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The treatment of giardiasis
438 TRANSACTIONS OFTHEROYALSOCIETY
OF TROPICAL
MEDICARE
AND
HYGIENE,
The treatment Formerly
VOL.
74, No.
4, 1980
of giardiasis
R. M. MENDELSON* Senior Registrar, Hospital for Tropical Diseases, London NW1 OPE
Introduction From the beginning of this century various treatments for Giardia lamblia infection have been tried; these included, in the early years, such potentially toxic substances as carbon tetrachloride, mercury and bismuth. The first effective treatment became available with the discovery of the antimalarial meuacrine in the 1930s. This drug continues in widespread use and remained largely unchallenged until the appearance of the imidazole derivatives in the early 1960s; the first of these was metronidazole and several others of this series have since appeared. Only those drugs in widespread use are discussed here. The studies named are intended to be representative and I have not attempted to provide a comprehensive list of references to the considerable literature on this subject. Indications for Treatment Symptomatic giardiasis is an indication for treatment; in pregnancy the benefits must be weighed against the potential hazards and the imidazole drugs should be avoided. Asymptomatic cyst passers, especially children and food-handlers, shouId also be treated as they pose a potentia1 threat to others and intermittent chronic symptoms are not infrequent. Drugs Mepacrine: Mepacrine is a member of the 9aminoacridine group of drugs. Other acridine derivatives, which share the property of being yellow dyes, have been tried in the treatment of giardiasis, as have the 4-aminoquinolines and Gunino-quinolines which have superceded mepacrine as anti-malarials. Although several have giardicidal effects, none are as effective as mepacrine. Variable degrees of success have been claimed for mepacrine. Whereas WOLFE (1978) claims a cure rate greater than 95y; in adults with the dosage that has come to be accepted as the norm (100 mg thrice daily), others have found it somewhat less effective. Even if one accepts the probable consensus that mepacrine is successful in eliminating the organism in around 90”,b of patients, there are problems associated with its administration. Firstly, the seven to ten-day course is considerably longer than that required by newer drugs. Secondly, unwanted effects are several and, in many studies, frequent. These include gastric irritation, fever, yellow staining of the skin (in about 10yO) and rashes. Wolfe reported the incidence of psychosis to be l-5 9:. Psoriasis is a contraindication. The drug is even less well tolerated by children.
However, mepacrine remains a useful drug for some adults, particularly those who have failed to respond to a course of metronidazole. It has been claimed to be more effective than metronidazole in the treatment of acute-stage infections, though this is unconfirmed. Metronidazole: Metronidazole was the first of several 5nitroimidazole derivatives that have appeared. Its chemical structure is as follows: H----C -$? O,N-
C-CH,
L L H&H
,OH
The others in the group are formed by variation of the side-chain attached to the imidazole ring. Metronidazole is a powerful anti-protozoa1 drug and usually well tolerated. Various dosages and durations of treatment have been studied. The “low-dose/longer-duration” regimes (of the order of 200 mg thrice daily for seven to ten days in adults) seem to give cure rates from 60”/, (I&AMBATTA. 1971) to 87% (LEVI et al.. 1977). The high single>dose regime, ‘on the other hand, ‘using 1.6yg (KHAMBATTA, 1971) to 2.4 g (JOKIPII & JOKIPII, 1978a) in adults and 50 mg per kg in children (GAZDER & BANERJEE, 1977), seems to give consistently poor results. The most effective regime seems to be a single dose of 2 g in adults taken on three successive days. At the Hospital for Tropical Diseases, London, WRIGHT et al. (1977) found this to give a success rate of 9 1 Y,. rising to 95 ‘I/, if a second similar course is given. At this- kind of dosage, however, sideeffects are frequent, though usually mild, consisting of gastro-intestinal irritation, lassitude and a metallic taste in the mouth. Occasionally, however, dizziness and disturbances of judgement occur and, therefore, patients on this high-dose regime are advised not to drive or operate hazardous machinery. The effects on the patient may be minimized if the drug is taken at bedtime. Metronidazole has a Disulfiram-like interaction with alcohol, and patients must be warned of this. Until recently one of the major disadvantages was that no metronidazole suspension was available for children. Now there is such a formulation and we have recently been trying the effects of Flagyl (benzoylmetronidazole) Suspension in young adults. In a small sample of patients we have found it to *Address for correspondence: 17, St. Peter’s Close, Cassington, Oxford OX8 IDX, UK.
R. M. MENDELSON
have tolerability similar to the tablets, but no doubt the ease of administration to children will prove an advantage. Furazolidone: Furazolidone is a nitrofuran derivative which has been used extensively abroad, particularly in India, but does not appear to have gained very wide acceptance in the UK. It had the major advantage of being available in suspension and therefore suitable for children. Various studies have used regimes of 8 to 16 mg per kg per day for three to seven days, with cure rates ranging from 72 to 100 %. Though side effects are usually mild, they occur in approximately 20% of patients (LEVI et al., 1977) and include headache, nausea, vomiting and rashes. The drug is capable of producing haemolysis in glucose-6phosphate deficient individuals and it has the potential to inhibit mono-amino-oxidase. Tinidazole : This imidazole derivative, which has been used extensively abroad, has only recently become available in this country but may well prove to be the treatment of choice in giardiasis. It appears to give extremely good cure rates of well over 99% in both adults and children. It has been given’ both in regimes of low-dosage/longerduration, (150 rng twice daily for seven days in adults) and of single high-dosage (2 g for adults). Both regimes are effective. SAWYER et al. (1976) reviewed experience with the drug. Unwanted effects are mild and, in most studies, infrequent. Tinidazole, like metronidazole has Disulfiram-like properties with alcohol. The advantages of an effective, well-tolerated, single-dose regime are self-evident. For this reason we have instituted a randomized trial at the Hospital for Tropical Diseases, London, comparing, in adults, tinidazole 2 g as a single dose, versus metronidazole 2 g on-three successive days, versus meoacrine 100 rng thrice dailv for 10 davs. So far ou; figures are t& small to draw conclusions, but the trend seems to be that cure rates are high with all three regimes and that tinidazole in its single convenient dosage is well-tolerated. Other Imidazole Derivatives: Other drugs in this group have been used with success. Examples are Ornidazole and Nitrimidazine. None seems to have any consistent advantage over those I have previously mentioned and several are not, in any case, generally available in the UK. No doubt others will appear. It must be borne in mind that the imidazole drugs have been shown to be carcinogenic and mutagenic in experimental animals. They should thus be avoided in pregnancy.
439
Follow-up of Patients Usually in giardiasis response to appropriate anti-protozoa1 drugs is rapid. Occasionally gastrointestinal symptoms may continue. Before attributing these to a failure to eliminate the parasite it is as well to consider other possibilities, such as temporary lactose intolerance or post-infective irritable bowel syndrome. In almost all patients the finding of three negative post-treatment stool specimens is an adequate test of elimination of the organism. However, it is desirable to follow up patients for several weeks, or even months, after therapy as late relapses and revision to stool positivity have been shown to occur in a few. This point has been made by JOKIPII & JOKIPII (1978b). Conclusion Very effective treatment for giardiasis is available. There is little to choose in efficacy between the major drugs I have mentioned, used at optimum dosage, but mepacrine probably has a higher frequency of unwanted effects than many of the newer dr;gs, and the required duration of treatment is longer. Tinidazole is a very promising drug, being effective in single dosage with infrequent side effects. References Gazder, A. J. & Banerjee, M. (1977). Single-dose treatment of giardiasis in children: a comparison of Tinidazole and Metronidazole. Current Medical Research and Opinion, 5, 164-168. Jokipii, A. M. M. & Jokipii, L. (1978). Comparison of four dosage schedules in the treatment of giardiasis with Metronidazole. Infection, 6, 92-94. Jokipii, A. M. M. & Jokipii, L. (1978). Comparative evaluation of two dosages of Tinidazole in the treatment of giardiasis. American Journal of Tropical Medicine and Hygiene, 27, 758-761. Khambatta, R. B. (1971). Metronidazole in giardiasis. Annals of Tropical Medicine and Parasitology, 65,487-489. Levi, G. C., Avila, C. A. de & Neto, V. A. (1977). Efficacy of various drugs for treatment of giardiasis. American Journal of Tropical Medicine and Hygiene, 26, 564-565. Sawyer, P. R., Brogden, R. N., Pinder, R. M., Speight, T. M. &Avery, G. S. (1976). Tinidazole: a review of its antiprotozoal activity and therapeutic efficacy. Drugs, 11, 423-440. Wolfe, M. S. (1978). Giardiasis. New England Journal of Medicine, 298, 319-321. Wright, S. G., Tomkins, A. M. & Ridley, D. S. (1977). Giardiasis : clinical and therapeutic aspects. Gut, 18, 343-350.
OF TROPICAL
MEDICARE
AND
HYGIENE,
The treatment Formerly
VOL.
74, No.
4, 1980
of giardiasis
R. M. MENDELSON* Senior Registrar, Hospital for Tropical Diseases, London NW1 OPE
Introduction From the beginning of this century various treatments for Giardia lamblia infection have been tried; these included, in the early years, such potentially toxic substances as carbon tetrachloride, mercury and bismuth. The first effective treatment became available with the discovery of the antimalarial meuacrine in the 1930s. This drug continues in widespread use and remained largely unchallenged until the appearance of the imidazole derivatives in the early 1960s; the first of these was metronidazole and several others of this series have since appeared. Only those drugs in widespread use are discussed here. The studies named are intended to be representative and I have not attempted to provide a comprehensive list of references to the considerable literature on this subject. Indications for Treatment Symptomatic giardiasis is an indication for treatment; in pregnancy the benefits must be weighed against the potential hazards and the imidazole drugs should be avoided. Asymptomatic cyst passers, especially children and food-handlers, shouId also be treated as they pose a potentia1 threat to others and intermittent chronic symptoms are not infrequent. Drugs Mepacrine: Mepacrine is a member of the 9aminoacridine group of drugs. Other acridine derivatives, which share the property of being yellow dyes, have been tried in the treatment of giardiasis, as have the 4-aminoquinolines and Gunino-quinolines which have superceded mepacrine as anti-malarials. Although several have giardicidal effects, none are as effective as mepacrine. Variable degrees of success have been claimed for mepacrine. Whereas WOLFE (1978) claims a cure rate greater than 95y; in adults with the dosage that has come to be accepted as the norm (100 mg thrice daily), others have found it somewhat less effective. Even if one accepts the probable consensus that mepacrine is successful in eliminating the organism in around 90”,b of patients, there are problems associated with its administration. Firstly, the seven to ten-day course is considerably longer than that required by newer drugs. Secondly, unwanted effects are several and, in many studies, frequent. These include gastric irritation, fever, yellow staining of the skin (in about 10yO) and rashes. Wolfe reported the incidence of psychosis to be l-5 9:. Psoriasis is a contraindication. The drug is even less well tolerated by children.
However, mepacrine remains a useful drug for some adults, particularly those who have failed to respond to a course of metronidazole. It has been claimed to be more effective than metronidazole in the treatment of acute-stage infections, though this is unconfirmed. Metronidazole: Metronidazole was the first of several 5nitroimidazole derivatives that have appeared. Its chemical structure is as follows: H----C -$? O,N-
C-CH,
L L H&H
,OH
The others in the group are formed by variation of the side-chain attached to the imidazole ring. Metronidazole is a powerful anti-protozoa1 drug and usually well tolerated. Various dosages and durations of treatment have been studied. The “low-dose/longer-duration” regimes (of the order of 200 mg thrice daily for seven to ten days in adults) seem to give cure rates from 60”/, (I&AMBATTA. 1971) to 87% (LEVI et al.. 1977). The high single>dose regime, ‘on the other hand, ‘using 1.6yg (KHAMBATTA, 1971) to 2.4 g (JOKIPII & JOKIPII, 1978a) in adults and 50 mg per kg in children (GAZDER & BANERJEE, 1977), seems to give consistently poor results. The most effective regime seems to be a single dose of 2 g in adults taken on three successive days. At the Hospital for Tropical Diseases, London, WRIGHT et al. (1977) found this to give a success rate of 9 1 Y,. rising to 95 ‘I/, if a second similar course is given. At this- kind of dosage, however, sideeffects are frequent, though usually mild, consisting of gastro-intestinal irritation, lassitude and a metallic taste in the mouth. Occasionally, however, dizziness and disturbances of judgement occur and, therefore, patients on this high-dose regime are advised not to drive or operate hazardous machinery. The effects on the patient may be minimized if the drug is taken at bedtime. Metronidazole has a Disulfiram-like interaction with alcohol, and patients must be warned of this. Until recently one of the major disadvantages was that no metronidazole suspension was available for children. Now there is such a formulation and we have recently been trying the effects of Flagyl (benzoylmetronidazole) Suspension in young adults. In a small sample of patients we have found it to *Address for correspondence: 17, St. Peter’s Close, Cassington, Oxford OX8 IDX, UK.
R. M. MENDELSON
have tolerability similar to the tablets, but no doubt the ease of administration to children will prove an advantage. Furazolidone: Furazolidone is a nitrofuran derivative which has been used extensively abroad, particularly in India, but does not appear to have gained very wide acceptance in the UK. It had the major advantage of being available in suspension and therefore suitable for children. Various studies have used regimes of 8 to 16 mg per kg per day for three to seven days, with cure rates ranging from 72 to 100 %. Though side effects are usually mild, they occur in approximately 20% of patients (LEVI et al., 1977) and include headache, nausea, vomiting and rashes. The drug is capable of producing haemolysis in glucose-6phosphate deficient individuals and it has the potential to inhibit mono-amino-oxidase. Tinidazole : This imidazole derivative, which has been used extensively abroad, has only recently become available in this country but may well prove to be the treatment of choice in giardiasis. It appears to give extremely good cure rates of well over 99% in both adults and children. It has been given’ both in regimes of low-dosage/longerduration, (150 rng twice daily for seven days in adults) and of single high-dosage (2 g for adults). Both regimes are effective. SAWYER et al. (1976) reviewed experience with the drug. Unwanted effects are mild and, in most studies, infrequent. Tinidazole, like metronidazole has Disulfiram-like properties with alcohol. The advantages of an effective, well-tolerated, single-dose regime are self-evident. For this reason we have instituted a randomized trial at the Hospital for Tropical Diseases, London, comparing, in adults, tinidazole 2 g as a single dose, versus metronidazole 2 g on-three successive days, versus meoacrine 100 rng thrice dailv for 10 davs. So far ou; figures are t& small to draw conclusions, but the trend seems to be that cure rates are high with all three regimes and that tinidazole in its single convenient dosage is well-tolerated. Other Imidazole Derivatives: Other drugs in this group have been used with success. Examples are Ornidazole and Nitrimidazine. None seems to have any consistent advantage over those I have previously mentioned and several are not, in any case, generally available in the UK. No doubt others will appear. It must be borne in mind that the imidazole drugs have been shown to be carcinogenic and mutagenic in experimental animals. They should thus be avoided in pregnancy.
439
Follow-up of Patients Usually in giardiasis response to appropriate anti-protozoa1 drugs is rapid. Occasionally gastrointestinal symptoms may continue. Before attributing these to a failure to eliminate the parasite it is as well to consider other possibilities, such as temporary lactose intolerance or post-infective irritable bowel syndrome. In almost all patients the finding of three negative post-treatment stool specimens is an adequate test of elimination of the organism. However, it is desirable to follow up patients for several weeks, or even months, after therapy as late relapses and revision to stool positivity have been shown to occur in a few. This point has been made by JOKIPII & JOKIPII (1978b). Conclusion Very effective treatment for giardiasis is available. There is little to choose in efficacy between the major drugs I have mentioned, used at optimum dosage, but mepacrine probably has a higher frequency of unwanted effects than many of the newer dr;gs, and the required duration of treatment is longer. Tinidazole is a very promising drug, being effective in single dosage with infrequent side effects. References Gazder, A. J. & Banerjee, M. (1977). Single-dose treatment of giardiasis in children: a comparison of Tinidazole and Metronidazole. Current Medical Research and Opinion, 5, 164-168. Jokipii, A. M. M. & Jokipii, L. (1978). Comparison of four dosage schedules in the treatment of giardiasis with Metronidazole. Infection, 6, 92-94. Jokipii, A. M. M. & Jokipii, L. (1978). Comparative evaluation of two dosages of Tinidazole in the treatment of giardiasis. American Journal of Tropical Medicine and Hygiene, 27, 758-761. Khambatta, R. B. (1971). Metronidazole in giardiasis. Annals of Tropical Medicine and Parasitology, 65,487-489. Levi, G. C., Avila, C. A. de & Neto, V. A. (1977). Efficacy of various drugs for treatment of giardiasis. American Journal of Tropical Medicine and Hygiene, 26, 564-565. Sawyer, P. R., Brogden, R. N., Pinder, R. M., Speight, T. M. &Avery, G. S. (1976). Tinidazole: a review of its antiprotozoal activity and therapeutic efficacy. Drugs, 11, 423-440. Wolfe, M. S. (1978). Giardiasis. New England Journal of Medicine, 298, 319-321. Wright, S. G., Tomkins, A. M. & Ridley, D. S. (1977). Giardiasis : clinical and therapeutic aspects. Gut, 18, 343-350.