHOHEH), F. D. (1956). Trans. R. Soc. troD. ~led. Hyg., 50, 114, .... & . . . . (1960). Ibid., 54, 389.
THE TREATMENT OF AMOEBIASIS: A FIELD STUDY OF VARIOUS METHODS BY
D. M. FORSYTtt*
The Ross Institute, lately Physician Kuwait Oil Co. Ltd. During recent years attempts have been made to compare the relative merit of the many drugs available for the treatment of amoebiasis. Probably the most valuable contributions in this field have come from WOODRUFF, BELL and SCHOFIELD (1956); BELL and WOODRUFF (1960) ; WOODRUFF and BELL (1960). T h e last-named wrote that it was undesirable to assay the efficacy of a particular drug when accurate follow-up is complicated by the possibility of re-infection. T h e point is well taken, but it is submitted that the facts reported below are worthy of notice in that the follow-up of individual cases appears to have been more thorough than that reported by some observers. MATERIAL During the year April, 1960--April, 1961, more than 300 staff and payroll employees of Kuwait Oil Company were treated for amoebiasis, but of these it was possible to follow up only 282 completely. The series reviewed consists of the first 245 unselected payroll employee patients from this group. METHODS
Diagnosis. This was based upon the finding of E. histolytica cysts or trophozoites in the stool. Nearly all cases were discovered following routine physical examination, and only 10 per cent. had symptoms suggesting that a stool examination was desirable. Very few had physical signs indicative of active amoebiasis and in the stools of only two were trophozoites seen. Several patients had a history of amoebic dysentery, trophozoites being demonstrated in their stool during the acute illness. Following the observations of HOARE (1952) no attempt was made to measure the size of the cysts of E. histolytica voided. Before treatment a full history was taken from all patients, followed by full routine physical examination. Sigmoidoscopy. It was intended to sigmoidoscope all in-patients. Some declined. In only one instance were amoebic ulcers seen in the colon, and this was in an asymptomatic cyst-passer. Follow-up. Simple slide preparations of a minimum of nine stools were examined from each patient by a technician having at least 2 years' experience in this speciality. It was hoped to examine three specimens on consecutive days 1 month after treatment had * I am grateful to Mr. M. J. Bagge, Chief Hospital Laboratory Technician, Kuwait Oil Company, for help, and to Sir Alexander Biggam for kind criticism and advice. The paromomycin (ttumatin) tablets were supplied by Dr. H. W. Pearson of Parke, Davis & Company, and the diloxanide furoate (Furamide) by Dr. E. V. B. Morton of Boots Pure Drug Company.
I). M. FORSYTH
401
been completed, three more after 2 months, and a final three at the end of 3 months. ()hen this was not possible, but each patient had nine or more negative stool examinations, and at least three of these were taken at the end of the third month.
R E S U L T S OF" T R F . A T M E N T
Emeline bismuth iodide Twenty-five patients were treated in the ward, using the method advocated by Bm(;AM (1961), except that enteric-coated tablets were used instead of capsules. 0.2 gramme (3 grains) were given each night, followed by a glass of water and preceded by 0.2 gramme (3 grains) sodium amytal, on 12 successive nights. Six (24 per cent.) relapsed. Anorexia, nausea, abdominal discomfort and general malaise were reported by the majority. The cost of treatment per patient was 11 :'-. 1)
Bialamicol kvdrochloride (Camoform). i lere all patients were given 2 tablets (0.5 gramme) thrice daily for 5 days, and this was repeated after an interval of 1 week. a) Twenty patients received the first course in hospital and the repeat as out-patients. ()f these, three (15 per cent.) continued to void cysts. b) l:ifty patients received both courses as out-patients, and there were 19 (38 per cent.) failures eight defaulted from treatment. Of the latter, one patient had severe urticaria. the only occasion that such a reaction has been seen in association with bialamicol hydrochloride medication over a period of many years. The cost of treatment per patient was 50/'-. 2)
Paromomvcin Three regimes were used: a) Twenty-five in-patients were treated, each receiving 30 mg. per kg. body weight daily for 10 days (BELL and WOOORVFF, 1960). Four (16 per cent.) relapsed. The drug was given in divided doses and occasionally caused mild abdominal upset. The cost of treatment per patient was 210/-. b) Fifty in-patients were given 30 rag. per kg. body weight in daily divided doses for 5 days (CMCrl~R, 1959). No untoward symptoms or signs were noted, and only three (6 per cent.) relapses were detected. The cost of treatment per patient was 105/-. c) Fifty out-patients were treated with the same regime except that the entire daily dose was administered by the sister i/c O.P.D. each morning. The course frequently caused diarrhoea and colic, and four patients defaulted. A further four relapsed, a total demonstrable failure rate of 16 per cent. The cost of treatment per patient was 105/-. 3)
Diloxanide .fitroate Twentv-five out-patients were treated, each receiving 20 mg. per kg. body weight daily in divided doses for 10 days. in five (20 per cent.) treatment was shown to be unsuccessful, but it is impossible to estimate how many of this group took the medicine as prescribed. No complaints were made about toxic or side-effects. The cost of treatment per patient was 5/'6d. 4)
402
THE TREATMENT OF AMOEBIASIS: A F I E L D STUDY OF VARIOUS METHODS DISCUSSION
The results reported for treating cases of amoebiasis with emetine bismuth iodide compare unfavourably with those of WOODRUFFet al. (1956) who had only one failure amongst 64 patients treated with the same daily dosage of E.B.I. for 10 days only. In the latter series, the average number of attendances per patient for follow-up was only 1.83. According to DOBELL (1917) the odds are 3:2 against E. histolytica cysts being found in a single examination of a stool from a patient known to be suffering from amoebiasis. With a follow-up of 1.83 examinations, a patient known to be still infected would have only a slightly better than even chance of being proved positive when only simple slide preparations are examined: indeed the authors stated " it is not supposed that the follow-up which has been possible has revealed all the relapses that have occurred." In observing the results obtained by colleagues in Kuwait treating amoebiasis with E.B.I., it appeared that the drug is not as effective as is commonly taught, but the possibility of re-infection of individual patients must always be borne in mind when comparing results with those achieved in a non-tropical environment. The system of follow-up adopted for the present study was not considered to be absolute, though according to SVENSSONand LINDERS (1934) it does give an almost certain chance against the inadequately-treated patient being missed. It is submitted that, as a result of the greater number of stool examinations made per subject, the relapse rate of 24 per cent. found during the present investigation is likely to be more accurate than that reported by WOODRUFFet al. However in view of the small numbers involved much of the difference could be due to chance. The results of treatment with bialamicol hydrochloride, first in in-patients and then in out-patients, are not so good as those claimed by BARRIOS (1954) whose follow-up was inadequate, but are strictly comparable with those of HOEKENOA and BATTERSON (1954) and also with those of WOODRUFF et al. (1956). When out-patient treatment only was given, the results were poor, although the drug was usually well tolerated. The therapeutic effect of paromomycin upon in-patients was most gratifying; there is no significant difference statistically in percentage success between the two in-patient groups (P > 0.05). Toxic or side-effects are insignificant. Gastro-intestinal upset was often conspicuous and troublesome when the drug was given to out-patients, the whole dose being administered each morning. Subsequently, it was found with Western staff volunteers that the regime was well tolerated in out-patients if the paromomycin were given daily in divided doses, but not usually if taken as a single dose each morning. It may well be that the smaller doses as used by ELIAS and OLIV~R-GONZALFZ(1959) are equally effective. Diloxanide furoate was well tolerated by our patients, the relapse rate being comparable with that noted by WOODRUFFand BELL in their preliminary report (1960) and by MARSDEN (1960). It has been argued that apparently healthy persons who are found to be passing the cysts of E. histolytica in their stools do not require treatment, especially when the discovery is made in an area where amoebiasis is prevalent (BoYD, 1960). These views are not held by myself, and I would much prefer to be treated should such a misfortune befall me. It has been the policy of the Medical Department of Kuwait Oil Company to treat all foodhandlers found to have E. histolytica cysts in the stool, and also all persons unlikely to be re-exposed to infection in the near future, and it is thought that this view is sound. It appears that diloxanide furoate and paromomycin are at least as effective in the treatment of amoebiasis as is E.B.I. The first has the advantage of being cheaper and much
D. IM. FORSYTE1
403
better tolerated. It is eminently suitable for administration to intelligent and co-operative out-patients. Paromomycin is much more expensive than either E.B.I. or diloxanide furoate, but a course of treatment occupies only 5 days. It appears, therefore, to be the drug of choice for the less co-operative patient who cannot be depended upon to take the medicine as prescribed and therefore requires in-patient treatment. Here the amount saved in occupying a hospital bed for the shorter period far outweighs the relatively high cost of the drug. Bialarnicol hydrochloridc is a useful alternative, but less effective when used for out-patients than is diloxanide furoate. With combined in-patient and out-patient courses, the results achieved are comparable to those obtained with the paromomycin 5-dav in-patient regime. T h e second or repeat course is a complication to be aw)ided, and does not offset the slight saving in drug costs. T o evaluate accurately the efficacy of the various methods of treatment of amoebiasis discussed here and elsewhere, it is necessary to have a much larger and more carefully controlled series of cases than has yet been reported, thus allowing accurate statistical analysis of the results obtained. In retrospect, six stool examinations on successive days, using the concentration technique of RIDLFY and HAW(;OOD (1956), 6 weeks after treatment was completed would be more effective and less time-consuming than the method used in the present study (Bm(;AM, 1961, pers. commun.) SUMMARY
An account is given of the results of treating non-dysenteric intestinal amoebiasis with some of the newer drugs and the results compared with those achieved by using E.B.I. It is thought that E.B.I., diloxanide furoate and paromomycin are all extremely effective and of approximately equal merit from a therapeutic standpoint. Diloxanide furoate is the cheapest and best tolerated and should be used to treat co-operative ambulant out-patients. T h e paromomycin course is the shortest and so should be used for the less co-operative person who requires in-patient treatment. REFERENCES BARRIOS, HI. (1954). Gastroenterology, 27, 81. [JELL, S. & WOODRUFF, A. W. (1960). Amer. J. trop. ~Vled. Hyg., 9, 155. BI(;(;AM, A. G. (1961). Textbook of ~Vledical Treatment, Davidson, Dunlop & Alstead. 8th Ed., Edinburgh: E. & S. Livingstone. BOYD, J. S. K. (1960). Trans. R. Soc. trop. ~1ed. Iqyg., 54, 505. CARTER,C. H. (1959). Antibiotic Med., 6, 586. DO,ELf, C. (1917). 5'pec. Rep. Ser. reed. Res. Comm. Lond., No. 4. DooxFn, H. P. (1960). Antibiotic. ~Ied., 7, 486. ELIAS, F. I~. & OI,IVER-(]ONZALEZ, J. (1959). Ibid., 6, 584. fIOAR~, C. A. (1952). Exp. Parasit., 1, 411. [~OEKEN(;A, ~I. ~F. & BATTERSON,D. I~. (1946). Amer. J. trop. ~/led. Hyg., 3, 849. MAnSD~X, P. D. (1960). Trans. R. Soc. trop. filed, tlyg., 54, 396. RIDI.EY, D. S. & HAW(;ool), B. C. (1956). J. clin. Path., 9, 74. SVENSSON, R. & LINDERS, F. J. (1934). Acta 3lied. Scan&, 81, 267. WOODnUr:F, A. W., BELL, S. & SCHOHEH), F. D. (1956). Trans. R. Soc. troD. ~led. Hyg., 50, 114, .... & . . . . (1960). Ibid., 54, 389.