Worm control in sheep in the future

Endoparasitic infestations cost the livestock industry many millions of pounds each year through losses in productivity and the costs of control measures. Effective control of these endemic ubiquitous diseases is important, particularly given the expanding world population and the expectation of an increasing demand for ruminant products. Currently, these debilitating ruminant infestations can be controlled prophylactically by using chemotherapy, immunomanipulation and/or management of the grazing environment, but most farmers currently rely upon having effective anthelmintics. Unfortunately, studies on the incidence and prevalence of anthelmintic resistance throughout the world suggest that production systems that are wholly reliant upon intensive chemotherapy/prophylaxis are not sustainable. Current research is examining chemical strategies that will provide good worm control and will also enable the conservation of efficacy of our current and any novel anthelmintics. Maintaining an infra- and supra-population of worms in refugia (i.e., unexposed to anthelmintics) is accepted by most veterinary parasitologists as the best means of maintaining the genes for susceptibility within the parasite population. Maintained susceptibility within a parasite population can be achieved in a variety of ways, all of which utilise a targeted treatment approach to some extent. Whole flock targeted treatment can be optimised using faecal egg count monitoring and individuals can have targeted selective treatments administered on the basis of morbidity markers, such as anaemia, production efficiency assessed by liveweight gain or milk production. There is also a growing interest in bioactive forages, which can have both direct anthelmintic effects and/or indirect anthelmintic effects, where the benefit derives from nutritional effects which boost the host immune responses against nematodes. In the future, arguably the most exciting area is that of immunomanipulation, where current advances in genomics and proteomics offer scope for the development of vaccines and genetic or bio-markers associated with infection or effective immunity. We have been able to identify and select genetically resistant animals for many years by using phenotypic markers for endoparasitism, but it is only recently that the first genetic marker for host resistance has become available. Further research is also needed to identify better phenotypic and genotypic markers for resilience, since in some production systems this may be a more desirable trait than resistance. The implementation of an integrated approach to control to develop sustainable control strategies represents a formidable challenge for the sheep industry. This integrated approach will require well-informed veterinarians; advisors and researchers will need to find the tools to support the practitioners, as well as to find ways of delivering them in an affordable way. Although at present these demands may seem both unobtainable and unaffordable, the development of collaborative multidisciplinary research programmes coupled with advancing high throughput technologies offers the prospect of real progress in this area in future.     

Influence of host nutrition on the development and consequences of nematode parasitism in ruminants.

Control of gastrointestinal nematodes of ruminants is based largely on use of anthelmintics combined, where practical, with pasture management. The increasing prevalence of resistance to anthelmintics has led to the search for alternative sustainable control strategies. Here, we consider how nutrition, as a short-term alternative, can influence the host--parasite relationship in ruminants, using gastrointestinal nematode infections of sheep as the model system. Nutrition can affect the ability of the host to cope with the consequences of parasitism and to contain and eventually to overcome parasitism. It can also affect the parasite population through the intake of antiparasitic compounds.     

Anthelmintic resistance: the state of play revisited

Helminthosis is one of the major constraints in the successful wool and mutton industry throughout the world. Anthelmintic Resistance (AR) is said to have been established when previously effective drug ceases to kill exposed parasitic population at the therapeutically recommended dosages. Anthelmintic resistance is almost cosmopolitan in distribution and it has been reported in almost all species of domestic animals and even in some parasites of human beings. Some of the most important species of parasites of small ruminants in which AR has been reported include: Haemonchus spp., Trichostrongylus spp. Teladorsagia spp., Cooperia spp. Nematodirus spp., and Oesophagostomum spp. All the major groups of anthelmintics have been reported for development of variable degrees of resistance in different species of gastrointestinal nematodes. This paper describes the global scenario of prevalence and methods used for detection of AR in small ruminants. Different mechanisms and contributory factors for the development of AR are discussed. Various options and alternate strategies for the control and/or delay in the onset of AR are suggested in the light of available information.     

To treat or not to treat: diagnostic thresholds in subclinical helminth infections of cattle

Helminth infections of cattle place significant burdens on livestock production and farm economic efficiency. Heavy infections are relatively easy to detect and treat with anthelmintics. However, subclinical infections have major but often hidden impacts on animals, necessitating more refined diagnostics to detect them and ideally inform farmers about the likely impact of anthelmintic treatment on animal and herd performance. Here, we review recent advances in diagnosing three major cattle helminth infections – gastrointestinal nematodes (GINs), liver flukes, and lungworms – and the search for subclinical infection thresholds to guide treatment decisions. Combining refined diagnostic thresholds with farm-specific information on grazing systems and animal history enables farmers to tailor helminth treatments to specific epidemiological circumstances, thereby limiting anthelmintic resistance (AR) and boosting agricultural efficiency and food security.     

Control of gastrointestinal strongyles in goats

Gastrointestinal (GI) parasitism are the most serious problem affecting sheep and goats worldwide. Economic losses caused by GI strongyles are related to decreased production, costs for treatment and prophylaxis and animal death. Effective control of internal parasites in small ruminants is one of the most difficult challenges encountered by veterinary in practice. For control of helminth parasites in grazing animals it is important knowledge of epidemiology of the parasite as it interacts with the host in a specific climatic, management and production environment. Sheep and goats are infected by many of the same GI nematodes, but feeding and management practices alter levels of parasitism between the two ruminants. The most commonly anthelmintics used for helminth control in small ruminants include three chemical groups: Imidazothiazoles/Pyrimidines (Im/Pm), Benzimidazoles/Probenzimidazoles (Bz/Pbz) and Macrocyclic Lactones (ML). The control of gastrointestinal strongyles infections in goats shows specific patterns. The use of anthelmintics in goats is based upon anthelmintics goats-suited dose rates taking into account the specific pharmacokinetics features of some anthelmintics in this species. Several types of control strategies: deworming programs, grazing management, biological control, supplementary feeding and breeding approaches are discussed.     

Efficacy evaluation of anthelmintics: which methods to use in the field?

Efficacy evaluation of anthelmintics is very important even in veterinary practice due to the existence of acquired resistance, poor quality of anthelmintics in several region of the world, and nedds for quarantine strategy prior introduction of new animals. Clearly, flock evaluation can be opposed to individually based evaluations. I propose that individually based evaluations should be preferred in field condition controls: although they are more sophisticated on a statistical basis, the availability of a software for calculations renders the proposal realistic.     

Anthelmintic resistance in human helminths: Learning from the problems with worm control in livestock

During the past decade, the prevalence of anthelmintic resistance in some economically important helminths of sheep, goats and horses has increased dramatically. In some regions of Australia, South America and South Africa, anthelmintic resistance has become a serious threat to the survival of the sheep industry. Mass treatment programmes and exclusive reliance on anthelmintics for worm control in livestock are amongst the most important reasons for the development of anthelmintic resistance. In this article, Stanny Geerts, Gerald Coles and Bruno Gryseels draw the attention to a number of errors that have occurred in the control of helminths in livestock and that should be avoided in the control of worms in humans.     

Genetic parameters for resistance to trichostrongylid infection in dairy sheep

In sheep, the traditional chemical control of gastrointestinal nematode (GIN) parasites with anthelmintics has led to the widespread development of anthelmintic resistance. The selection of sheep with enhanced resistance to GIN parasites has been suggested as an alternative strategy to develop sustainable control of parasite infections. Most of the estimations of the genetic parameters for sheep resistance to GIN parasites have been obtained from young animals belonging to meat- and/or wool-specialised breeds. We present here the estimated genetic parameters for four parasite resistance traits studied in a commercial population of adult Spanish Churra dairy ewes. These involved two faecal egg counts (FECs) (LFEC0 and LFEC1) and two serum indicator traits, the anti-Teladorsagia circumcincta fourth stage larvae IgA (IgA) and the pepsinogen (Peps) levels. In addition, this study has allowed us to identify the environmental factors influencing parasite resistance in naturally infected Spanish Churra sheep and to quantify the genetic component of this complex phenotype. The heritabilities estimated for the two FECs analysed (0.12 for LFEC0 and 0.09 for LFEC1) were lower than those obtained for the examined serum indicators (0.19 for IgA and 0.21 for Peps). The genetic correlations between the traits ranged from 0.43 (Peps-IgA) to 0.82 (LFEC0-LFEC1) and were higher than their phenotypic counterparts, which ranged between 0.07 and 0.10. The heritabilities estimated for the studied traits were lower than previously reported in lambs. This may be due to the differences in the immune mechanisms controlling the infection in young (antibody reactions) and adult (hypersensitivity reactions) animals/sheep. In summary, this study demonstrates the presence of heritable variation in parasite resistance indicator traits in the Churra population studied, which suggests that genetic improvement is feasible for this complex trait in this population. However, further studies in which the experimental variables are controlled as much as possible are needed to identify the best trait that could be measured routinely in adult sheep as an indicator of parasite resistance.     

Multiple resistance to anthelmintics by Haemonchus contortus and Trichostrongylus colubriformis in sheep in Brazil

The objective of this study was to determine the level of resistance of Haemonchus contortus and Trichostrongylus colubriformis in sheep to levamisole, albendazole, ivermectin, moxidectin, closantel and trichlorfon. The parasites were isolated from sheep naturally infected by gastrointestinal nematodes and were then kept in monospecifically-infected lambs for production of infective larvae (L3) of both species. Forty-two lambs, at three months of age, were simultaneously artificially infected with 4000 L3 of H. contortus and 4000 L3 of T. colubriformis. The animals were allocated into seven groups with six animals each that received one of the following treatments: Group 1--control, no treatment; Group 2--moxidectin (0.2mg/kg body weight (BW)); Group 3--closantel (10mg/kg BW); Group 4--trichlorfon (100mg/kg BW); Group 5--levamisole phosphate (4.7 mg/kg BW); Group 6--albendazole (5.0mg/kg BW); and Group 7--ivermectin (0.2mg/kg BW). Nematode fecal egg counts (FEC) were carried out on the day of treatment and again at 3, 7, 10 and 14 days post-treatment. On the same occasions, composite fecal cultures were prepared for each group for production of L3, which were identified into genus. The animals were sacrificed for worm counts at 14 days after treatment. The efficacy of each treatment was calculated from the arithmetic mean of the FEC or worm burden of the treated group, compared with the values of the control group. Only trichlorfon and moxidectin treatments resulted in a significant reduction of H. contortus recorded at necropsy (73% and 45% respectively). Moxidectin reduced T. colubriformis worm burdens by 82% and albendazole by 19%. All other anthelmintics resulted in no significant reduction in the numbers of worms found at necropsy. In conclusion, the isolates of H. contortus and T. colubriformis showed multiple resistance to all groups of anthelmintics tested. This is the first report, based on the controlled efficacy test, to show resistance of T. colubriformis to macrocyclic lactones in Brazil.     

Levamisole receptors: a second awakening

Levamisole and pyrantel are old (1965) but useful anthelmintics that selectively activate nematode acetylcholine ion channel receptors; they are used to treat roundworm infections in humans and animals. Interest in their actions has surged, giving rise to new knowledge and technical advances, including an ability to reconstitute receptors that reveal more details of modes of action/resistance. We now know that the receptors are plastic and may form diverse species-dependent subtypes of receptor with different sensitivities to individual cholinergic anthelmintics. Understanding the biology of the levamisole receptors is expected to inform other studies on anthelmintics (ivermectin and emodepside) that act on ion channels.     

A survey in Louisiana of intestinal helminths of ponies with little exposure to anthelmintics

Ponies reared with minimal or no exposure to anthelmintics were surveyed for intestinal helminths in order to estimate prevalence and intensity of parasite populations unaltered by frequent exposure to anthelmintics. Thirty-seven mixed breed ponies of varying ages were examined. Thirty-four species of nematodes and 2 species of cestodes were found. Twenty-four of the nematode species (including 1 new species) were in the subfamily Cyathostominae (small strongyles). Eighty-seven percent of the total burden of adult small strongyles in the large intestine was composed of 10 species. By comparing the results of the present survey with those of recent surveys of horses from herds which had been subjected to treatments with anthelmintics, the effect of prolonged usage of anthelmintic treatment on the prevalence of individual species possibly can be estimated. The general ranking of the 10 most common cyathostome species was similar to those described in recent surveys of horses, suggesting that anthelmintic pressure does not affect the prevalence of most cyathostome species. The lack of anthelmintic treatment appeared not to affect prevalence rates for Anoplocephala perfoliata and Anoplocephala magna when compared to other studies. Conversely, prevalence rates for Strongylus spp., Triodontophorus spp., Craterostomum acuticaudatum, Oxyuris equi, and Parascaris equorum were higher than those reported for these species in recent studies of horses.     

Effect of chemoprophylaxis on immunity to gastrointestinal nematodes in cattle

Control of gastrointestinal nematodes in first-season grazing cattle is largely based on either strategic anthelmintic treatment or use of anthelmintic-release devices. Control is evolving towards more efficacious anthelmintics and delivery systems, almost annihilating parasite contact. Here, Jozef Vercruysse, Hans Hilderson and Edwin Claerebout focus on the inverse relationship between the intensive use of modern anthelmintics and the build-up of immunity to gastrointestinal nematodes.     

Anthelmintic resistance in nematode parasites of cattle: a global issue?

Acceptable performance of grazing cattle frequently depends on the availability of effective broad-spectrum anthelmintics to remove, or prevent infection with, gastrointestinal nematodes. This control is increasingly threatened by populations of nematodes resistant to the most commonly used anthelmintics. Although this appears to have developed more slowly than in nematodes infecting small ruminants, the number of reports in the literature over the past five years suggests a rapidly escalating problem. This review discusses this literature, several issues unique to cattle parasitism and anthelmintics, and how previous research in small ruminants can improve the management of anthelmintic resistance in cattle.     

Isolation and characterization of a naturally occurring multidrug-resistant strain of the canine hookworm,Ancylostoma caninum

Soil-transmitted nematodes infect over a billion people and place several billion more at risk of infection. Hookworm disease is the most significant of these soil-transmitted nematodes, with over 500?million people infected. Hookworm infection can result in debilitating and sometimes fatal iron-deficiency anemia, which is particularly devastating in children and pregnant women. Currently, hookworms and other soil-transmitted nematodes are controlled by administration of a single dose of a benzimidazole to targeted populations in endemic areas. While effective, people are quickly re-infected, necessitating frequent treatment. Widespread exposure to anthelmintic drugs can place significant selective pressure on parasitic nematodes to generate resistance, which has severely compromised benzimidazole anthelmintics for control of livestock nematodes in many areas of the world. Here we report, to our knowledge, the first naturally occurring multidrug-resistant strain of the canine hookworm Ancylostoma caninum. We reveal that this isolate is resistant to fenbendazole at the clinical dosage of 50?mg/kg for 3?days. Our data shows that this strain harbors a fixed, single base pair mutation at amino acid 167 of the β-tubulin isotype 1 gene, and by using CRISPR/Cas9 we demonstrate that introduction of this mutation into the corresponding amino acid in the orthologous β-tubulin gene of Caenorhabditis elegans confers a similar level of resistance to thiabendazole. We also show that the isolate is resistant to the macrocyclic lactone anthelmintic ivermectin. Understanding the mechanism of anthelmintic resistance is important for rational design of control strategies to maintain the usefulness of current drugs, and to monitor the emergence of resistance. The isolate we describe represents the first multidrug-resistant strain of A. caninum reported, and our data reveal a resistance marker that can emerge naturally in response to heavy anthelminthic treatment.     

Mechanism-based screening: discovery of the next generation of anthelmintics depends upon more basic research

The therapeutic arsenal for the control of helminth infections contains only a few chemical classes. The development and spread of resistance has eroded the utility of most currently available anthelmintics, at least for some indications, and is a constant threat to further reduce the options for treatment. Discovery and development of novel anthelmintic templates is strategically necessary to preserve the economic and health advantages now gained through chemotherapy. As the costs of development escalate, the question of how best to discover new drugs becomes paramount. Although random screening in infected animals led to the discovery of all currently available anthelmintics, cost constraints and a perception of diminishing returns require new approaches. Taking a cue from drug discovery programmes for human illnesses, we suggest that mechanism-based screening will provide the next generation of anthelmintic molecules. Critical to success in this venture will be the exploitation of the Caenorhabditis elegans genome through bioinformatics and genetic technologies. The greatest obstacle to success in this endeavour is the paucity of information available about the molecular physiology of helminths, making the choice of a discovery target a risky proposition.     

Controlled release devices for the delivery of anthelmintics in cattle

Control of cattle helminths is not so much a problem of drug choice, but of drug delivery and livestock management. Several effective anthelmintics are available for domestic livestock, but their efficiency in limiting infection and disease attributed to important parasites such as Ostertagia and Haemonchus has been mainly due to good management practice and strategically timed treatment based on detailed epizootiological studies of parasite transmission. In most situations, treated animals remain fully susceptible to reinfection if continually grazed on contaminated pastures, and this is the rationale behind techniques for continuous or multiple treatment with anthelmintics. In response to these treatment requirements, the animal health industry has developed controlled release devices, or boluses, that can be implanted orally into the rumen (Fig. 1) to release anthelmintics over an extended period - either in a delayed or pulsed fashion. In this article, Gary Zimmerman and Eric Hoberg discuss same of the most promising of such devices.     

Genetic variability following selection of Haemonchus contortus with anthelmintics

Genetic diversity in nematodes leads to variation in response to anthelmintics. Haemonchus contortus shows enormous genetic diversity, allowing anthelmintic resistance alleles to be rapidly selected. Anthelmintic resistance is now a widespread problem, especially in H. contortus. Here, I compare the genes involved in anthelmintic resistance in H. contortus with those that confer susceptibility or resistance on the free living nematode Caenorhabditis elegans. I also discuss the latest knowledge of genes associated with resistance to benzimidazoles, levamisole and the macrocyclic lactones and the need for DNA markers for anthelmintic resistance.     

Anthelmintics for horses

Modern equine anthelmintics can be divided into at least seven principal groups based on mode of action, i.e., benzimidazoles, pro-benzimidazoles, imidothiazoles, tetrahydropyrimidines, organophosphates, piperazines, and avermectins. The spectrum of activity of these drugs varies and resistance of cyathostomes to benzimidazole and pro-benzimidazole drugs has been observed in many areas. Cross resistance with other groups has not been reported in equines, however. Control is dependent upon understanding the capabilities of anthelmintics and the epizootiology of the important parasites, e.g., large strongyles, cyathostomes, ascarids and bots. Development of effective programs in a given region should be based on routine fecal analysis to ensure that treatment schedule and products selected are adequate for local climatic conditions and management methods.     

Development of breeding values for susceptibility to virulent footrot in sheep: A strategy to accommodate variable disease progression at time of scoring

Genetic evaluations utilising footrot scores from industry flocks in their essence, incorporate data from a wide range of challenge environments, resulting in potentially large differences in means, variances and distribution of scores across challenges. The date that commencement of infection occurs is generally unknown, and progression of the infection varies with the prevailing environmental and management conditions, virulence of the bacterium Dichelobacter nodosus, as well as the genetic potential and (permanent) environmental ability of animals to resist footrot. In practice, animals are unlikely to be repeatedly scored to identify the best time for comparison, or monitor development of disease progression. Furthermore, field challenges are limited by the need to treat animals before their welfare is compromised. Therefore, the duration and intensity of infection varies and this affects comparisons between animals for their susceptibility. Diseases such as footrot are characterised by multiple categorical scores reflecting clinical stages that describe the progression and relative impact of the disease. This provides the opportunity for the transformation of the data to a standardised prevalence. Scoring events from multiple footrot field challenges under a standardised protocol were used to establish a series of transition matrices to describe disease progression between scores over time. These transition matrices were used to standardise challenge events to the more severe scoring events, observed later in the challenge. The accuracy of the transition technique was tested by comparing the ranking of animals and sires against the observed scores. Transitioning the data from low disease prevalence to the higher prevalence at the subsequent scoring event improved the correlations between the scoring events, at the animal level, by upwards of 0.10 across challenges. The utilisation of a transition matrix to transform low prevalence disease challenges by taking into account the natural biological rate of progression through the clinical stages of the disease provides a more accurate technique to account for variation in disease prevalence. The transition technique increases the acceptable range of disease expression targeted by producers when scoring virulent footrot challenges reducing the need for repeat scoring and allowing earlier treatment and reducing the impact of the disease on the host animal.     

A research agenda for helminth diseases of humans: intervention for control and elimination

Recognising the burden helminth infections impose on human populations, and particularly the poor, major intervention programmes have been launched to control onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, and cysticercosis. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A summary of current helminth control initiatives is presented and available tools are described. Most of these programmes are highly dependent on mass drug administration (MDA) of anthelmintic drugs (donated or available at low cost) and require annual or biannual treatment of large numbers of at-risk populations, over prolonged periods of time. The continuation of prolonged MDA with a limited number of anthelmintics greatly increases the probability that drug resistance will develop, which would raise serious problems for continuation of control and the achievement of elimination. Most initiatives have focussed on a single type of helminth infection, but recognition of co-endemicity and polyparasitism is leading to more integration of control. An understanding of the implications of control integration for implementation, treatment coverage, combination of pharmaceuticals, and monitoring is needed. To achieve the goals of morbidity reduction or elimination of infection, novel tools need to be developed, including more efficacious drugs, vaccines, and/or antivectorial agents, new diagnostics for infection and assessment of drug efficacy, and markers for possible anthelmintic resistance. In addition, there is a need for the development of new formulations of some existing anthelmintics (e.g., paediatric formulations). To achieve ultimate elimination of helminth parasites, treatments for the above mentioned helminthiases, and for taeniasis and food-borne trematodiases, will need to be integrated with monitoring, education, sanitation, access to health services, and where appropriate, vector control or reduction of the parasite reservoir in alternative hosts. Based on an analysis of current knowledge gaps and identification of priorities, a research and development agenda for intervention tools considered necessary for control and elimination of human helminthiases is presented, and the challenges to be confronted are discussed.