Triclabendazole is the best fasciolicide available with activity against very young fluke. But there are increasing numbers of reports of resistance including failure of therapy in humans. Determining the resistance status on ‘fluky’ farms is essential as high mortality of sheep can occur if it is not realised resistance is present. The options for control are confined to other less effective products and failure of closantel as well could lead to the closure of some sheep farms in the UK. Preventing fluke infections though pasture management is difficult or may be impossible so development of a vaccine is urgently required.

Coles GC (2017) The Significance of Triclabendazole Resistance. J Vet Med Res 4(7): 1098.

The pathology of fasciolosis is well known and occurs as two main forms, the acute infection resulting from the migration of large numbers of immature fluke through the liver and chronic infection caused by adult fluke in the bile ducts and loss of blood giving rise to sub mandibular oedema (bottle jaw) and lost production. Acute fluke, which can be fatal, is largely confined to sheep and lambs due to the smaller size of their livers compared with those of cattle. The introduction of triclabendazole revolutionised the control of fasciolosis due to its activity against fluke as young as one week of age making it the most effective fasciolicide. The result was the over reliance on one product (monotherapy) that had the almost inevitable consequence of the selection of triclabendazole resistant fluke. The first reportof resistance to triclabendazole came from Australia in 1995 [1]. Other reports followed and are summarised in (Table 1). Apart from the obvious implication for animal health, triclabendazole is used in treatment of human infections with F. hepatica and failure of triclabendazole has been reported in infected patients in Peru [2]. The implications of triclabendazole resistance can be severe when its presence has not been recognised. In central Wales a farmer informed his veterinary surgeon that he had used triclabendazole in September and in November his sheep were sick. Treatment with triclabendazole was recommended with faecal egg counts after 3 weeks. As triclabendazole had not worked treatment with closantel was given but it was too late and 60% of the flock died [3].

For a long time sheep farmers have been advised to establish the anthelmintic resistant status of nematodes on their farms due to the widespread occurrence of anthelmintic resistant nematodes, but so far this has not been adopted widely [4]. Now a similar recommendation must be made for all farms where liver fluke infections are known to occur especially where triclabendazole is used. A recent survey in Northern Ireland fortunately suggests fluke control practices are beginning to change [5]. It is also important that the effectiveness of other fasciolicides is established as resistance has been described to some alternative therapies (Table 2). The biggest concern is that resistance will be described to closantel, the other product used in sheep. Closantel, which is only effective against immature fluke from about six weeks of age, is more toxic and less effective than triclabendazole. Another uncoupler, nitroxynil, is used in cattle as it can be injected whilst triclabendazole is usually given orally to sheep. However, Novobilsky et al. [6], described the failure of closantel pour-on on cattle in Sweden. If due to resistance it could be of considerable concern as no therapy would be left for immature fluke in sheep. However, some veterinary surgeons in Wales have been advising farmers against the use of pour-on preparations of closantel on cattle due to their lack of full efficacy [7]. In areas where fluke are very common and there is no effective immature fasciolicides farmers may have to stop keeping sheep. Fortunately if acute fluke is not of primary concern, adult triclabendazole resistant fluke can be controlled with some other fasciolicides [8,9].

In theory farmers should be able to use combination fasciolicides which would be more effective and slow the development of resistance, but once resistance has developed to one product combinations are less effective. In practice, there are no combination products so use of alternative products at different times of year is recommended. Fluke transmission in North West Europe peaks in the autumn so this is the time when a product effective against immature fluke is required, i.e. triclabendazole. By the spring all fluke should be adult so a product effective against only adults should be used. This could prevent the release of eggs from the host to infect the new generation of snails. However, with milder winters Due to global warming, infected snails may over winter and infect the spring herbage. An increased dose albendazole appears to the product of choice, but albendazole resistance has already been described (Table 2).

In the upland areas of the UK Nematodirus battus can be a serious infection in young lambs and albendazole is usually used for control as there is presently very little benzimidazole resistance in this species and this spares the use of other anthelmintics. However, if sheep are dosed with albendazole to control adult F. hepatica this may encourage the development of benzimidazole resistance in N.battus. With the apparent growing importance of paramphistomes, at least in the British Isles [10], oxyclozanide could be used as it controls adult rumen fluke [11]. However this might select for resistance in the most common fluke, Calicophora daubneyi, leaving no product for this infection when it is required.

Diagnosis of infection usually involves the counting of fluke eggs in faeces at the time of treatment and three weeks later. This time is required to allow the breakdown of adult fluke in the liver and expulsion of all eggs. Unlike with nematodes release of fluke eggs from the liver/gall bladder into the faeces is not continuous so several animals must be tested to ensure fluke infections are not missed. In this regard use of composite sampling can reduce the costs of tests [12]. Immunological tests have been developed but have not yet been widely used for routine diagnosis [13]. However, they do have the advantage of detecting the presence of immature fluke infections. Another method of detecting resistance may be the use of FAMACHA which determines the degree of anaemia by inspecting of eye colour [14]. However, it cannot be used where there is Haemonchus contortus this nematode causes anaemia.

In an ideal world, farmers would prevent the introduction a triclabendazole resistant fluke through the movement of animals. But given the long pre-patent period (10-12 weeks) and thus the need to keep animals off pastures where there may be snail intermediate hosts this is unlikely to be adopted. Once triclabendazole resistant fluke are in an area they can be spread by rabbits and deer which are good final hosts. So, without a rabbit proof fence that is too high for deer to jump over, spread of triclabendazole resistant fluke is almost inevitable. Another recommended method for control is to either fence off ‘fluky fields’ or wet spots in fields, e. g. areas around natural springs which are sufficiently moist to support the intermediate snail host (Galba truncatula, or related species). But in hill country in the UK this method of control is not practical particularly where there is common grazing land. In the UK and presumably some other countries spraying of molluscicides is prohibited due to the risk of contamination of water supplies. Drainage of upland fields is also strongly discouraged so that rainfall is slowly released from the land which ensures amore steady flow in the rivers rather than rapid run off. This is particularly important where drinking water is extracted from rivers. Wet land conservation is also encouraged to maintain biodiversity with grazing for vegetation control. This, of course, encourages infection of animals.

Even if a new fasciolicide with a different mechanism of action has already been discovered, it takes a long time to develop and is very expensive. So alternative methods of control are required and the obvious answer is development of vaccines. Efforts have been expended on proteins as potential vaccine candidates so far without a vaccine fully effective in grazing animals [15]. The development of resistance to triclabendazole has complicated the control of liver fluke [16] and the use of alternative productsis not as straight forward as at first site appears. It is to be hoped that further surveys of the resistance will be undertaken and published so that the true extent of resistance on a world basis can be established.

Table 1: Reports of triclabendazole resistance in Fasciola hepatica.

Table 2: Resistance to fasciolicides other than triclabendazole.

1. Overend DJ, Bowen FL. Resistance of Fasciola hepatica to triclabendazole. Aust Vet J. 1995; 72: 275-276.

2. Cabada MM, Lopez M, Cruz M, Delgado JR, Hill v, White AC Jr. Treatment failure after multiple courses of triclabendazole among patients with fascioliasis in Cusco, Peru: a case series. PLoS Negl Trop Dis. 2016; 10: e0004361.

3. Jones EM, Danial R, Coles GC. Diagnosis of resistance to triclabendazole. Vet Rec. 2014; 174: 560.

4. Morgan ER, Coles GC. Nematode control practices on sheep farms following an information campaign aiming to delay anthelmintic resistance. Vet Rec. 2010; 166, 301-303.

5. McMahon C, Edgar HW, Hanna RE, Ellison SE, Flanagan AM, McCoy M et al. Liver fluke control on sheep farms in Northern Ireland: A survey of changing management practices in relation to disease prevalence and perceived triclabendazole resistance. Vet Parasitol. 2016; 216: 72-83.

6. Novobilsky A, Höglund J. First report of closantel treatment failure against Fasciola hepatica in cattle. Int J Parasitol Drugs Drug Resist. 2015; 5: 172-177.

7. Jones EM. Personal communication (2017).

8. Coles GC, Rhodes KA, Stafford K. Activity of closantel against adult triclabendazole resistant Fasciola hepatica. Vet Rec. 2000; 146: 504.

9. Coles GC, Stafford KA. Activity of oxyclozanide, nitroxynil, clorsulon and albendazole against adult triclabendazole resistant Fasciola hepatica. Vet Rec. 2001; 148: 723-724.

10. Zintl A, Garcia-Campos A, Trudgett, A, Chryssafidis, AL, Talavera-Arce S, Fu y, et al. Bovine paramphistomes in Ireland. Vet Parasitol. 2014; 204: 199-208.

11. Rolf PF, Boray JC. Chemotherapy of paramphistomes. Aust Vet J. 1987; 64: 328-322.

12. Daniel R, van Dijk J, Jenkins T, Akca A, Mearns R, Williams DJ. Composite faecal egg count reduction test to detect resistance to triclabendazole in Fasciola hepatica. Vet Rec. 2012; 171: 1-5.

13. Alvarez Rojas CA, Jex AR, Gasser RB, Scheerlinck JP. Techniques for the diagnosis of Fasciola hepatica infections in animals: room for improvement. Adv Parasitol. 2014; 85: 65-107.

14. Olah S, van Wyk JA, Wall R, Morgan ER. FAMACHA: A potential tool for targeted selective treatment of chronic fasciolosis in sheep. Vet Parasitol. 2015; 212: 188-192.

15. Molina-Hernández V, Mulcahy G, Pérez J, Martinez-Moreno A, Donelly S, O’Neill SM et al. Fasciola hepatica vaccine: we may not be there yet but we are on the right road. Vet Parasitol. 2015; 208: 101-111.

16. Kelley JM, Elliott TP, Beddoe T, Anderson G, Skuce P, Spithill TW. Current threat of triclabendazole resistance in Fasciola hepatica. Trends Parasitol. 2016; 32: 458-469.

17. Thomas I, Coles GC, Duffus K. Triclabendazole resistant Fasciola hepatica in southwestern Wales. Vet Rec. 2000; 146: 200.

18. Gasseenbeek CP, Moll L, Cornelissen JB, Vellema P, Borgsteede FH. An experimental study on triclabendazole resistance of Fasciola hepatica in sheep. Vet Parasitol. 2001; 95: 37-43.

19. Alvarez-Sánchez MA, Manar-Jaime RC, Pérez-Garcia J, Rojo-Vázquez FA. Resistance of Fasciola hepatica to triclabendazole and albendazole in sheep in Spain. Vet Rec. 2006; 159; 424-425.

20. Oliveira DR, Ferreira DM, Strival CC, Romero F, Csavagnolli F, Kloss A, et al. Triclabendazole resistance involving Fasciola hepatica in sheep and goats during an outbreak in Almirante Tamandare, Paraná, Brazil. Rev Bras Parasitol Vet. 2008; 17: 149-153.

21. Ortiz P, Scarcella S, Cerna C, Rosales C, Cabrera M, Guzmán M, et al. Resistance of Fasciola hepatica against triclabendazole in cattle in Cajamarca (Peru): a clinical trial and an in vivo efficacy test in sheep. Vet Parasit. 2013; 195: 118-121.

22. Elliott TP, Kelley JM, Rawlin G, Spithill T. High prevalence of fasciolosis and evaluation of drug efficacy against Fasciola hepatica in dairy cattle in the Maffra and Bairnsdale districts of Gippsland, Victoria, Australia. Vet Parasitol. 2015; 209: 117-124.

23. Hanna RE, McMahon C, Ellison S, Edgar HW, Kajugu PE, Gordon A, et al. Fasciola hepatica: a comparative survey of adult fluke resistance to triclabendazole, nitroxynil and closantel on selected upland and lowland sheep farms in Northern Ireland using faecal egg counting, coproantigen ELISA testing and fluke histology. Vet Parasitol. 2015; 207: 34-43.

24. Venturina VM, Alejandro MA, Baltazar CP, Abes NS, Mingala CN. Evidence of Fasciola spp. resistance to albendazole, triclabendazole andbromofenfos in water buffaloes (Bubalusbubalis). Ann Prasitol. 2015; 61: 283-289.

25. Novobilsky A, Amaya Solis N, Skarin M Höglund J. Assessment of flukicide efficacy against Fasciola hepatica in sheep in Sweden in the absence of a standardised test. Int J Parasitol Drugs Drug Resist. 2016; 6: 141-147.

26. Sanabria R, Ceballoa L, Moreno L, Romero J, Lanusse C, Alvarez L. Identification of a field isolate of Fasciola hepatica resistant to albendazole and susceptible to triclabendazole. Vet Parasitol. 2013; 193: 105-110.

27. Canevan J, Ceballos L, Sanabria R, Romero J, Olaechea F, Ortiz P, et al. Testing albendazole resistance in Fasciola hepatica: validation of an egg hatch test with isolates from South America and the United Kingdon. J Helminthol. 2014; 88: 286-292.

28. Martinez-Valladares M, Cordero-Pérez c, Rojo-Vázquez FA. Efficacy of an anthelmintic combination in sheep infected with Fasciola hepatica resistant to albendazole and clorsulon. Exp Parasitol. 2014; 136: 59- 62.