Chapter 6 TREATMENT OF MIXED OESOPHAGOSTOMUM AND HOOKWORM INFECTION: EFFECT OF ALBENDAZOLE, PYRANTEL PAMOATE, LEVAMISOLE AND THIABENDAZOLE

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1 Chapter TREATMENT OF MIXED OESOPHAGOSTOMUM AND HOOKWORM INFECTION: EFFECT OF ALBENDAZOLE, PYRANTEL PAMOATE, LEVAMISOLE AND THIABENDAZOLE HP Krepel, T Haring, S Baeta and AM Polderman Published in the Transactions of the Royal Society of Tropical Medicine and Hygiene ;8:88

2 8 Abstract Oesophagostomum bijurcum has recently been recognised as a common parasite of man in northern Togo and in Ghana In a preliminary trial several anthelmintics were evaluated in the treatment of mixed Oesophagostomum and hookworm infections Diagnosis was based on coproculture, since the eggs of Oesophagostomum and hookworm cannot be distinguished on morphological grounds Of the anthelmintics tested, albendazole was most effective against both parasites Pyrantel pamoate, x 0 mg/kg, was effective against Oesophagostomum but not against hookworm The cure rates for both parasites were moderate for thiabendazole, and poor for levamisole

3 Treatment Introduction Oesophagostomum spp are nematodes classified in the same superfamily as hookworm (Strongyloidea), and are common parasites in animals Infections in humans were considered to be accidental and the parasite was thought not to be able to complete its life cycle [,,] In northern Togo and northeast Ghana, however, clinical manifestations of human oesophagostomiasis are quite common and 'helminthoma' is frequently observed [] In a recent survey, it has been shown that man can be considered a normal host of Oesophagostomum in these regions Thirdstage Oesophagostomum larvae were cultured from % of the population studied, and adult Oesophagostomum worms were isolated after anthelmintic treatment These were identified as Oesophagostomum bifiircum, a common parasite of monkeys [,] There is virtually no experience with anthelmintic treatment of human Oesophagostomum infections Earlier reports of human oesophagostomiasis were mainly clinical and infections were recognized only during surgery or at autopsy Other methods of diagnosis were not available Anthelmintic treatment was, therefore, not considered Many anthelmintic drugs might be effective against O bifurcum, such as those used for chemotherapy of human hookworm infection and thiabendazole which has been used in the treatment of Oesophagostomum infection in monkeys [] Some data on the efficacy of various anthelmintics in treating hookworm infection are shown in Table Since Oesophagostomum eggs are similar to those of hookworm, diagnosis is based on distinguishing the thirdstage larvae of both parasites, which are obtained after culture of infected faeces This paper reports the effect of a number of anthelmintics on mixed Oesophagostomum and hookworm infections, evaluated using this method In addition, the most promising anthelmintic, albendazole, was evaluated in more detail using egg counts as well as faecal cultures, and during followup at week and month Materials and methods Preliminary trials Research was carried out in northern Togo between July 88 and November 8 In three villages with a high prevalence of Oesophagostomum infection (Pana, Dassoute and Tami), volunteers were screened for the presence of Oesophagostomum infection using a single faecal culture Pregnant women and children under years old were excluded Three

4 80 Table Reported cure rates of hookworm infection obtained with several anthelmintics Anthelmintic Dosage Cure rate (%) References Albendazole Levamisole Pyrantel pamoate Thiabendazole Mebendazole 00 mg 0 mg/kg S x 0 mg/kg 0 mg/kg ^ x 0 mg/kg 0 mg/kg x 00 mg, d > x 00 mg, d ,,0,,,, hundred and thirteen double infections with Oesophagosiomum and hookworm were identified The very great majority of hookworm larvae cultured were Namericanus On very rare occasions a few larvae of Aduodenale were also found Eighteen additional cases of single Oesophagosiomum infections were not included for statistical reasons The subjects (0 females and 0 males) were asked to participate, after the treatment trial had been thoroughly explained to them Name, age, sex and village of the participants were recorded Pretreatment stool samples were taken on the day of treatment; posttreatment samples were obtained one to weeks later Stool samples were collected in plastic vials and were taken to the laboratory to be processed on the same day Stool cultures were performed using the classical petridish method [] Because of the wide variation in the number of larvae obtained from a single culture, cultures of each stool sample were made to reduce the variability (unpublished observations) The total number of Oesophagosiomum and hookworm larvae found in these cultures was counted and classified and scored as follows:, no larvae found;, larvae found;, 0 larvae found; and, > 00 larvae found Albendazole was given to groups in single doses of 00 mg or 800 mg A third group was treated with pyrantel pamoate 0 mg/kg; the fourth group received doses of pyrantel pamoate 0 mg/kg on consecutive days Levamisole treatment consisted of 0 mg for children and 0 mg for adults; a double dose, 00 and 00 mg respectively, was given to the sixth group Thiabendazole was given in doses of mg/kg on two consecutive days (Table )

5 Treatment 8 Table Treatment schedules, numbers of participants, and cure rates for Oesophagostomum and hookworm infection Cure rate(%) i Oesophagostomum Hookworm Drug Dosage Males Females Albendazole Pyrantel pamoate Levamisole(*) Thiabendazole 00 mg 800 mg 0 mg/kg x 0 mg/kg 0/0 mg 00/00 mg x mg/kg % 8% % 8% % % % % % % 8% % 0% % (*) Dosages shown are for children and adults Further evaluation of albendazole With the most promising drug, albendazole, a second trial was carried out Twentyeight persons ( males, females; mean age years, range 0) were treated with 00 mg albendazole Stool samples were collected before, and one week after and one month after, treatment With each stool sample, egg counts were made by KatoKatz method using mg of faeces Stool cultures were processed and classified as in the preliminary trials Results Preliminary trials For Oesophagostomum, the most effective single dose treatment was albendazole, 00 mg (Table ) Cure rates were high, and posttreatment larval scores (postls) were low, irrespective of the corresponding pretreatment larval scores (prels) (Table ) Treatment was less successful in participants treated with pyrantel pamoate, 0 mg/kg, or thiabendazole, x mg Cure rates were moderate and the postls were higher than with albendazole With pyrantel pamoate, particularly poor results were obtained in persons with high prels With levamisole, 0/0 mg, cure rates were low, regardless of the prels (Table )

6 8 Table Pre and posttreatment larval scores (*) of infections with Oesophagostomum and hookworm Treatment Albendazole 00mg Score Oesophagost mum Posttreatment Pretreatment 0 Pretreatment Hookworm Posttreatment Albendazole 800 mg Pyrantel pamoate 0 mg/kg 8 " 8 " " Pyrantel pamoate x 0 mg/kg 8 8 Levamisole 0/0 mg (**) 0 ll 8 Levamisole 00/00 mg (**) Thiabendazole x mg l ' 0 (*) Larval scores indicated by (negative) and,, or (see text) (**) Dosages shown are for children/adults

7 Treatment 8 Table Egg count and larval scores (*) of hookworm and Oesophagostomum before, one week and one month after, treatment with albendazole 00 mg Pretreatment (/»=8) week (n : =) month (n = =) L larvae of Oesophagost omum 8 L larvae of hookworm 0 X Egg counts > (*) Larval scores indicated by (negative),,, or (see text) When the dosages were doubled, a significant increase of the cure rates was observed in persons treated with pyrantel pamoate, x 0 mg/kg The cure rates in participants treated with a double dose of albendazole or levamisole were virtually the same as with single dose regimens For hookworm, treatment was less effective in all treatment groups Of the single dose treatments, the highest cure rate (%) and the lowest postls were achieved in persons treated with albendazole, 00 mg The effect of treatment with pyrantel pamoate, 0 mg/kg, was small (cure rate %) and there was almost no effect with levamisole, 0/0 mg, and thiabendazole In the latter groups, higher postls were seen especially in persons with higher prels In the double dose groups, cure rates with albendazole differed only slightly from those of the single dose treatments (% vs %) Although a double dose of levamisole (00/00 mg) was more effective than a single dose (0% vs %), the cure rate remained low

8 8 Treatment with pyrantel pamoate, x 0 mg/kg, gave even lower cure rates than the single dosage (8% vs %) Further evaluation of albendazole Egg counts and larval scores for Oesophagostomum and hookworm before and after treatment are given in Table Most participants had pretreatment egg counts of less than 000 eggs/g PreLS of hookworm were slighlty higher than those for Oesophagostomum Oesophagostomum larvae were detected in none of the posttreatment cultures For hookworm, 0% (/) and % (/) of the patients were negative on culture and weeks after treatment, respectively One week after treatment, only stool samples contianed eggs Four weeks after treatment, stools contained eggs; of these, cultures remained negative in three cases, and a species diagnosis could not be made Discussion When O bifurcum was recognized as a common parasite of man, treatment of the infected subjects became one of the many aspects to be investigated The present study showed that albendazole was more effective than pyrantel pamoate, levamisole or thiabendazole in the treatment of mixed Oesophagostomum and hookworm infection For Oesophagostomum infection, the effect of albendazole was approached only by pyrantel pamoate, x 0 mg/kg Pyrantel pamoate, 0 mg/kg, gave poorer results, as did thiabendazole The low cure rate of the latter, as well the occurrence of side effects reported by others [,], excluded this drug from further evaluation The cure rates achieved with levamisole were low For hookworm also, albendazole was more effective than the other drugs tried The low cure rate achieved with thiabendazole confirmed earlier reports [,] The poor results obtained with pyrantel pamoate and levamisole can be accounted for by the presence of Necator americanus as the predominant hookworm in the region, as it is reported to respond less well to treatment with these drugs [,,] In general, faecal cultures are used qualitatively to detect the presence of thirdstage larvae of hookworm, Strongyloides stercoralis and other nematodes In the present study the mean larval counts of cultures were used in a semiquantitative way as well This is permissable because there is a significant association between the mean larval count of cultures and the egg counts (unpublished observations)

9 Treatment 8 Although albendazole was the most effective drug for the treatment of Oesophagostomum infection in the preliminary trial, the cure rates for hookworm were poor in comparison to those of earlier reports (Table ) In part, this could be explained by the use of a more sensitive method of evaluation (faecal culture) In the second experiment, however, the effect of treatment was assessed with both egg counts and larval counts one week as well as weeks after treatment Again, cure rates were high for Oesophagostomum (00%) but not for hookworm Assessed one week and one month after treatment respectively, the cure rates for hookworm were 0% and % when based on cultures and 8% and % when based on egg counts Rapid reinfection was unlikely because the treatment trial was conducted in the middel of the dry season, when little transmission occurs In this population a single dose of albendazole (00 mg) would seem satisfactory for the treatment of Oesophagostomum but insufficient to achieve high cure rates in hookworm

10 8 Acknowledgements The research in Togo was supported and assisted by the Minister of Health and the Minister of Education The advice Mr KD Amouzou, administrative director of Dapaong Hospital, and the assistance of Ms Lamboni Assibi, were of great value The contributions of B de Jonge and A de Joode were much appreciated We thank Dr J Horton, Smith Kline and French Laboratories, who provided us with albendazole, and Dr O Vanparijs, Janssen Pharmaceuticals, who supplied levamisole This research was funded by the Netherlands Foundation for the Advancement of Tropcial Research (WOTRO)

11 Treatment 8 References Anthony PP, McAdam IWJ, Helminthic pseudotumours of the bowel: Thirtyfour cases of helminthoma Gut : 8 Barrowclough H, CromeL, 8 Oesophagostomiasis in man Tropical and Geographical Medicine :8 Chabaud AG, Larivière M, 8 Sur les Oesophagostomes de 'homme Bulletin de la Societé de Pathologie Exotique :8 Gigase P, Baeta S, Kumar V, Brandt J, 8 Frequency of symptomatic human oesophagostomiasis (helminthoma) in Northern Togo, in Geerts and others, eds, 8 Helminth Zoonosis : Martinus Nijhoff, Krepel HP, Baeta S, Polderman AM, Human Oesophagostomum infection in northern Togo and Ghana: epidemiological aspects Annals of Tropical Medicine and Parasitology 80:800 Polderman AM, Krepel HP, Baeta S, Blotkamp J, Gigase P, Oesophagostomiasis a common infection of man in northern Togo and Ghana American Journal of Tropical Medicine and Hygiene : Cullum LE, Hamilton BR, Thiabendazole as an anthelmintic in research monkeys American Journal of Veterinary Research :80 8 Mbendi N, Mashako MM, Herabo M, Bahavu WM, 8 L'albendazole dans le traitement des nematodoses intestinales a Kinshasa Zaire Annates de la Societé Beige de Medicine Tropicale 0: Pugh RNH, Teesdale CH, Burnham GM, 8 Albendazole in children with hookworm infection Annals of Tropical Medicine and Parasitology 80: 0 Ramalingam S, Sinniah B, Krishnan U, 8 Albendazole an effective single dose broad spectrum anthelmintic drug American Journal of Tropical Medicine and Hygiene :8 8 Miller MJ, 80 Use of levamisole in parasitic infections Drugs :0

12 88 Farahmandian I, Arfaa F, Jalali H, Reza M, Comparative studies on the evaluation of the effect of new anthelmintics on various intestinal helminthiasis in Iran Chemotherapy :80 Ghadirian E, Sanati A, Preliminary studies on the treatment of hookworm with pyrantel pamoate in Iran Journal of Tropical Medicine and Hygiene :0 Migasena S, Sumtharasamai P, Harinasuta T, 8 Mebendazole tetrachloroethylene and pyrantel pamoate in the treatment of hookworm infection Annals of Tropical Medicine and Parasitology :00 Sinniah B, Sinniah D, 8 The anthelminthic effects of pyrantel pamoate oxantelpyrantel pamoate levamisole and mebendazole in the treatment of intestinal nematodes Annals of Tropical Medicine and Parasitology : Coulaud JP, 8 Traitement des nematodes intestinales Annates de la Societé Beige de Medicine Tropicale :0 PenaChavarria A, Swartzwelder JC, Villarejos VM, Kotcher E, Argueda J, Mebendazole, an effective broadspectrum anthelmintic American Journal of Tropical Medicine and Hygiene :