The ‘Toolbox’ of strategies for managing Haemonchus contortus in goats: What’s in and what’s out

Veterinary Parasitology 220 (2016) 93–107

Contents lists available at ScienceDirect

Veterinary Parasitology journal homepage: www.elsevier.com/locate/vetpar

Review article

The ‘Toolbox’ of strategies for managing Haemonchus contortus in goats: What’s in and what’s out P.E. Kearney a,∗,1 , P.J. Murray a , J.M. Hoy a , M. Hohenhaus a , A. Kotze a,b a b

The University of Queensland, Gatton Campus, QLD, Australia CSIRO, Bioscience Precinct, St Lucia, QLD, Australia

a r t i c l e

i n f o

Article history: Received 25 September 2015 Received in revised form 19 February 2016 Accepted 25 February 2016 Keywords: Haemonchus contortus Goats Integrated management Vaccine Goat behaviour ‘Barbervax® ’

a b s t r a c t A dynamic and innovative approach to managing the blood-consuming nematode Haemonchus contortus in goats is critical to crack dependence on veterinary anthelmintics. H. contortus management strategies have been the subject of intense research for decades, and must be selected to create a tailored, individualized program for goat farms. Through the selection and combination of strategies from the Toolbox, an effective management program for H. contortus can be designed according to the unique conditions of each particular farm. This Toolbox investigates strategies including vaccines, bioactive forages, pasture/grazing management, behavioural management, natural immunity, FAMACHA, Refugia and strategic drenching, mineral/vitamin supplementation, copper Oxide Wire Particles (COWPs), breeding and selection/selecting resistant and resilient individuals, biological control and anthelmintic drugs. Barbervax® , the ground-breaking Haemonchus vaccine developed and currently commercially available on a pilot scale for sheep, is prime for trialling in goats and would be an invaluable inclusion to this Toolbox. The specialised behaviours of goats, specifically their preferences to browse a variety of plants and accompanying physiological adaptations to the consumption of secondary compounds contained in browse, have long been unappreciated and thus overlooked as a valuable, sustainable strategy for Haemonchus management. These strategies are discussed in this review as to their value for inclusion into the ‘Toolbox’ currently, and the future implications of ongoing research for goat producers. Combining and manipulating strategies such as browsing behaviour, pasture management, bioactive forages and identifying and treating individual animals for haemonchosis, in addition to continuous evaluation of strategy effectiveness, is conducted using a model farm scenario. Selecting strategies from the Toolbox, with regard to their current availability, feasibility, economical cost and potential ease of implementation depending on the systems of production and their complementary nature, is the future of managing H. contortus in farmed goats internationally and maintaining the remaining efficacy of veterinary anthelmintics. © 2016 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 What’s in . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 3.1. Bioactive forages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 3.1.1. Anthelmintic activity of polyphenolic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 3.1.2. Preference for plants containing polyphenols increases with challenge by Haemonchus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 3.1.3. Feeding behaviour of goats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 3.1.4. Forages which structurally inhibit larval migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

∗ Corresponding author. E-mail addresses: [email protected], [email protected] (P.E. Kearney). 1 This paper is part of the Ph.D. thesis of P. Kearney. http://dx.doi.org/10.1016/j.vetpar.2016.02.028 0304-4017/© 2016 Elsevier B.V. All rights reserved.

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Vaccine development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Pasture contamination management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Natural immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Immunonutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Therapeutic minerals and vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 3.7.1. Variations of copper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 3.7.2. Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.8. Breeding and selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.9. Targeted selective strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.9.1. FAMACHA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.9.2. Refugia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.9.3. Strategic drenching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 What’s out . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 4.1. Nematophagous fungi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 4.2. Cysteine proteinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 4.3. Break in case of emergency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 4.3.1. Veterinary anthelmintics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 3.2. 3.3. 3.4. 3.5. 3.6. 3.7.

4.

5.

1. Introduction Haemonchus contortus, arguably the most important gastrointestinal (GI) nematode infecting small ruminants, has severe detrimental effects on the health and management of goats (TorresAcosta and Hoste, 2008). As the most consumed meat in the world, and with Australia the biggest goat meat exporter (Matthews et al., 2015), it is important that efficient, sustainable and high standard goat management practices are followed by goat farmers in this country. Veterinary anthelmintics have been the primary strategy for the control of Haemonchus infection for decades, however resistance to these anthelmintics continues to be documented in Haemonchus populations around the world, including the new commercial anthelmintics. For example within 2 years of its release, complete failure of monepantel (Zolvix) has been recorded at a farm in New Zealand (Scott et al., 2013). The preceding investigation into alternative options to anthelmintic treatment that were available or being developed was a review published 8 years ago by Krecek and Waller (2006). Given the time elapsed since this paper was published, it is timely to again review the progress that has been made in developing alternative options for worm control in goats, with an emphasis on feasibility and effectiveness. This process will identify those strategies being researched and invested in (Torres-Acosta and Hoste, 2008; van Wyk et al., 2006), yet are not reaching effective use commercially (Gray et al., 2012). Thus decades of research, including some new approaches have yielded a veritable toolbox of strategies, varying in their ease of implementation; the economic investment required; the specialist knowledge and industry support necessary; the target of host, parasite or environment; and the target phase of the nematode lifecycle. Control of H. contortus must be integral to the overall management plan of a goat farm if resources are to be put to efficient and effective use. To avoid reliance on veterinary chemicals, management of Haemonchus must be adaptive and proactive and include different strategies from the toolbox. Therefore, the strategies investigated for this toolbox to control Haemonchus include: • • • •

Vaccines Bioactive forages Pasture/grazing management Behavioural management

• • • • •

Natural Immunity FAMACHA, Refugia and strategic drenching Minerals/Vitamins − iron, copper, vitamin C Copper Oxide Wire Particles (COWPs) Breeding and selection—selecting resistant and resilient individuals • Biological control—Nematophagous fungi • Cysteine Proteinases • Veterinary/anthelmintic drugs 2. Background H. contortus poses an immense threat to the productivity and viability of small ruminant farmers around the world (Waller, 2006a). The adult stage of this nematode inhabits the abomasum (the fourth stomach) of goats and sheep, burrowing into the mucosal lining. It consumes up to 0.5 ml of blood per worm each day (Holmes, 1987) and there may be thousands of adult worms in the abomasum consuming blood, which causes serious production and economic losses (Holmes, 1993; Hoste, 2001). Haemonchus females are capable of producing up to 10,000 eggs per day which is a very high reproductive rate and results in rapid contamination of pasture (Holmes, 1987). The eggs are released and expelled in the faeces to hatch and develop on the pasture, perpetuating the lifecycle (Hoste et al., 2012). Analysis of the lifecycle shows that three main principles can be applied to interrupt its continuity: 1. Improve host resistance and/or resilience 2. Eliminating worms in the host and 3. Limiting the contact between the host and the infective thirdstage larvae (L3) on the pasture. Veterinary anthelmintics have been the primary method of management of Haemonchus and other nematode species since the discovery and release of Thiabendazole in the 1960s, as it was simple, relatively cheap, and highly effective with broadspectrum activity (Waller, 1997). With Haemonchus populations developing increasing resistance this and subsequently produced anthelmintics, the efficacy and simplicity of their use has been under increasing challenge (Besier and Love, 2003; Coles, 2005; Coles et al., 2006; Jabbar et al., 2006; Jackson and Coop, 2000; Jackson et al., 2012; Waller, 1999). In 2010, monepantel was released, an amino-acetenonitrile derivative (Besier, 2009), which was the first new anthelmintic chemical since Ivermectin in the

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1980s. Yet in less than two years, complete failure of this drench occurred on a farm in New Zealand (Scott et al., 2013). The failure of monepantel on this farm, after having been used 17 times in less than two years, shows the abuse of drugs by graziers has poor consequences; repeated drug use leading to resistance, and highlights the need to adopt non-chemical approaches to use in combination. Whether targeting the parasite in the host or in the environment, the goal of new alternative strategies is to restrict host parasite contact to levels that minimise the impact of Haemonchus on goat welfare and performance (Jackson and Miller, 2006; Waller, 1999, 2006a,b). It is evident that farmers of small ruminants must develop and use sustainable Haemonchus management plans with integrated strategies, instead of hoping that a ‘silver bullet’ treatment will emerge from the research to solve the problem the same way chemical anthelmintics did half a century ago. This research into methods of controlling Haemonchus by targeting the host, the parasite or the environment has ultimately created a ‘toolbox’ of strategies that this review will discuss and put forward recommendations that will allow a range of options to be selected to create a tailor-made Haemonchus control program specific to every farm and group of goats. Factors taken into consideration in the selection of strategies from the toolbox, include ease of implementation; complexity; financial and labour costs; amount of benefit; availability; management goals for the farm; farm size and climate; breed; and the purpose of the goats. These strategies will be discussed separately and then a combination of them will be selected in response to a hypothetical problem.

3. What’s in 3.1. Bioactive forages The exploitation of forages containing active compounds has an important role to play in animal health, and it is a critical addition to the Toolbox, even though further research is necessary, focusing on defining appropriate strategies to better utilise bioactive species in ruminant feeding (Piluzza et al., 2014). Plants contain a myriad of active compounds, some of which are already exploited for medicinal purposes, have been modelled for the production of synthetic drugs, or even consumed by animals for the health benefits they provide (Behnke et al., 2008; Grade et al., 2008). Ivermectin, the commercial anthelmintic, owes its discovery to investigation into natural sources with anthelmintic properties (Geary, 2005). The idea of natural product therapy has flourished from two factors: the fact that modern pharmacopoeia (medical and veterinary) has as its foundation drugs derived from plants or synthetic analogues of herbal compounds and the emerging interest by animal ethologists into the self-curing behaviours of wild animals (Engel, 2002; Grade et al., 2008; Waller, 2006a). Considering the vastness of the potential plant pharmacy, animals are surrounded by powerful pharmacological substances and have ample opportunity to self-medicate, yet the crux of the matter is whether they actively exploit this opportunity. This is the critical consideration from a farming perspective, and the popularity of this field has flourished particularly as societal trends move away from the use of chemicals which are negatively stigmatized with leaving residues and towards the perceived more natural alternatives. This has triggered interest in the evaluation of plants traditionally applied for their anthelmintic properties with a view to discovering their secrets (Rahmann and Seip, 2007). There are many plants that are currently used for livestock treatment in developing countries, known as ethnoveterinary medicine, although they are not only used to deal with helminth infections, but also a range of other diseases, often with successful outcomes. The wider use and development

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of plant-based anthelmintics is often restricted by limited knowledge of the actual efficacy of the plant compound against specific parasites, appropriate dosages, methods of preparation and administration for different livestock species and possible toxicity (Grade et al., 2008). Although many plant species have been listed as having anthelmintic activity, only a few have been subjected to rigorous scientific validation. Although many active compounds have not stood up against rigorous scientific testing, some truly exceptional natural products like Ivermectin have been identified and become widely accepted (Behnke et al., 2008). Bioactive compounds are an incredibly valuable addition to the Toolbox. Due to the vast number of as yet undiscovered and uncategorised plant compounds, there is considerable benefit to be gained even on the farm level from offering goats the opportunity to browse a wide variety of species and observe for medicinal effects and correlations between preference and infection levels. A single research project investigating the in vitro anthelmintic activity of the extracts of 85 Australian native shrubs found approximately 40% of species had significant activity in inhibiting Haemonchus larval development (Kotze et al., 2009). What could be discovered if goats were given access to and offered the opportunity to choose from a variety of species such as this? 3.1.1. Anthelmintic activity of polyphenolic compounds The mechanisms by which plant extracts affect parasite viability, mobility and fecundity both in vitro and in vivo are being identified (Hoste et al., 2012; Martínez-Ortíz-de-Montellano et al., 2013; Zhu et al., 2013). The recent use of scanning electron microscopy (SEM) allowed observation of dramatic physical changes to the cuticle of adult Haemonchus exposed to tannin-rich material compared to the cuticle of Haemonchus not exposed to this material (Martínez-Ortíz-de-Montellano et al., 2013). Among plant secondary metabolites (PSMs), phenolic compounds, Fig. 1, have received much research interest due to their role in plant defence and resistance against pests and diseases, particularly parasitic nematodes (Wuyts et al., 2006). Phenolic compound levels are higher in nematode-resistant plant cultivars, and enzymes of the phenolic compound biosynthetic pathways are induced in plants after nematode infection. The anthelmintics properties of polyphenols to GI nematodes of small ruminants has been extensively reviewed (Athanasiadou and Kyriazakis, 2004; Hoste et al., 2006, 2012; Villalba and Landau, 2012). Three main mechanisms of direct impact has been associated with the consumption of tanniferous plants by infected ruminants: 1) a reduced establishment of the infective third-stage larvae in the host; 2) a reduced excretion of nematode eggs by the adult worms; and 3) a reduced development of eggs to third-stage larvae (Hoste et al., 2012). Both mechanisms 2 and 3 contribute to reduce the environmental contamination with infective larvae and therefore reduce the rate of reinfection for grazing ruminants. Tannins, particularly condensed tannins, have been the subject of intensive investigation and of the large variety of plants with condensed tannin content, only those with higher amounts are considered bioactive (Rahmann and Seip, 2007). Feeding tanniferous forages has both positive and negative effects. High concentrations of condensed tannins are known to reduce feed digestibility, feed intake and consequently lower production. For herbivorous animals, condensed tannins are highly astringent, causing the tongue to pucker, the mucous membranes of the mouth and throat to dry, and once consumed cause physiological problems by interfering with digestion by disrupting the micro-organism and enzyme environment in the GI tract (Engel, 2002). By their capacity to bind with proteins, condensed tannins affect dietary protein availability, inactivate digestive enzymes, irritate the GI tract and can cause systemic toxicity (Landau et al., 2000). All this would suggest grazing animals would avoid tannin-

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Fig. 1. An overview of the polyphenol family, classified according to common chemical structure. These compounds are found in a range of concentrations within numerous plant species (picture by P. Kearney).

rich plants, and yet, animals have been observed to actively seek out and graze tanniferous forages. This is the basis of the self-medication hypothesis, that herbivores choose to eat certain plants for medicinal purposes rather than nutritional purposes, and condensed tannins are generally known to have anthelmintic, antibacterial, antiseptic, antidiarrheal, and antifungal properties. For example lambs, infected with nematode parasites, grazing sulla (Hedysarum coronarium), a tanniferous forage, showed superior performance in liveweight gain, and wool growth and lower FECs compared to lambs grazing lucerne (Niezen et al., 1995). Parasite-induced anorexia was evident in the lambs grazing lucerne but not in those grazing sulla. This superior performance in liveweight gain was attributed to protein-binding of condensed tannins in the sulla, decreasing protein degradation by the microbes in the rumen, and thus increasing post-ruminal protein available in the small intestine. This suggests condensed tannins can be used efficiently by taking into account the pH of the rumen promotes its binding to proteins, while the acidic pH of the abomasum liberates these bindings (Makkar, 2003; McSweeney et al., 2001). Thus the condensed tannins can act directly on the adult Haemonchus infecting the abomasum, while the undegraded protein reaches the small intestine for absorption, effectively an additional benefit for the animal. Small ruminants control their intake of tanniferous plants, preferring to graze them only when negative consequences are offset by the positive effects attributed to the anti-parasitic and protein-binding properties (Engel, 2002; Rahmann and Seip, 2007). Trade-off theory has been effectively used to suggest that herbivores vary their foraging behaviour in the presence of parasites in three ways: firstly by avoiding grazing areas contaminated by faeces, secondly by selecting diets to increase resistance and resilience and thirdly, by selecting foods with direct anti-parasitic properties, self-medication (Hutchings et al., 2006). During browsing, goats generally reject feedstuffs containing more than 5% condensed tannins, a rejection level which interestingly coincides with the condensed tannins ceiling below which improved protein and amino acid utilisation is observed (Kabasa et al., 2000). In a natural ecosystem, such as the rangelands, browsing goats control the amount of condensed tannins ingested to optimise the beneficial effects and limit negative effects, and this selective feeding by goats which be addressed in the next section.

3.1.2. Preference for plants containing polyphenols increases with challenge by Haemonchus Small ruminants, like any other herbivores, prefer feeds that supply them with the nutrients they require and avoid those with excess nutrients and PSMs that may elicit adverse effects (Juhnke et al., 2012). Considering this and the capacity of animals to select feeds according to their internal state and post-ingestive feedback, the feed preference of goats during Haemonchus infection is of particular interest. Mamber goat kids showed a propensity to increase consumption of the tannin-rich shrub Pistacia lentiscus in response to Haemonchus infection, compared with uninfected kids who preferred to minimize their consumption (Amit et al., 2013). Lambs familiarized with a tannin-rich feed quebracho learned the antiparasitic effects of the condensed tannins and increased their preference for the tannin-rich feed while parasitized (Juhnke et al., 2012). This preference subsided following anthelmintic treatment to remove the Haemonchus burden, indicating the preference was due to the infection (Juhnke et al., 2012). These results suggest that a management system that allows animals to select appropriate tannin-rich feeds can enable parasitized animals to self-medicate (Juhnke et al., 2012). This particular study was conducted with sheep, however goats are considerably more likely to display this self-medication behaviour (Hoste et al., 2010). When fed a diet supplemented with condensed tannins, sheep had enhanced rumen fermentative activity to degrade tannin-rich browse, due to the appearance and proliferation of tannin-tolerant bacterial species and/or to the stimulation of changes in the existing bacteria to enhance their tolerance to these phenolic compounds (Ammar et al., 2009). Being naturally predisposed to consuming browse, goats are better suited to tolerate and detoxify natural toxins of such forages, particularly PSMs (Hoste et al., 2010). These metabolic adaptations to natural PSMs also have consequences for the pharmacology and pharmacokinetics of therapeutic drugs; as goats metabolise anthelmintics much faster than sheep (Hoste et al., 2010). The ability of animals to self-medicate, a field known as zoopharmacognosy, is an invaluable field of study capable of providing ecologically-sound methods for the control of Haemonchus, either by plant-based medicines or medicinal forages (Engel, 2002; Huffman, 2003). Examples of self-medication has been extensively documented in primates, including swallowing of whole leaves to

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physically expel parasites and chewing the bitter pith of Veronia amygdalina for the control of intestinal nematode infections (de Roode et al., 2013; Huffman, 2003). Observations of goats browsing the anti-parasitic plant, Albizia anthelmintica, prompted a survey in Uganda to gather evidence for livestock engaging in other self-medicating behaviours (Gradé et al., 2009). The results added more support for the hypothesis that animals graze specific plants when sick. Another investigation, into breed differences in propensity to self-medicate, exposed infected goats of the Mamber and Damascus breeds to Pistacta lentiscus, Phillyrea latifolia or hay during the course of their infection (Amit et al., 2013). The results implied subtle trade-offs between the roles of P. lentiscus as a food, a toxin and a medicine. Damascus goats, exhibiting a higher propensity to consume P. lentiscus may use it as a drug prophylactically, whereas Mamber goats, preferring not to ingest it, selected P. lentiscus therapeutically in response to infection. This recent research is the first evidence of self-medication in goats under controlled conditions. Similarly sheep have shown a preference for tanniferous forages under controlled conditions, implicating an ability to learn the medicinal effects of a particular forage, and select that forage during Haemonchus infection, leading to reductions in FEC (Juhnke et al., 2012). Identifying, testing and determining efficacy of the myriad of PSMs has proven to be a massive undertaking (Kotze et al., 2009). There is a unique relationship between laboratory and animal experimentation of these compounds. A particular compound may be identified by either model initially, however both are required for a compound to be quantified and utilised effectively. 3.1.3. Feeding behaviour of goats The natural feeding behaviour of goats has been significantly under-utilised. Goats include browse as the major component of their diet whenever possible; therefore, browsing goats rely on the presence of tannin-adapted ruminal flora, superior nitrogen recycling and salivary adaptations (Hoste et al., 2010; Landau et al., 2000). Goats have shown great dietary adaptability. For example woodland goats have a special composition of saliva and ruminal microbial populations capable of detoxifying tannins while desert goats are characterised by high digestibility of structural carbohydrates, superior urea recycling capacity and paradoxically high mean ruminal retention time. Observations of goats selecting foods that were non-nutritional inspired investigation into the health benefits versus the nutritional benefits of what goats choose to eat, whether their preferences change and under what circumstances do preferences change (Hoste et al., 2010; Hutchings et al., 2006). Herbivores preferences originate from the interrelationships between the vast array of nutrients and PSC, the chemical characteristics, their palatability and the physiological state of the animal (Provenza, 1996). Changes in the physical environment alter the distribution, abundance, nutritional and toxicological characteristics of plants, which in turn, affects food preferences by goats (Provenza et al., 1998). Most importantly, the state of an animal’s health influences diet selection by diminishing the importance of a foods astringency/lack of nutritional value and increasing the importance of health/medicinal benefits. Palatability has been described as the interrelationship between the senses (i.e. taste) and post-ingestive feedback as influenced by an animal’s physiological conditions and a food’s chemical characteristics (Landau et al., 2000; Provenza et al., 1998). While taste and smell enable an animal to discriminate among foods and provide hedonic sensations with foods, post-ingestive feedback calibrates those hedonic sensations with the homeostatic utility of the food. Palatability of feed has been manipulated through experiments;

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palatability increases for poorly nutritious foods when accompanied with intragastric infusions of energy and protein while palatability decreases for highly nutritious foods when accompanied with intragastric infusions of toxins. This research has great implications as to the sophistication of post-ingestive feedback, its relationship to palatability and the role the two can play in health management of goats. Given that an animal’s physiological condition has a direct impact on palatability, that palatability of certain foods will be influenced by physiological changes caused by infection with Haemonchus, herein lies the basis for self-medication behaviour. The state of an animal’s health influences diet selection by diminishing the importance of a foods astringency or lack of nutritional value and increasing instead the importance of bioactive PSM. Any behaviour is a function of its consequences; positive consequences from a behaviour significantly increase the likelihood that the behaviour will be performed again (Provenza et al., 1998). Palatability, post-ingestive feedback and feed choice are elements in a complex relationship, presented in Fig. 2, designed not only to meet nutritional needs, but also to meet health needs, utilising the plants present in the physical environment of an animal. A new way of looking at the goat and nematode interaction has been put forward by Hoste et al. (2010), to consider the natural behavioural adaptations of goats and sheep to worms as a flight or fight response to micro-predators. Sheep took the fight pathway and invested resources into developing an immune response to infection with Haemonchus, an immunity that stays with them through their lives (Hoste et al., 2010; Villalba and Landau, 2012). While goats, being predominantly browsing animals and as such avoiding contaminated pasture, as well as browsing forages that can be high in secondary compounds and copper, known to have anthelmintic activity, have evolved predominantly a flight response. Goats appear to have developed self-medicating behaviour over developing sophisticated immunity to Haemonchus; everything in an animal’s life is a choice in resource investment (Hutchings et al., 2006). As primarily grazing animals, sheep had much more to benefit from investing resources into immunity; they are continually at risk of being infected by larvae as they graze. As browsing animals, also known to travel quite long distances in their foraging, goats had less to benefit from investing in immunity and instead developed a higher tolerance for copper (browse has higher copper levels) and salivary adaptations to deal with secondary compounds (Hoste et al., 2006). The implication of this is that most goats have been ineffectively farmed. They have been forced into grazing situations, unable to browse, unable to choose plants to benefit their health, unable to express behaviour to manage their GIN burdens, treated with veterinary anthelmintics off label and at the dosages used for sheep in the absence of dosages for goats, requirements much higher than for sheep due to their ability to better metabolise xenobiotics. Thus effectively goats have been under-dosed for years, accelerating the development of resistance in nematode populations to the point that complete drench failure has become reality on some farms (Hoste et al., 2010). Given available browse and the opportunity to choose, goats could significantly reduce their levels of infection through a combination of consuming browse species with medicinally active compounds and avoiding the larvae on the pasture. 3.1.4. Forages which structurally inhibit larval migration Physical structure of a forage species can impact the ability of larvae to migrate up to height for consumption by grazing ruminants. An inhibitory sward structure in addition to anthelmintic activity would pinpoint a particular plant species as substantially valuable to a goat farmer and to the Toolbox. It is a serious hazard that chicory (Chicorium intybus L.) has faded from focus as a valuable tool for goat farmers, under the misconception that it does not

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Fig. 2. The relationships between the multiple affecting goat feeding behaviour are complex and multi-faceted. Each arrow represents an ‘influenced by’ relationship between two factors. (P. Kearney).

provide anthelmintic or health benefits as a return for investment. Chicory has shown both anthelmintic activity under both in vitro and in vivo experimental conditions, and reduction of the development/survival/migration of larvae due to sward structure (Marley et al., 2006). Most importantly, there is evidence for both direct and indirect activity of chicory. Direct activity includes decreased frequency of anthelmintic use (Hoskin et al., 1999; Marley et al., 2003b; Niezen et al., 1998) reduced worm egg numbers in faeces (Athanasiadou et al., 2007; Heckendorn et al., 2007; Hoskin et al., 1999), reduced ability of infective larvae to establish within the host (Tzamaloukas et al., 2005), reduced abomasal worm burdens (Hoskin et al., 1999; Marley et al., 2003b; Tzamaloukas et al., 2005), reduced number of male worms in parasitized animals and a decreased ability of infective larvae to develop or survive in faeces (Marley et al., 2003a). It was the concentration of the active compounds in the chicory in each of these trials, which was the critical component to these resulting impacts on Haemonchus infections. Lambs grazing chicory showed increased performance, decreased FEC and reduced GIN infection, with Haemonchus as the predominant species; results that could have been due to direct, indirect or pasture structure effect, or a combination of these (Miller et al., 2011). Chicory has been found to inhibit egg hatching of Haemonchus eggs (Foster et al., 2011b) and to have a profound effect on larvae motility in a larval migration assay (LMI) (Molan et al., 2003). In a field trial, grazing chicory affected the development/survival of infective larvae in the faeces (Marley et al., 2003a). Lambs grazing chicory were found to have fewer total adult abomasal nematodes than lambs grazing ryegrass/white clover (Marley et al., 2003b). Those trials that resulted in a lack of direct anthelmintic activity was attributed to the PSM composition of chicory; the PSM content was very low and comparable to the grass/clover plots. Trials investigating the effect of chicory on nematode infections have been confounded by experimental

lambs showing a consistent aversion to chicory, and the hypothesis that there is a threshold level of chicory that is necessary to be effective (Nielsen et al., 2009). Importantly, goats have not shown the same aversion to chicory as lambs in previous experiments, and despite their ability to detect very minute variations in SL, this did not influence their preference for it (Cassida et al., 2010). Commercially available chicory cultivars are developed to meet a variety of farm system requirements, from nutritive value to survivability in all climates, benefiting from 30 years of research and selection (Li and Kem, 2005; Li et al., 2010). These cultivars are available from a number of seed companies in Australia and New Zealand, for example Agricom Ltd., PGG Wrightson Seeds Pty Ltd and Specialty Seeds Ltd (Agricom, 2012; PGG Wrightson Seeds Australia, 2014; Specialty and Seeds, 2015). The phenolic compound profile of chicory includes condensed tannins, the sesquiterpene lactones lactucin, lactupicrin and 8-deoxylactucin, Chicoriin (a coumarin) and chicoric acid (a caffeic acid derivative) (Li and Kem, 2005). The anthelmintic activity of chicory is attributed to condensed tannins (CTs) and sesquiterpene lactones (SLs) and both have shown an effect on the motility of nematode larvae (Li and Kem, 2005; Molan et al., 2003). The anthelmintic effects of chicory compounds in vitro, with the egg hatch assay (EHA) and a predominantly Haemonchus nematode population, the activity shown by chicory was attributed to SLs (Foster et al., 2011b). Chicory cultivars differ in their concentrations of SLs, and based on SL content, the Puna and Lacerta cultivars were identified as most attractive as bioactive pastures (Foster et al., 2011a). 3.2. Vaccine development The development of a vaccine to protect sheep and goats from infection of H. contortus has been the objective of serious research for 30 years (Torres-Acosta and Hoste, 2008). Recently, there has

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been successful development of a Haemonchus vaccine for sheep named ‘Barbervax® ’, registered by the Australian Pesticide and Veterinary Medicine Authority (Besier, 2014; Besier et al., 2012). Unfortunately, Barbervax® is untested in goats, and there is currently no estimation as to whether goat farmers may begin to plan to include it in Haemonchus management plans. Regardless, the moment Barbervax® is trialled, tested and registered for goats, it is guaranteed inclusion into the Toolbox. As it has not proved possible to reproduce specific proteins by recombinant systems, the mass production of this vaccine appeared constrained by the amount of whole worms required to produce adequate quantities of antigen necessary to provoke a response (Besier et al., 2012). The use of a specialised worm harvesting machine has allowed large quantities of Haemonchus to be recovered rapidly at slaughter, and only a relatively low dose of antigen is necessary to provoke a protective response (Besier et al., 2015). In this news release on the Australian Sheep CRC website, Besier et al. (2015) reported the initial release of the vaccine in Australia consisted of 300,000 doses, enough for 60,000 lambs. The reductions in Haemonchus egg counts in lambs given vaccine doses of 5 ␮g and above exceeded 85% over the course of the trial, with the protective response including both the reduced development of worm burdens from larval uptake and an anthelmintic response shown by a sharp fall in egg count after vaccination (Besier et al., 2012). This vaccine has only been tested in sheep, and then only in lambs. Registration to use Barbervax® in yearling and adult sheep is currently being sought (Besier et al., 2015). For goats, it will be critical that a vaccine is effective for all age groups as goats do not develop immunity to Haemonchus with maturity the same way as sheep do (Hoste et al., 2010). There is also further investigation required in different environments and under different rates of Haemonchus challenge. Of course, there is no guarantee that Barbervax® will prove effective in goats. Goats have been observed as more susceptible to infection by goat-derived strains of Haemonchus, versus sheep-derived strains (Rahman and Collins, 1990). This observation implies that Haemonchus specialises external proteins based on the host species, which is important from a parasitic perspective, to avoid triggering immune response and expulsion from the GI tract. Whether this proves to be the case with antigens derived from the interior of the worm, unexposed to the host, will be determined when testing the sheep-derived Barbervax® in goats. The limitations of the vaccine is that coverage for the season requires up to 6 vaccinations to offer effective protection (Besier et al., 2015). Currently Barbervax® is only registered for use in lambs. Prior to the initial vaccination at lamb marking, faecal egg counts (FECs) must be conducted and if necessary, anthelmintic treatment be given to ensure high worm burdens do not affect the efficacy of the vaccine. The rollout of the vaccine is a slow process with only a limited number of vaccine doses initially released in Australia in October 2014, as stated in a news release by Moredun Research Institute (MRI), the developers of Barbervax® (MRI, 2015). Vaccination will reduce the dependence on anthelmintics by providing a sustainable replacement strategy. The mode of action of a vaccine is to trigger the immune system; preventing the establishment of Haemonchus within the host and thereby also reducing the contamination of the pasture by the resulting eggs and larvae, effectively interrupting the lifecycle. Progress was made a decade ago in identifying several antigens from Haemonchus which stimulated useful levels of protective immunity, between 70 to 95% reduction in faecal egg output in ovine hosts (Knox et al., 2003). A recent preliminary study with a novel vaccine based on recombinant Haemonchus DNA induced a partial immune response, suggesting protective potential against goat haemonchosis (Yan et al., 2013). Vaccination of goats with glyceraldehyde-3-phosphate dehydrogenase DNA from Haemonchus also induced a partial

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immune response against Haemonchus (Han et al., 2012). Another study investigated the significance of the genetic diversity in cysteine proteinase genes from two Haemonchus strains, cysteine proteinases having shown a protective effective, concluded the possibility of further exploration into mechanisms involved in natural protection (Molina et al., 2012). So, until Barbervax® is tested and registered for goats, farmers need to take advantage of the others strategies in this Toolbox. Importantly, the developers of Barbervax® have identified that the vaccine is not a ‘silver bullet’, rather it is another tool to be used in conjunction with other strategies to break dependence on drenches in managing a significant parasite (Besier et al., 2015). 3.3. Pasture contamination management Pasture and grazing management has been used to varying degrees for decades and ideally used strategically with anthelmintics and the concept of Refugia (discussed in detail in Section 2.9.2) with the goal of reducing pasture contamination and rate of reinfection by Haemonchus (Bailey et al., 2009). To determine the most effective form of this strategy for a particular farm, a comprehensive knowledge of the epidemiology of Haemonchus as it interacts with the host in the specific climatic, management and production environment is necessary (Barger, 1999). The successful and sustainable use of pasture and grazing management requires knowledge and understanding of seasonal parasite larval availability, the origin of the larvae contributing to any peaks in worm burden and the climatic requirements for worm egg hatching, larval development and survival. In some cases, the new recommendations for goat farmers are contradictory to the previous message, as research has expanded knowledge regarding this strategy, concepts and recommendations of the past have become obsolete (TorresAcosta and Hoste, 2008). Thus it is not surprising that there are farmers unaware of what strategies are available to them for control Haemonchus and that they fail to implement them effectively. The height of the forage clearly influences larval uptake as the larvae are only capable of migrating a short distance up the plant, a distance that is impacted by environmental temperature (Santos et al., 2012) and if the goats are grazing above the larvae, this impacts their uptake and thus infection. Stocking rate affects the rate of forage mass decrease and the rate of contamination of a pasture (Aumont, 1999; Bailey et al., 2009; Barger, 1999). Following treatment with an anthelmintic, where possible goats are not returned to the same contaminated pasture; instead they are moved to a new pasture that has been spelled for a period of time dependant on the environment (i.e. tropical, temperate) and season (i.e. summer, winter). This practice avoids the immediate reinfection of animals, thus reducing the need for veterinary chemicals, and reduces the contamination rate of the new pasture, thus reducing the rate of reinfection (Burke et al., 2009). Of course, if resistance is present in the Haemonchus population, this strategy would select for the resistant worms, resulting in the next generation contributed entirely by resistant individuals (Torres-Acosta and Hoste, 2008). Thus poor grazing management can have a serious effect on selection for drench resistance in the Haemonchus surviving on the pasture, known as in refugia (Barger, 1997, 1999). For farmers without the physical space or resources to spell paddocks, rotational grazing with other species is another effective strategy (Barger and Southcott, 1975). Decades ago, decontamination experiments determined that by grazing sheep in cattle paddocks during autumn, populations of Ostertagia ostertagia and Trichostrongylus axei could be reduced, in the calves that subsequently grazed the paddock and on the pasture for up to 12 months after treatment. The same population reductions were observed on pastures grazed by cattle repeatedly dosed with anthelmintics, and on ungrazed pasture highlighting that a strategy

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without anthelmintic produces the same reductions in parasites, with added sustainable and economic benefits. These decontamination trials also determined that varying times of grazing with an alternate host was necessary to achieve the reductions in parasites; six weeks of sheep grazing did not elicit reductions in parasite burdens in cattle, 12 weeks of sheep grazing reduced O. ostertagia but not Cooperia oncophora, and 24 weeks of sheep grazing reduced both species (Southcott and Barger, 1975). Information unique to each farm is required to determine the optimum timing of sequential stocking in farming situations and depending on the environmental conditions of the region, pasture rotation may be extensive or intensive for best results (Colvin et al., 2012). The nutritional quality of a pasture and the presence and/or absence of bioactive forages will have implications for other strategies from the toolbox; such as species available and consumed, the immunity status of the animal, the ability of the larvae to climb the sward, the opportunity for the goats to self-medicate and all of these elements together dictate the necessity and frequency of drenching. 3.4. Natural immunity Resistance to Haemonchus is the ability of the goat host to elicit and maintain an immune response to infection (Hoste, 2001). Host resilience is characterised as modifications of digestive and general physiology resulting in maintenance of homeostasis in the host during Haemonchus infection. Traditionally, goats have been believed as unable to produce a sustained immune response to Haemonchus infection, however it has since been determined that goats do express components of what might be considered the complete immune response displayed by sheep, Table 1 (Hoste et al., 2010). It could be argued that if continued to be forced to graze and confront burdens of Haemonchus from contaminated pastures, goats would slowly evolve the same immune response as sheep, out of necessity; their resilience strategies ineffective. Any adaptation to GIN infection by a host requires an investment from the finite resources available to that animal (Hoste et al., 2010; Villalba and Landau, 2012). By considering GIN infection differently, goats and sheep simply invested resources into two different strategies; strategies that are not mutually exclusive. Through comparative epidemiological surveys, on ligneous rangelands sheep were more heavily infected, while on herbaceous pastures, the goats were significantly heavily infected. Placed in heterogeneous ecosystems, sheep, preferring to feed on grass and forbs, are highly exposed to the infective L3 stage and development of an effective immune response is a justifiable investment of resources. Goats, on the other hand, preferentially ingest substantial amounts of browse, which limits their contact with the infective L3 on the pasture as well as exposing them to the vast array of tannins and other secondary compounds (Hoste et al., 2010; Martín García et al., 2006). In this case, resource investment was into the ability of goats to tolerate and detoxify natural toxins and plant secondary metabolites (Hoste et al., 2010; Huffman, 2003). The relationship between these three main processes, 1) resistance against Haemonchus by developing an immune response; 2) limiting contact with the infective stages by avoidance feeding behaviour and 3) alleviating worm challenges by self-medication is unique to goats, evolved under natural conditions to counteract GIN infection. This represents an opportunity to redevelop goat farming systems. With the understanding of what goats require to respond to Haemonchus burdens, comes the opportunity of new sustainable tools. Knowing that goats have a limited immune response, and that any immune response is further limited by available resources, there is opportunity to improve immune response with nutritional supplementation, by increasing the quality and quantity of available nutrients.

3.5. Nutrition It is important to understand the effects GI nematodes have on goats in order to appreciate that investment in the nutrition of parasitised goats is an investment in their ability to mount an immune response and continue to be productive during infection. GI nematodes impair goat productivity through reductions in voluntary feed intake and/or reductions in the efficient use of absorbed nutrients (Coop and Kyriazakis, 2001; Fox, 1997; Lu, 2011). Key features of GI parasitism are disturbances in protein metabolism, and reduced absorption and retention of minerals, particularly phosphorus. The species of worms present, the number of worms and the size of the larval challenge influences the magnitude of these effects (Coop and Kyriazakis, 1999, 2001; Hoste et al., 2008). Increased loss of endogenous protein into the GI tract is a common feature of parasitic GI infections, attributable to increased leakage of plasma protein, increased sloughing of epithelial cells and increased secretion of muco-proteins (Coop and Kyriazakis, 2001; Houdijk et al., 2012). The GI tract has a limited reabsorptive capacity, depending on the location of lesions and the capacity for compensatory absorption, and in the case of any subsequent recycling of nitrogen there is an energy cost (Abbott et al., 1986b; Hoste et al., 2005; Rowe et al., 1988). Regardless of some reabsorption, protein losses are large, particularly with Haemonchus infections where the host body sacrifices protein from other body processes in order to keep the GI tract functioning (Athanasiadou et al., 2008; Coop and Kyriazakis, 2001; Hoste et al., 2008). This explains the observed reductions in protein synthesis in muscle, fibre and milk of production goats infected with Haemonchus. These effects of a parasitic burden are exacerbated by reductions in voluntary feed intake (Coop and Kyriazakis, 2001; Houdijk et al., 2012). The interaction of nutrition and immune response has become an area of research known as immunonutrition (Kyriazakis and Houdijk, 2006). 3.6. Immunonutrition The term ‘immunonutrition’ refers to the use of nutrition to boost immunity. This section is a nice showcase of the concept of the Toolbox; using multiple complimentary strategies. There is a direct relationship between nutrition and immune function in small ruminants, and by improving nutrition, particularly dietary protein, immune response and the ability to maintain production during parasitic burden greatly improves (Abbott et al., 1986; Athanasiadou, 2012; Coop and Holmes, 1996; Coop and Kyriazakis, 1999, 2001; Hoste et al., 2005, 2008; Houdijk et al., 2012; Kyriazakis and Houdijk, 2006). Lambs provided a low protein diet displayed a more pronounced loss of appetite, and this was crucial in determining the ability of the infected lambs to withstand the pathophysical effects of haemonchosis (Abbott et al., 1986). When given a choice between high or low protein, lambs choose to modify their intake to alleviate the increased protein demand (Coop and Holmes, 1996). Within the model of nutrients as a scarce resource allocated between competing functions of the host body, the host appears to give priority to the reversal of consequences of parasitism over other body functions (Coop and Kyriazakis, 1999; Kyriazakis and Houdijk, 2006). The exceptions to this general rule include growth, pregnancy and lactation, which are prioritized above the expression of immunity, and thus improved nutrition during these phases will improve the expression of immunity. A high protein diet improved the ability of 9–12 month old pubertal West African Dwarf goats to resist the establishment of Haemonchus, manifested as a significant increase in resistance to Haemonchus estabilishment in the GI tract, compared to the low protein group (Nnadi et al., 2009). Many studies have shown goats respond to supple-

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Table 1 Comparison of small ruminant immune response to GIN infection (Hoste et al., 2010). Expressed Immune Response

Sheep

Goats

Reduction of establishment of L3 Reduced growth & development Reduced female fertility Reduced persistence of adult worm population

Strongly expressed Strongly expressed Strongly expressed Strongly expressed

Weakly expressed Strongly expressed Strongly expressed Weakly expressed

mentary feeding with improvement in resilience first, with effects on host resistance less evident, attributed to the acknowledged lower aptitude of goats to develop an efficient immune response against GI nematodes (Hoste et al., 2005). On the high protein diet, young West African Dwarf goats showed an enhanced resilience to parasite establishment Instead goats’ aptitude is to be far more resilient to nematode infections than sheep. Remember, the two species face GI nematode infections with very different strategies. Sheep regulate infection with immune mechanisms, whereas goats use avoidance by feeding behaviour and consumption of bioactive plant species (Hoste et al., 2015). The majority of immunonutrition studies have been conducted in sheep and goat studies tend to confirm the bulk of the data, though the specific mechanism of benefit may differ. Due to their peculiarities in feeding behaviour as intermediate browsers, goats represent a valuable model in their own right to explore the relationships for nutrient investment during infection with GI nematodes (Hoste et al., 2008). Solid evidence does exist on the effects of nutrition on the manifestations of immunity at the phenotypic level, what remains to be established is the interactions at the molecular level to allow predictions as to risk of infection and indicators of predisposition to disease (Athanasiadou, 2012). Perhaps the buzzword ‘immunonutrition’ is unnecessary and it is the understanding of nutrition that must expand. Expand to accept nutrition as an access to targeting different drivers of parasite epidemiology, different processes in the parasite lifecycle or different phases of acquired immunity to GI parasites (Houdijk et al., 2012). Creating nutrition in small ruminant production systems to = sufficient nutrient availability (targeting host) + access for medicinal PSM input (targeting parasite) + impacting feeding behaviour, physically moving up above contaminated pasture (targeting environment). For goats, this could culminate in the discovery of plant species able to fulfil all three of these strategies to provide a single tool with additive benefits.

3.7. Therapeutic minerals and vitamins 3.7.1. Variations of copper There are three main varieties of copper available for use by goat farmers; copper sulphate, copper oxide wire particles (COWPs) and the high levels of copper available in browse compared to pasture (Khan, 2011). Copper sulphate was extensively used for treating Haemonchus infections prior to the emergence of chemical anthelmintics in the 1960s (Clunies-Ross and Gordon, 1936). Recently the statement that goats with adequate copper status have no problems with worms (Coleby, 1993), combined with the need to seek new strategies in the face of anthelmintic resistance, renewed attention on copper as a proactive addition to control Haemonchus, rather than a reactive curative strategy. Coleby (1993) published her book with learnings from 30 years of farming goats, the husbandry methods that she found to be effective, particularly the relationship of copper status and reduced incidence of GI worm infection. Given the anecdotal nature of this evidence, the anthelmintic potential of copper sulphate against Haemonchus was investigated using LDA and LMI assays, and a strong dose/response relationships was observed (Kearney et al., 2015, unpublished data). Further work is necessary to replicate

these results and later to expand these results to determine dosage rates for animal treatment, given the complexities of the host environment. Recently, a sustained-release multi-trace element/vitamin ruminal bolus, containing 3.7 g of copper, reduced the FECs of treated mature does within 7 days compared to untreated does during late gestation with Haemonchus as the predominant nematode (Burke and Miller, 2006). This study did not identify copper as the anthelmintic ingredient, it could only conclude that improved trace element/vitamin status reduced FECs and did so for 3–4 weeks, similar to an anthelmintic treatment. Copper oxide wire particles (COWPs) are boluses containing only copper, available and used by farmers to treat clinical signs of copper deficiency in cattle, providing an access to introducing copper to the GI tract of goats to determine anthelmintic activity, and to do so in a slow-release manner (Burke et al., 2010, 2007b; Soli et al., 2010). COWPs move from the rumen to the abomasum, where the capsules remain, releasing copper wire particles for at least 32 days, to move throughout the GI tract, and importantly raising copper concentrations in the abomasal digesta, creating an unfavourable environment for Haemonchus and causing the expulsion of the adult worms (Burke et al., 2007b; Galindo-Barboza et al., 2011). The abomasal pH was also observed to change with copper oxide particles, with treated does reaching 3.4–4.4 and untreated does did not exceed 2.8 (Chartier et al., 2000). COWPs have demonstrated high anthelmintic activity against Haemonchus, but only limited effects on the other GIN species in the small intestine, Teladorsagia, Trichostrongylus and Oesophagostomum, under both natural and experimental conditions (Burke et al., 2010; Chartier et al., 2000). The efficacy against Haemonchus was clearly established in reducing worm burdens (75%) as well as lowering egg output (37–95%) in relation to the establishment of new infections over several weeks. Further research is needed to determine if this is due to direct damage to the nematode cuticle, due to a higher susceptibility of Haemonchus to copper or due to the changes in abomasal pH. COWPs are equally effective provided as a capsule or feed additive. Young goats consistently benefitted more from the use of COWPs than did mature does (Soli et al., 2010), and reduction in FECs were more obvious in summer months than winter months, implying seasonality of dominant GIN species will impact this Toolbox strategy. Within the model of multiple complementary strategies, it was important to determine if copper, known to act as a fungicide, would affect the nematophagous nematode Duddingtonia flagrans (a strategy discussed in Section 3.1) (Burke et al., 2005). When no adverse effects on D. flagrans were found, it appeared the two strategies were complementary and could be applied together for additive benefits. Culminating in fewer eggs excreted due to copper effect on Haemonchus and the additional larval-reducing effect of D. flagrans creating a much lower larval challenge on the pasture when the two strategies are used together in a control program. Another study investigated the combination of COWPs and supplementary feeding as complimentary strategies (de Montellano et al., 2007). The rationale was to control Haemonchus with COWPs and leave the animals to defend themselves against two other species by the supplementary feeding strategy. This combination showed a tendency to improve live weight gain in the browsing kids, compared to using

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supplementation alone. According to tracer kids, the browsing area of this study showed low Haemonchus infectivity, potentially allowing the goats to take real advantage of complimentary strategies in the absence of heavy Haemonchus challenge. As browsing animals, goats are known to have a higher tolerance for copper compared to sheep, however caution must be given to applying COWPs to browsing goats that copper toxicity is not induced (Khan, 2011; Landau et al., 2000). This suggests that given the opportunity to naturally behave as intermediate browsers, goats will experience the benefits of copper effects on Haemonchus infection, by copper acting as a bioactive anthelmintic from Section 3.1. 3.7.2. Iron Anaemia is a critical clinical sign of haemonchosis and therapeutic treatment of iron loss is designed to hasten the recovery of the goat host; it does not affect the parasite. As a blood-consuming nematode, high burdens of Haemonchus can effectively lead to blood loss, including iron, a key constituent of haemoglobin, the oxygen carrying molecule of the red blood cell (Fox, 1997; Holmes, 1987, 1993; Simpson, 2000). Past studies into the therapeutic use of iron following anthelmintic treatment have not provided goat farmers with any insight into the value of iron as a therapeutic tool to alleviate the anaemia associated with haemonchosis (Berry and Dargie, 1978; Mahanta and Roychoudhury, 1978; Sen and Rabman, 1976). Eighteen goats, male and female between 3 and 18 months old were divided into three groups, group 1 received 200 mg iron each and group 2 received a dose of 100 mg of iron each day for four days, in the form of an iron-dextran complex, with group 3 the control group receiving no iron dose. This experiment measured the effect iron supplementation had on the recovery of parameters affected by Haemonchus infection such as PCV (packed cell volume), haemoglobin and body weight (Berry and Dargie, 1978; Mahanta and Roychoudhury, 1978; Sen and Rabman, 1976). A subsequent experiment measured the changes in total serum iron (TRI) levels over the course of a Haemonchus infection and concluded TRI level was a parameter useful to measure the effect of therapeutic doses of iron to assist recovery from infection (Mahanta and Roychoudhury, 1978). In the decades since this research, and taking into consideration the considerable anecdotal evidence as to the therapeutic value of commercial iron supplements, such as Ironcyclen, on the recovery of goats from haemonchosis (Coleby, 1993), further investigation could be valuable. Studies into the effects of iron supplementation on the recovery rate of goats following an anthelmintic treatment to eliminate a known Haemonchus burden are currently being undertaken (Kearney et al. unpublished data). Inconsistent results as to the efficacy of iron as anthelmintic and/or therapeutic strategies to control Haemonchus indicate complex interactions between dietary minerals, the age of the animal, its breed, the level of parasite infection, and environmental conditions that might affect level of infection and availability of minerals to the animal. 3.8. Breeding and selection Discovering the ‘golden’ animal capable of surviving or withstanding Haemonchus infection is highly sought. Breeding for and selecting resistant/resilient goats is a complimentary strategy; for an animal to express its full genetic potential into phenotypic presentation, external environment factors such as nutrition, discussed in Section 3.5, are critical. Attention directed to the quantification of genetic variation between animals in their resistance or resilience to Haemonchus is a search that has been unsuccessful (Baker, 1999; Bishop and Morris, 2007; Bisset and Morris, 1996; Gruner et al., 2004). Unfortunately, goats have been less thoroughly

studied than sheep (Bishop and Morris, 2007). Recently, Interleukin 13 (IL-13) was identified as enhancing gut contractions, able to propel parasites to detach from the gut wall (Corley and Jarmon, 2012). Parasite resistant goats have been found to express more IL-13 than susceptible goats, indicating IL-13 expression as a potential biomarker for identifying Haemonchus resistant goats, however further research is necessary. Members of a population are not all equally susceptible to infection with Haemonchus nematodes; some individuals show considerably more resistance than others and may survive infections which prove lethal to, or cause serious disease in, other individuals (Stear and Wakelin, 1998). Genetic differences between host animals in nematode parasite resistance have been observed in all major production environments (Bishop and Morris, 2007; Kahn et al., 2003). Genetics provide a valuable foundation for building and improving phenotypic expression of resistance and resilience. Three strategies for utilizing genetic resistance include: 1) use of resistant/resilient breeds, 2) cross-breeding, 3) selective breeding (Stear, 2010). The desirability of breeding for Haemonchus resistance/resilience for a farmer depends whether there are trade-offs with other economically important traits (Stear et al., 2001). If unfavourable associations are found, selection indices for these traits can maximise desired responses while minimising undesirable effects. Identifying high or low resistance breeds will have implications for the geolocation of goat farms. A farm producing low resistance animals in a tropical/sub-tropical environment is going to have to implement highly effective strategies to not be undone with the production losses due to Haemonchus burdens. Susceptible and resistant individuals can be determined within a population of goats without identification of specific genes responsible, as described by Corley and Ward (2013). Using parasite loads and clinical anaemia status, determined by FEC, PCV and FAMACHA measurements, animals from a mixed herd of Spanish and Myotonic goats were divided into resistant and susceptible groups. In sheep, heritabilities of resilience traits have been found to be generally low (Bisset and Morris, 1996) while heritabilities of resistance are generally high (Stear and Wakelin, 1998). As stated earlier, sheep develop resistance over resilience to GI nematodes, and that goats develop the resilience over resistance (Hoste et al., 2010), therefore it would be erroneous to assume heritabilities will be the same between the sheep and goats without conducting relevant studies. Breeding programs selecting for resistance to GIN is a long term strategy that requires consistent investment in record keeping regarding infection levels, frequency of anthelmintic treatment, susceptibility to infection, FECs and FAMACHA scores. Individual goats consistently displaying high egg counts, poor performance in response to infection, once identified can be removed from the breeding stock. Animals with heavy GI parasite burdens lead to contaminated pastures, increased challenge to other animals, thereby compromising the health of the entire herd and any Haemonchus management plan (Torres-Acosta and Hoste, 2008). Benefits from genetically improving nematode resistance include decreased anthelmintic requirements, reduced pasture contamination which correlates to decreased larval challenge, and indirect benefits on health and performance (Bishop and Morris, 2007). The selection of breeding stock involves accepting the importance of Haemonchus resistance and/or resilience as valuable production traits. 3.9. Targeted selective strategies Targeted selective strategies such as FAMACHA to identify individual goats in a herd with high Haemonchus burdens, strategic drenching of those individuals and the maintenance of untreated

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Haemonchus in the remaining goats, in refugia, aim to reduce the selection pressure for anthelmintic resistance in Haemonchus (Jackson and Miller, 2006). These targeted strategies are based on clinical signs of infection and estimates of worm burdens resulting in selective treatment of individual goats and are most effectively used in combination (Jackson and Miller, 2006; Jackson et al., 2012). 3.9.1. FAMACHA FAMACHA, as described by Van Wyk and Bath (2002), is designed to identify animals suffering Haemonchus infection based on their level of anaemia and recommend the necessity of anthelmintic treatment (Burke et al., 2007a). Using FAMACHA, individual goats can be strategically drenched, leaving other animals untreated and maintaining infections that are not treated, thus reducing the use of anthelmintics and slowing the rate of resistance development (Burke et al., 2007a; Jackson and Miller, 2006). 3.9.2. Refugia The untreated animals maintaining infections, provide adult and subsequent larval Haemonchus escaping treatment that are the basis of the concept of refugia (Besier, 2012). Initially, it was thought that highly resistant populations could be diluted through introducing susceptible strains and maintaining this susceptibility using refugia (Coles, 2005). Refugia delayed the development of resistance of Haemonchus to thiabendazole in a study by Martin et al. (1981), determined by the use of an egg hatch assay (EHA) for resistance. The number of larvae in refugia shows a direct relationship with the rate of resistance development. Later, it was demonstrated in the field that by creating a reservoir of untreated parasites, the surviving Haemonchus population comprised of a combination of non-resistant and resistant parasites, thus slowing the development of anthelmintic resistance, in addition to emphasising the risk of treating all animals prior to relocating them to a pasture with low levels of Haemonchus contamination (Waghorn, 2008). The resulting higher levels of pasture contamination from the untreated animals exposed the complexity of managing worm control and resistance development using the refugia strategy. In recent years, the refugia concept has been identified as a fundamental principle in the management of resistance in Haemonchus in goats (Besier, 2012; Jackson and Miller, 2006; Jackson et al., 2012; Waghorn et al., 2009). 3.9.3. Strategic drenching There will be situations that necessitate treatment with a veterinary anthelmintic. Strategic drenching is an alternative to blanket treating all animals so only the goats requiring anthelmintic intervention are treated. Reducing the frequency of anthelmintic treatments and targeting specific goat hosts requiring treatment, slows the rate of resistance development by Haemonchus, and extends the effective life of veterinary anthelmintics. 4. What’s out Although, for different reasons, the following strategies of nematophagous fungi, cysteine proteinases and veterinary anthelmintics are not currently included on the main shelf of the Toolbox, strategies in this category are pending inclusion until further developments and discoveries improve their efficacy and sustainability. 4.1. Nematophagous fungi Nematophagous fungi have been a biological control measure of interest for the last 20 years (Larsen et al., 1991). This strategy of micro-predation of nematodes by specifically nematode-consuming fungi on the cusp of commercial availability

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still requires collaboration and co-operation with a research body to access it as a strategy in Haemonchus control programs. Duddingtonia flagrans, is the species that has received the bulk of the investigation in this field around the world (Buske et al., 2013; Epe et al., 2009; Eysker et al., 2006; Fontenot et al., 2003; Kahn et al., ˜ et al., 2002; Waller et al., 2001; Waller 2007; Knox et al., 2002; Pena and Larsen, 1993). A member of the Dueteromycetes of the class Fungi Imperfecti, members of which are well known as nematode destroying fungi (Larsen et al., 1998; Waller and Faedo, 1993). D. flagrans produces thick walled chlamydospores capable of enduring passage through the ruminant GI tract to emerge and develop in the faeces (Larsen et al., 1994) D. flagrans acts directly by trapping the Haemonchus larvae that also hatch and develop in the faeces (Kahn et al., 2007). Other nematophagous species that have been identified and isolated for study include Arthrobotrys robusta (Silva et al., 2010), Monacrosporium thaumasium (Vilela et al., 2012), Arthrobotrys musiformis (Acevedo-Ramírez et al., 2015), Arthrobotrys conoides (Falbo et al., 2015) and Monacrosporium salinum (Liu et al., 2015). In determining the role of D. flagrans application in a farm based setting, numerous factors have been researched, including the impact of D. flagrans on natural soil flora/fauna, the efficiency of feeding D. flagrans chlamydospores, even a model of deploying D. flagrans in an improved pasture system (Knox et al., 2002; Ojeda-Robertos et al., 2008; Yeates et al., 2007a, 2007b). The work with improved pasture involved a well-established, predominantly Phalaris aquatica L. and Trifolium repens L. pasture that was prepared by excluding livestock and mowing mechanically to a 5–10 cm sward height to simulate grazing for 4 weeks before use. The results of this study showed no detectable negative environmental impacts of D. flagrans in a typical improved pasture; D. flagrans was not found to spread horizontally outside the point of faecal deposition. Recently, research has progressed to investigating how to practically apply these species of fungi in a farm setting. Nutritional pellets containing D. flagrans chlamydospores were tested following exposure to 4 different storage conditions for efficacy on larval reductions, in an effort to determine the long-term shelf-life of the chlamydospores (Fitz-Aranda et al., 2015). Larval reductions were similar at all times, unaffected by storage method of indoor shelves, refrigeration at 4oC, outdoors under a roof or 100% outdoors, suggesting the viability of this spore dosage technology. An alternative application strategy is spraying pasture with the fungus conidia, as tested with Arthrobotrys conoides to control GI nematode infection pressure in lambs (Falbo et al., 2015). Spraying was performed weekly by a manual sprayer, at an application rate of 7.5 × 104 conidia per m2 and the lambs grazing these sprayed pastures were found to remain quite healthy in the absence of anthelmintic treatment, despite developing quite high average worm egg counts (Falbo et al., 2015). Specficially interesting about this study was the use of Arthrobotrys sp. The majority of research in the literature has been done with D. flagrans. Arthrobotrys conoides was chosen for this study because: 1) results from in vitro tests after the passage through GI tract of lambs showed very promising results and 2) the fungus was isolated from the same location where the field tests were performed and fungal species from the same location are preferable for controlling nematodes. Spraying conidia on pasture may be a more feasible than oral application for small ruminants raised in commercial farms without supplements. What remains to discover regarding nematophagous fungi includes indentifying the substances they produce, their optimal conditions of activity, how they interact with each other, and how do they work at the field level for best application strategy, culminating in decreasing the parasite population while simultaneously having fewer negative consequences for animal, human and environmental health (Acevedo-Ramírez et al., 2015).

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4.2. Cysteine proteinases Cysteine proteinases have been investigated from two different perspectives. As a potential new anthelmintic drug and as a vaccine (Behnke et al., 2008; Molina et al., 2012). Centuries old anecdotal evidence from Panama and South America native inhabitants describes using fruits containing cysteine proteinases to treat worm infections. Papaya latex has a high concentration of cysteine proteinases and has shown anthelmintic activity, however not specifically against Haemonchus (Behnke et al., 2008). Unfortunately, some species of human GI nematodes, particularly hookworms, have already begun developing resistance. The problem of resistance is attached to any anthelmintic, synthetic or plant-derived, and at most a cysteine proteinase anthelmintic will join the current commercial anthelmintics, to be discussed in Section 3.3. Cysteine proteinases have also been derived from strains of Haemonchus for investigation into immunological control using these enzymes against haemonchosis (Molina et al., 2012). Results showed that a cysteine proteinase fraction, developed from adult Haemonchus, had a protective effect against Haemonchus infection in both sheep and goats, regardless of whether it was adapted from a sheep or goat-adapted strain. Ultimately, cysteine proteinases was a promising area, particularly considering its versatility, and required further research into mechanisms and development. Unfortunately, further research and development may not be considered as critical or as economical with the development and release of Barbervax® . 4.3. Break in case of emergency 4.3.1. Veterinary anthelmintics The resistance of H. contortus to commercial anthelmintics is extensively documented and reviewed and is beyond the scope of this review, refer to Waller et al. (1989); Prichard (1990); Waller (1997); Sangster (1999); Besier and Love (2003); Coles (2005); Taylor et al. (2009); Jackson et al. (2012); (Kaplan and Vidyashankar, 2012). The emergence of anthelmintic resistance on a farm is gradual, often escaping notice until overt drug inefficacy is apparent (TorresAcosta and Hoste, 2008). Thus, the use of anthelmintics must be closely monitored with regular Faecal Egg Count Reduction Tests (FECRT). Through this method, the FECs of the goats are monitored before and after an anthelmintic treatment, and records are kept over time, to identify any reductions in efficacy of the anthelmintics being used (Coles, 2005; Dobson et al., 2012; Taylor et al., 2009). Until the 2010 release of monepantel, there had not been a new class of anthelmintics delivered to the livestock market since ivermectin almost 30 years before. Monepantel may offer a temporary reprieve yet there is no reason to believe that resistance to any newly developed drugs will not appear. In fact, a small property in the North Island of New Zealand has experienced monepantel failure in less than two years of the product being first used. With high costs associated with the development of new drugs, combined with the reduced levels of industry investment into veterinary research, it is unrealistic to expect a renewed phase of continuous supply of new anthelmintic compounds (Waller, 2006a). Thus it is imperative that the efficacy of commercial drenches is preserved for as long as possible and goat farmers are weaned of their dependency on them. Another point of note is that current veterinary anthelmintics are registered for use in sheep, cattle, pigs, horses and with the exception of one ivermectin drench Caprimec® , all use of veterinary anthelmintics for goats is off-label. This is significant, as incomplete testing has not determined effective dosages required for goat treatment, resulting in consistent under-dosing and misman-

agement of goat treatment (Hoste et al., 2010). The consideration that goats are similar to sheep has been repeatedly proven wrong, particularly with regards to the metabolism of veterinary chemicals. As discussed earlier, goats have adapted to metabolise plant toxins they encounter during browsing, an ability that also affects their metabolism of veterinary drugs. As a result, the goat industry is experiencing the negative impact of under-dosing of veterinary anthelmintics and the consequential selection of chemical resistant nematodes (Hoste et al., 2010). Therefore, the strategic use of veterinary anthelmintics is critical to preserve their remaining efficacy. 5. Conclusion Following its release in 2010, complete failure of monepantel (Zolvix) has occurred on a small farm in New Zealand in less than two years (Scott et al., 2013). This is evidence of the seriousness of anthelmintic resistance and the critical need for sustainable management options for control of GI parasites in goats. A number of control strategies have been researched in the past 30 years, often for small ruminants in general rather than specifically goats, achieving varying degrees of successful implementation and availability (Hoste et al., 2010). Goat producers can no longer afford to consider these strategies individually but rather as options in a Toolbox. Even if Barbervax® where to be registered for use in goats, it too will be but one strategy in the Toolbox. The selection and implementation of strategies from this Toolbox, based on individual situation requirements, will result in a tailor-made and multi-faceted management program for the control of Haemonchus. In particular, the use of tanniferous/polyphenolic plants as anthelmintic browse has shown considerable promise (Hoste et al., 2012). The use of bioactive plants as a strategy has two benefits: the goats are foraging high above the infective larvae on the pasture and the anthelmintic activity of the plant matter interrupts the development/motility/survivability of Haemonchus in the goats, reducing their worm burdens. There is a vital opportunity to take this research further with goats, investigating their preferences for bioactive forages, their preference to consume these forages during an infection and the opportunity to investigate new forages for bioactive properties. Chicory (Chicorium intybus L.) is one forage already commercially available for its nutritive value to grazing animals, and evidence has shown particular strains have anthelmintic potential, goats display a preference for these, and the structure of the plant itself inhibits larvae from migrating to grazing height. The farming of goats has often been modelled on sheep, severely undervaluing the requirements of and behavioural preferences of goats. The promotion of and education of strategies beyond anthelmintic treatment will not only prolong the remaining efficacy of veterinary anthelmintics but will avoid the disaster of drench failure. Relationships between research bodies and goat farmers are critical to develop successful Haemonchus management control programs. The integration of a multi-faceted Haemonchus management plan into the greater management plan for the goats and the farm will lead to greater productivity, reduced economic losses through product quality and stock mortality, reduced chemical inputs and of course, greatly improved welfare and a sustainable farming system. References Abbott, E.M., Parkins, J.J., Holmes, P.H., 1986. The effect of dietary protein on the pathophysiology of acute ovine haemonchosis. Vet. Parasitol. 20, 291–306. Acevedo-Ramírez, P.M.D.C., Figueroa-Castillo, J.A., Ulloa-Arvizú, R., Martínez-García, L.G., Guevara-Flores, A., Rendón, J.L., Valero-Coss, R.O., Mendoza-de Gives, P., Quiroz-Romero, H., 2015. Proteolytic activity of extracellular products from Arthrobotrys musiformis and their effect in vitro against Haemonchus contortus infective larvae. Vet. Rec. 2, 1–6. Agricom, 2012. Herbs: Chicory. Agricom Ltd company webpage, http://agricom. com.au/products/herbs/ (accessed 19.03.15.).

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