The management of anthelmintic resistance in grazing ruminants in Australasia—Strategies and experiences

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The management of anthelmintic resistance in grazing ruminants in Australasia—Strategies and experiences D.M. Leathwick a,∗ , R.B. Besier b a b

AgResearch, Grasslands Research Centre, Private Bag 11008, Palmerston North 4442, New Zealand Department of Agriculture and Food Western Australia, 444 Albany Highway, Albany, WA 6330, Australia

a r t i c l e

i n f o

Keywords: Nematode control Anthelmintic resistance Refugia Combination Quarantine

a b s t r a c t In many countries the presence of anthelmintic resistance in nematodes of small ruminants, and in some cases also in those infecting cattle and horses, has become the status quo rather than the exception. It is clear that consideration of anthelmintic resistance, and its management, should be an integral component of anthelmintic use regardless of country or host species. Many years of research into understanding the development and management of anthelmintic resistance in nematodes of small ruminants has resulted in an array of strategies for minimising selection for resistance and for dealing with it once it has developed. Importantly, many of these strategies are now supported by empirical science and some have been assessed and evaluated on commercial farms. In sheep the cost of resistance has been measured at about 10% of the value of the lamb at sale which means that losses due to undetected resistance far outweigh the cost of testing anthelmintic efficacy. Despite this many farmers still do not test for anthelmintic resistance on their farm. Many resistance management strategies have been developed and some of these have been tailored for specific environments and/or nematode species. However, in general, most strategies can be categorised as either; identify and mitigate high risk management practices, maintain an anthelmintic-susceptible population in refugia, choose the optimal anthelmintic (combinations and formulations), or prevent the introduction of resistant nematodes. Experiences with sheep farmers in both New Zealand and Australia indicate that acceptance and implementation of resistance management practices is relatively easy as long as the need to do so is clear and the recommended practices meet the farmer’s criteria for practicality. A major difference between Australasia and many other countries is the availability and widespread acceptance of combination anthelmintics as a resistance management tool. The current situation in cattle and horses in many countries indicates a failure to learn the lessons from resistance development in small ruminants. The cattle and equine industries have, until quite recently, remained generally oblivious to the issue of anthelmintic resistance and the need to take pre-emptive action. In Australasia, as in other countries, a perception was held that resistance in cattle parasites would develop very slowly, if it developed at all. Such preconceptions are clearly incorrect and the challenge ahead for the cattle and equine industries will be to maximise the advantages for resistance management from the extensive body of research and experience gained in small ruminants. © 2014 Elsevier B.V. All rights reserved.

∗ Corresponding author. Tel.: +64 6 3518085; fax: +64 6 3538134. E-mail address: [email protected] (D.M. Leathwick). 0304-4017/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.vetpar.2013.12.022

Please cite this article in press as: Leathwick, D.M., Besier, R.B., The management of anthelmintic resistance in grazing ruminants in Australasia—Strategies and experiences. Vet. Parasitol. (2014), http://dx.doi.org/10.1016/j.vetpar.2013.12.022

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1. Introduction Nematode parasites are a significant threat to the productivity of grazing livestock throughout much of the world, and many livestock owners depend on anthelmintics to minimise worm populations and maintain animal performance (Waller, 2006). However, the effectiveness of anthelmintics, and the welfare and production benefits they bring, is threatened by the increasing prevalence and severity of anthelmintic resistance (Besier, 2007; Kaplan and Vidyashankar, 2012). In sheep and goats, and in some countries also in cattle and horses, the presence of resistant worm populations is the status quo rather than the exception (Kaplan, 2004; Waghorn et al., 2006a; Kaplan and Vidyashankar, 2012). In many cases, the presence of resistance does not jeopardise effective worm control, which can be maintained simply by switching to use of an alternative class of anthelmintic to which resistance has not yet developed. However, as has been clearly demonstrated by experiences in goats and sheep, this is not a long-term solution, as resistance eventually develops to other classes as well. Hence, anthelmintic resistance in small ruminants in some countries involves all anthelmintic groups and combinations, except for the new actives monepantel and derquantel, and all major nematode genera (Besier and Love, 2003; Kaplan, 2004; Waghorn et al., 2006b; Kaplan and Vidyashankar, 2012). It is an inevitable conclusion that consideration of anthelmintic resistance and its management should be an integral component of anthelmintic use regardless of country or host species (Besier, 2007; Kaplan and Vidyashankar, 2012; Leathwick, 2013). The need to combat anthelmintic resistance in small ruminants has resulted in considerable research effort to understand the dynamics of selection for resistance, and to develop strategies to minimise either initial or ongoing selection (Barnes et al., 1995; Leathwick et al., 2001, 2009; Woodgate and Besier, 2010; Kenyon and Jackson, 2012). As a result, in Australasia and some other countries such as the United Kingdom and South Africa, there exists today an array of resistance management strategies; many based on sound scientific evidence and some of which have been evaluated on commercial farms (van Wyk and Bath, 2002; Besier, 2012; McMahon et al., 2013; Leathwick, 2013). Unfortunately, there is little equivalent information regarding the management of anthelmintic resistance in cattle (Sutherland and Leathwick, 2011) or horses (Nielsen, 2012). While some aspects of the selection process, and therefore resistance management, are likely to be universal across host species, there will also be aspects which are different (Sutherland and Leathwick, 2011). For example, the dynamics of development and survival within the faecal pat (Young, 1983), and the pharmacokinetics and routes of administration of anthelmintics are likely to differ between sheep and cattle (González et al., 2009; Sutherland and Leathwick, 2011). The opportunity presented by the previous work in small ruminants is to capitalise on the knowledge and principals which have universal application, and to allow the focussing of resources onto those aspects which are specific to a given host or environment. Here, we review strategies for the management of anthelmintic resistance in Australasia, the evidence

supporting their development, and, where appropriate, experiences regarding their adoption on-farm. While most of the literature reports on studies involving parasites of sheep, we attempt to take a more general view encompassing general principles and aspects applicable to a wider range of host species. 2. Economic costs of anthelmintic resistance Although sub-clinical worm burdens are wellrecognised as a major cause of reduced animal production (Barger, 1982), few investigations have quantified the potential effects of impaired worm control resulting from anthelmintic resistance. Two recent New Zealand studies have quantified the cost in lamb production of using an anthelmintic for which efficacy is compromised by resistance at approximately 10–15% of carcass value (Sutherland et al., 2010; Miller et al., 2012). These trials measured only the immediate cost in lamb value and did not attempt to measure less tangible effects of sub-clinical parasitism such as ewe fecundity. However, the second trial (Miller et al., 2012) did demonstrate additional costs in that resistance necessitated holding lambs on the farm for longer (an average of 17 days), which would have required consumption of more pasture and reduced other financial opportunities. Further, the resistant parasites involved in these studies were Teladorasgia (Ostertagia) circumcincta and Trichostrongylus colubriformis. Had the resistance involved more pathogenic species, such as Haemonchus contortus, then production losses would undoubtedly have been greater. A study in Western Australia indicated a similar scale of loss attributable to anthelmintic resistance in T. circumcincta and Trichostrongylus spp. Lambs treated with an anthelmintic that had reduced efficacy due to resistance suffered a 10% loss of wool production and growth rate compared to lambs given a fully effective anthelmintic. This study also highlighted the often insidious nature of anthelmintic resistance, in that clinical differences between the groups were minimal for most of the yearlong study, only becoming obvious towards the end as efficacy declined and worm burdens accumulated (Besier et al., 1995). By the time overt anthelmintic failure is noted in such situations, the anthelmintic involved is likely to be ineffective for further use, except perhaps in a combination formulation. There are few reports of the effects of anthelmintic resistance in nematodes of cattle. A recent study in Brazil (Borges et al., 2013) found that anthelmintic treatments which failed to adequately control resistant Haemonchus placei and Cooperia spp. resulted in a reduction in average daily weight gain of 60–90 g/day, which at 112 days posttreatment equated to a difference in liveweight of >9 kg. A small scale New Zealand study (i.e. 4 groups of 15 animals) found that use of an anthelmintic which did not adequately control Cooperia spp. reduced daily weight gain by an average of 100 g, resulting in a 6 kg difference in liveweight after 60 days (Leigh and Hunnam, 2013). A larger New Zealand study compared the growth rates of beef steers up to 18 months of age under routine treatment with anthelmintics that were either effective or ineffective against resistant

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Cooperia oncophora. Failing to control C. oncophora resulted in liveweight differences of 7.1 kg and 14.4 kg at 12 months of age in different years. Interestingly, in both years these differences decreased by 18 months of age, to 3.5 kg and 9.1 kg, suggesting compensatory growth in those animals which had experienced greater exposure to C. oncophora (Waghorn et al., 2012, unpublished report to Beef and Lamb NZ #09AR03). These results from both sheep and cattle studies estimated a cost of anthelmintic resistance which would far out-weigh the cost of testing anthelmintic efficacy, even though there are no obvious visual signs of parasitism in the animals. In both the New Zealand and Australian studies, the main effect of sub-optimal anthelmintic performance was to reduce the effectiveness of parasite control programs, and therefore farmer income. Although the intensive use of anthelmintics to suppress worm populations may be economically most attractive in the short term (Pech et al., 2009), the eventual loss of anthelmintic efficacy has serious implications for longer term animal productivity. 3. Resistance management strategies An array of possible strategies have been proposed for the management of anthelmintic resistance in small ruminants (Leathwick et al., 2009; Molento, 2009) and in horses (Nielsen, 2012), but few in cattle. Some of these have been developed for specific environments (Besier et al., 2001; Besier, 2012) or parasites (van Wyk and Bath, 2002). However, most strategies can be generally grouped into one of the following categories: 1. Identification and mitigation of high risk management practices. 2. Maintenance of an anthelmintic-susceptible population in refugia. 3. Optimal choice of anthelmintics (combinations of effective anthelmintics and appropriate formulations). 4. Prevention of the introduction of resistant nematodes. 4. Identification and mitigation of high risk management practices The identification of management practices that are likely to result in a rapid increase in the prevalence of resistant genotypes is important for several reasons. Firstly, once a practice is recognized as being inherently high risk, alternative approaches can be sought. Further, if no practical alternative to achieving the same goals is available, then steps may be taken to negate or minimise the associated risk, i.e. the practice may be modified in some way. Some nematode control practices originally identified as significant causal factors for resistance in sheep worms in Australia and New Zealand, such as an excessive frequency of treatment, remain important in some circumstances. However, the major principle underpinning most resistance management strategies is the requirement for sufficient dilution of resistant worms, and their off-spring, after a flock is treated, so that the proportion of resistance worms does not increase (the “refugia” concept).

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4.1. Excessive frequency of treatment Frequent anthelmintic treatment may be necessary in sheep and goats where few non-chemical options are available and there is a risk of severe parasitism, especially where the highly-pathogenic H. contortus is the major species. In some regions of Australia a dependence on frequent drenching for control of H. contortus has resulted in wide-spread resistance to all of the older anthelmintic classes, including long-acting narrowspectrum anthelmintics and anthelmintic combinations (Besier and Love, 2003; Playford et al., 2013). Similarly, frequent anthelmintic use is common where environmental conditions are favourable for the development of the freeliving stages over a protracted season, as occurs in New Zealand (Lawrence et al., 2007; Waghorn et al., 2011). However, this does not necessarily imply an increased risk of resistance development, as frequent treatment itself is not always indicative of high selection for resistance. Provided high-frequency treatment schedules are confined to particular groups of animals, such as juveniles, and a significant proportion of the parasite population remains on pasture as free-living stages, then resistance development need not be rapid. An excellent illustration of this is a comparison of resistance development under the Mediterranean climate of Western Australia and the more temperate climate of New Zealand. Despite significantly fewer anthelmintic treatments given annually in Western Australia (Besier and Love, 2003) compared with New Zealand (Lawrence et al., 2007), resistance in the former region developed faster and to higher levels. In cattle, treatment frequency is typically lower than in sheep, as in general, cattle are more resilient to the impact of nematode infections (Waller, 1994). Nevertheless, appropriate treatment programmes for different environments appear to be less well understood for cattle, and there appears to be a greater variation in farmer practice. For example, in both Australia and New Zealand, although the average number of treatments to young cattle is lower than in sheep, a proportion of cattle owners continue to treat at unrealistically frequent intervals (Jackson et al., 2006; J. Cotter, pers. com.). In New Zealand, a quarter of farmers treated their cattle with anthelmintic between 8 and 12 times in their first year of life (Jackson et al., 2006). On some cattle farms, therefore, the treatment frequency is likely to be excessive to the point of significantly contributing to the selection of anthelmintic resistance. Further, the majority of treatments to cattle will be with pour-on or injectable products, all of which possess varying lengths of persistent activity against some nematode species. Compared to sheep worms, the period to which cattle worms are exposed to anthelmintic will therefore be longer than indicated by a straight comparison of treatment frequency (Pomroy, 2006). In both countries, it appears that the lessons learnt from small ruminants, and the resulting strategies and recommendations on resistance management, have not been adopted by cattle producers and their advisors. This reflects a perception, which was also held in other countries, that resistance in cattle parasites would develop very slowly, if it developed at all (Gasbarre et al., 2009).

Please cite this article in press as: Leathwick, D.M., Besier, R.B., The management of anthelmintic resistance in grazing ruminants in Australasia—Strategies and experiences. Vet. Parasitol. (2014), http://dx.doi.org/10.1016/j.vetpar.2013.12.022

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Another example of excessive treatment with anthelmintics involves horses. Nematode control in horses is often based on frequent prophylactic treatments (often at 6–10 week intervals) throughout the year without consideration to the size or identity of the parasite burden (Nielsen et al., 2007; Rogers et al., 2007). Given that in many cases this high frequency of treatments coincides with monocultures of stock class (i.e. 100% horses) and high stocking densities (Rogers et al., 2007) it is hardly surprisingly that anthelmintic resistance is a serious concern to the equine industries globally (Kaplan, 2004).

Low-contamination pastures are not, however, restricted to regions with long periods of low rainfall. In parts of both Australia and New Zealand, drenching animals onto crops, hay aftermath or pastures prepared by grazing with alternative stock classes has long been promoted on productivity grounds (Brunsdon, 1980). Field trials have demonstrated that treatment of lambs followed immediately by a shift onto cattle pastures can result in a significant and protracted increase in the resistance status of the eggs passed (Waghorn et al., 2009). 4.4. Treatment of ewes immediately pre- or post-lambing

4.2. Under-dosing with anthelmintics Although considered important in sheep when anthelmintic resistance was first recognised (Prichard et al., 1980), this is now of less significance in Australia and New Zealand. Recognition of routine under-estimations of sheep weights by farmers led to intensive education campaigns regarding the need for appropriate dose rates (Besier and Hopkins, 1988), and general industry practice in both countries is now to dose to the heaviest animal in the group (Lawrence et al., 2007). However, there may be a greater potential for inaccurate weight estimation in larger animals such as horses and cattle, where animals are less likely to be weighed prior to treatment. In Western Australia, a survey of cattle owners indicated that only 22% weighed animals as a routine (J. Cotter, pers. com.). In contrast, a survey of New Zealand cattle farmers in 2005 indicated that all had scales capable of weighing cattle and 75% of farmers routinely weighed animals they were rearing for sale (Jackson et al., 2006). However, it was less clear how often animals were weighted to determine anthelmintic dose rate. Further, different routes of administration may contribute to the possibility of under-dosing in some host species (Section 6.2). 4.3. Treatment on low-contamination pastures Undoubtedly the most recognized high-risk practice today is the use of anthelmintic treatments associated with pastures carrying low numbers of susceptible nematode larvae (van Wyk, 2001). Any treatment of stock which coincides with the grazing of low-contamination pastures potentially yields a substantial advantage to those nematodes which survive the treatment (Michel, 1985; Martin, 1989). Because the rate of reinfection post-treatment is slow, the surviving worms remain undiluted by new infection for a protracted period (Martin, 1989; Waghorn et al., 2009). Further, the resistant eggs passed by these worms make up a major proportion of the subsequent larval population on pasture (Waghorn et al., 2008). Perhaps the most extreme example of selection for anthelmintic resistance with this practice is the ‘summer-drenching’ programme as applied in the Mediterranean climate zone of Western Australia. In areas where dry summer conditions result in almost no survival of nematode larvae on pasture, a single anthelmintic treatment to all livestock at an appropriate time can produce excellent worm control, but also be highly selective for resistance (Besier et al., 2001; Woodgate and Besier, 2010).

Anthelmintic treatment of adult ewes around lambing has been a common practice for many years (Brunsdon et al., 1983), particularly since the advent of longacting anthelmintic products such as slow-release capsules (Lawrence et al., 2007). It has long been recognised that treating ewes with anthelmintic at this time can select for anthelmintic resistance (Brunsdon et al., 1983), especially where nematode eggs passed by the ewes contribute significantly to subsequent infection in lambs (Cawthorne and Whitehead, 1983; Michel, 1985; Taylor and Hunt, 1989). A modelling study by Leathwick et al. (1995) showed that an anthelmintic treatment administered to adult ewes at lamb-docking (tailing or lamb marking) could be highly selective for resistance because it both pre-selected the larval challenge to lambs and removed a source of unselected nematodes ‘in refugia’. Further modelling (Leathwick et al., 1997) suggested that a pre-lambing treatment of ewes with a long-acting anthelmintic was likely to be even more selective for resistance than the short-acting oral treatment at lamb-docking. These conclusions were subsequently tested in a 5-year replicated field trial in which the development of benzimidazole resistance was compared under four different drench management regimes; two of which included periparturient treatments for ewes, either pre-lambing with an albendazole slow-release capsule or at lamb-docking time with a short-acting oral albendazole formulation (Leathwick et al., 2006a). The results were consistent with the conclusions from the modelling studies, in that compared with lamb-only treatment programmes, drenching programmes that included a treatment of ewes significantly increased the rate at which resistance developed in several parasite species, even though the same number of albendazole treatments was administered in all cases. A similar conclusion came from another New Zealand study which identified a significant association between treatment of ewes pre-lambing with long-acting macrocyclic lactone products and the presence of resistance (Lawrence et al., 2006). However, another smaller-scale study failed to detect such an association (Hughes et al., 2007). 4.5. Monocultures of young stock A common practice on sheep farms in both New Zealand and Australia is to separate ewes and lambs at weaning, with the lambs being reared to sale weights on areas of better pasture. This practice effectively creates a monoculture

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of young stock, which are commonly treated intensively with anthelmintics (Lawrence et al., 2007), to suppress parasite infection and maximise productivity. A modelling study by Leathwick et al. (1995) showed that, by eliminating the ewes as a source of unselected parasites, this practice is likely to significantly accelerate the development of resistance on the area grazed by the lambs. In New Zealand, under an intensive cattle rearing system, dairy or dairy × beef weaners are purchased in the spring, and are often grazed in monocultures until about 18-months of age. This system relies heavily on regular treatment with anthelmintics to suppress parasitism, and it is difficult to identify any potential source of infective larvae in refugia, except for the short period between treatments when the effects of the anthelmintic are negligible (Pomroy, 2006). Hence it is likely that this farming system imposes intense selection for resistance, which possibly contributed to the very high levels of anthelmintic resistance detected in cattle parasites in New Zealand (Waghorn et al., 2006a). 5. Maintenance of an anthelmintic-susceptible population in refugia Minimising the impact of high-risk management practices for the development of anthelmintic resistance almost always requires the retention of susceptible genotypes in refugia. There is considerable evidence from field trials that incorporating the refugia concept in worm control programs is likely to reduce the build-up of resistant worms (Martin et al., 1981; Besier et al., 2001; Leathwick et al., 2006a; Waghorn et al., 2008, 2009). However, finding a balance between retaining sufficient susceptible worms to slow the development of resistance with minimising the potential impact on productivity can be complex, and it is essential that an efficient basis is available for the selection of animals or flocks which can be safely left untreated. Provided other factors contributing to anthelmintic resistance, such as an excessive treatment frequency, are addressed, then the key approach to retaining susceptible genotypes is based on the concept of leaving a proportion of a flock untreated at epidemiologically critical times. Recent investigations have focused on “Targeted Selective Treatment” (TST: individually determined treatment to animals within a flock), and “Targeted Treatment” (TT: some flocks left untreated while other flocks are drenched; Kenyon and Jackson, 2012). 5.1. Targeted selective treatment TST approaches have been shown to be effective using various criteria for the selection of individual sheep for treatment, including liveweight or liveweight gain (Leathwick et al., 2006a,b; Stafford et al., 2009; Gaba et al., 2010) and milk yield for temperate region nematodes (Hoste et al., 2002; Cringoli et al., 2009). Individual-animal drenching decisions have also proved feasible where H. contortus is the dominant parasite, using the “FAMACHA” system to indicate those requiring treatment (van Wyk et al., 2006; Besier, 2008; Kenyon and Jackson, 2012). The use of more complex objective indices, based on

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weight-gains in relation to individual animal performance, has the potential to discriminate between animals in their likely response to drenching (Greer et al., 2009; Busin et al., 2013; Kenyon et al., 2013). In Australia, recent field trials involving large flocks have demonstrated that using indices for individual animal drenching decisions, based on body condition scores, can enable a large proportion of animals to remain untreated with no significant production penalty (Besier et al., 2010). Initial attempts at extending the TST concept into cattle have been made (Greer et al., 2010; Höglund et al., 2013). Both of these studies showed substantial reductions in anthelmintic inputs, but also small production losses, associated with TST. While these studies suggest that TST has potential as a resistance management strategy in cattle, more work is still required to optimise the decision guidelines in order to maintain production levels. Further, given the high levels of FEC measured in these studies, and therefore the likely high levels of pasture contamination associated with TST, longer term studies will be required to ensure that TST is sustainable from a productivity perspective. In addition to the requirement that TST strategies do not prejudice animal production or health, a key factor affecting the likely uptake by owners is the practicality of implementation (van Wyk et al., 2006; Besier, 2012). The size of flock or herd is an obvious determinant of the feasibility of individual-animal indices, especially where this requires time for close examination. However, modelling studies indicate that provided there is an adequate proportion of the population in refugia, and the anthelmintic used is highly effective, only a relatively small proportion (in some situations as low as 1–5%) of the flock need be left untreated to achieve a significant reduction in the selection for resistance (Dobson et al., 2011a; Leathwick, 2013). A potential additional benefit from TST strategies based on the identification of individuals with greater tolerance of parasitic effects is the selection of superior animals for breeding (van Wyk and Riley, 2009). A greater resilience to nematode infections has the dual benefits of enhanced productivity under parasitic challenge in these individuals, and a reduction in the selection pressure for resistance in the flock due to their reduced need for anthelmintic treatments. 5.2. Targeted treatment In contrast to TST approaches, “Targeted Treatment” involves decisions regarding leaving entire flocks untreated. This is especially suitable where it is impractical to apply individual-sheep treatment decisions to large flocks, and where the possibility of miss-categorising individual sheep to treatments may result in deaths. An example from Western Australia is the move from routine “summer drenching” of all sheep on a property (highly effective for worm control, but heavily selective for resistance; Besier et al., 2001), to a “summer-autumn drenching” strategy (Woodgate et al., 2012). This ensures that while lambs, which still receive summer treatments, are not penalised by worm infections, refugia is provided by moving drenches in mature sheep to autumn, after the

Please cite this article in press as: Leathwick, D.M., Besier, R.B., The management of anthelmintic resistance in grazing ruminants in Australasia—Strategies and experiences. Vet. Parasitol. (2014), http://dx.doi.org/10.1016/j.vetpar.2013.12.022

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seasonal development of worm larvae on pasture has commenced. In the H. contortus-region of northern New South Wales, a decision matrix based on worm egg counts and epidemiological factors, and accompanied by integrated parasite management approaches, has been demonstrated to allow treatment times to differ between flocks on a farm, with a consequent refugia benefit (L. Kahn and S. WalkdenBrown, pers. commun.). Under New Zealand conditions, perhaps the most promising approach to retaining refugia for lambs also employs untreated adult ewes as the primary source of refugia. A 2-year field trial was conducted in which the size and composition of worm burdens and pasture larval populations were compared in lambs grazing alone or grazing in rotation with untreated adult ewes over summer-autumn (Leathwick et al., 2008). Results indicated that adult ewes contributed unselected parasites of most species, without increasing the overall levels of infestation of pasture. Further, in the presence of anthelmintic resistance, the ingestion of larvae by the ewes suppressed the growth of parasite populations, resulting in reduced challenge to the lambs. Importantly, this study indicated that maintaining a refuge of susceptibility is not necessarily inconsistent with maintaining production levels (Leathwick et al., 2008). Another TT model now often applied to adult sheep around lambing time in New Zealand is to target flocks based on ultra-sound pregnancy scanning results, where treatments are given preferentially to those animals considered most likely to benefit from a treatment (e.g. lambing hoggets or multiple lamb-bearing ewes). In this case, single lamb-bearing ewes are left untreated as a source of refugia, on the basis that they are more able to cope with a parasite challenge. Another approach, which is a blend of TST and TT, has found acceptance with some New Zealand sheep farmers. Co-grazing 20–30 untreated lower condition score ewes with a mob of routinely-treated lambs meets multiple objectives. Traditionally, these ewes would have been treated with anthelmintic and remained within the ewe flock. However, by transferring them to the superior quality pastures normally allocated to the lambs, their body condition improves without the use of anthelmintic and at the same time they provide a source of refugia for the regularly treated lambs. Implicit in all these refugia-based strategies is the requirement that there will be sufficient mixing of resistant worms, either in the hosts or on pasture, with susceptible worms to achieve the necessary resistancedilution effect. 6. Optimal choice of anthelmintics The choice of anthelmintic product for use in a particular situation is influenced by a number of factors, with perhaps the most important of these being the spectrum of parasites required to be controlled. Some situations require the use of narrow spectrum and/or long-acting actives (e.g. the threat of haemonchosis), while others may require actives with different spectra of activity (e.g. targeting both nematodes and flukes in a single treatment). Anthelmintics are available in a range of different formulations, routes of administration and combinations of

actives. Along with the physico-chemical characteristics of the active molecule, the formulation and route of administration influence the pharmacokinetics (McKellar and Gokbulut, 2012) and therefore the efficacy (Sargison et al., 2009), and/or periods of persistent activity (Lifschitz et al., 2007). These characteristics, along with ease of administration, have always influenced product choice, but until recently the implications of these factors on selection for anthelmintic resistance have received little attention. 6.1. Long-acting anthelmintics The attributes of long-acting anthelmintic products and how their interaction with different nematode genotypes can influence the development of resistance have been reviewed previously (Dobson et al., 1996; Leathwick et al., 2001, 2009). While field trials have shown the potential for long-acting anthelmintics to provide significant worm control benefits (Cleale et al., 2004), this is not always the case (Gogolewski et al., 1997), and both modelling and empirical studies have provided compelling arguments for regarding them as potentially high-risk for anthelmintic resistance selection. Modelling studies by Dobson et al. (1996) and le Jambre et al. (1999) investigated the processes of selection for resistance by both short- and long-acting anthelmintics. They described the initial survival of resistant-genotype worms which were present at the time of treatment, and which continued to pass eggs onto pasture in the period after treatment, as ‘head’ selection (le Jambre et al., 1999). This occurs with all anthelmintic treatments, unless they are 100% effective, and gives a reproductive advantage to the resistant genotypes for at least the pre-patent period of new infection establishing from larvae on pasture. Persistent efficacy against susceptible-genotype larvae extends this period of reproductive advantage to the worms surviving the initial treatment (i.e. the period for which only resistant eggs are passed is extended) and this occurs regardless of the efficacy against ingested resistant larvae (Dobson et al., 1996). However, persistent efficacy invariably comes with a period where the drug concentrations are sufficient to prevent establishment of susceptible but not resistant larvae (le Jambre et al., 1999; Sutherland et al., 2003) and so the drug continues to screen the parasite population for resistance. Collectively, these latter processes can be regarded as ‘tail’ selection (Dobson et al., 1996). Modelling studies have shown that the relative importance of these different processes in the selection for resistant worms is likely to vary with the attributes of the anthelmintic and with operational and climatic factors. However, all these studies have shown the potential for long-acting products to select strongly for resistance (Dobson et al., 1996; le Jambre et al., 1999; Leathwick and Sutherland, 2002). In an indoor trial, le Jambre et al. (1999) repeatedly challenged groups of sheep with a mixture of macrocyclic lactone-susceptible and resistant H. contortus before and after treatment with ivermectin or moxidectin. Animals treated with moxidectin were shown to have a smaller total worm burden but a higher proportion of these were resistant than from animals treated with ivermectin. Those

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authors concluded that the persistent activity of moxidectin allowed only resistant larvae to establish after treatment, resulting in a proportional increase in resistant genotypes. In a replicated field study, Leathwick et al. (2006a) compared the rate of development of BZ resistance under four different drenching regimes. Where adult ewes were administered albendazole controlled-release capsules prior to lambing, resistance developed more rapidly than in a treatment regime which was identical except that the ewes were administered only a single oral treatment of albendazole at lamb-docking time. Although the mechanism by which the capsules increased selection for resistance was not explained by the results of the study, the fact that it was indicated in three nematode species (T. circumcincta, T. colubriformis and H. contortus) suggests a strong epidemiological basis. Other studies have found that long-acting anthelmintics can influence aspects of parasite dynamics (Leathwick et al., 2009), including the development of eggs in faeces, egg laying by adult worms, the development and/or maintenance of anti-parasite immunity and the survival and/or fecundity of those parasites which survive exposure to the anthelmintic (Leathwick, 2004). Interpreting the risks of selecting anthelmintic resistance by use of longacting anthelmintics is complex and the best indications undoubtedly come from these empirical studies. The risks associated with the use of long-acting anthelmintics can often be reduced, although not completely eliminated, by the administration of an effective treatment (“exit” or “tail cutter” drench) close to the end of the product’s period of persistent efficacy (Leathwick, unpublished data). This treatment functions to remove those resistant genotype worms which have been able to establish in the treated animals over the period where the product’s persistent effect prevents establishment of susceptible genotypes. 6.2. Routes of administration The routes by which anthelmintics are administered to different stock classes are largely influenced by practical issues (McKellar and Gokbulut, 2012) with sheep and goats generally treated orally, but cattle by either injection or pour-on (topical) treatments. In many countries the cattle anthelmintic market is dominated by pour-on products, presumably because they offer ease of application and a lower risk of injury for both users and animals. However, the bioavailability of anthelmintics after pour-on administration is generally much lower than after subcutaneous injection or oral delivery (Forsyth et al., 1983; Lifschitz et al., 1999; Sallovitz et al., 2005; Gokbulut et al., 2010; Leathwick and Miller, 2013), and delivery of the active via the pour-on route is inherently variable due to differences between animals and irregular absorption from the site of application (McKellar and Gokbulut, 2012). In addition, very large differences in pharmacokinetics and efficacy of pour-on products can occur as a result of oral absorption through self-licking, or through licking other animals (Laffont et al., 2003; Bousquet-Mélou et al., 2004, 2011; Sallovitz et al., 2005). The potentially lower bioavailability

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and increased variability must be expected to lead to the possibility of increased selection for anthelmintic resistance, due to significant under-dosing in a proportion of the treated animals. Somewhat surprisingly, Leathwick and Miller (2013) found that moxidectin administered as a subcutaneous injection was no more effective, and no less variable, against mainly macrocyclic lactone-resistant populations of C. oncophora than was moxidectin pour-on. However, in this study moxidectin administered orally was significantly more effective and significantly less variable than both the pour-on and injectable administrations. Given that the same worm populations were tested in all cases, it is presumed that higher concentrations of moxidectin reached the target worms in the small intestine following oral administration (Leathwick and Miller, 2013), a conclusion supported by the finding of a recent study in sheep (Lloberas et al., 2012). Evidence is mounting that the route by which anthelmintics are administered is important in the development of resistance. For gastrointestinal nematodes it appears that oral administration delivers the highest dose of drug to the target worms, and this is often associated with higher efficacy against resistant worm genotypes than either pour-on or injection routes (Gopal et al., 2001; Lloberas et al., 2012; Leathwick and Miller, 2013). Combined with the shorter period of declining drug profile, and therefore a reduced opportunity for ‘tail’ selection, the use of oral anthelmintics would appear least likely to select for resistance. 6.3. Combination anthelmintics Combination anthelmintics (products containing two or more actives with similar spectra of activity) have several advantages (Leathwick et al., 2009). Firstly, in the presence of widespread resistance, combinations often achieve acceptable levels of worm control (McKenna, 2010). This enables the continued use of actives which, on their own, are not sufficiently effective. For example, in New Zealand, the very high prevalence of resistance to both macrocyclic lactone and benzimidazole anthelmintics in C. oncophora has resulted in the widespread use of combination products containing levamisole along with a benzimidazole and/or macrocyclic lactone active. The use of combinations in situations such as this can have significant financial advantages over the use of new anthelmintic classes (monepantel and derquantel where these are available) which are considerably more expensive than combinations of the older classes. The continued use of the older anthelmintic classes will also be important in minimising the development of resistance to these new anthelmintics. There is now compelling evidence that use of combinations, especially when they are introduced before resistance becomes evident, will slow the development of resistance (Leathwick et al., 2009, 2012; Dobson et al., 2011b; Bartram et al., 2012; Geary et al., 2012). A comprehensive range of dual and triple combination products are available for use in sheep and cattle in some countries, including Australia and New Zealand (Bartram et al., 2012). The registration of combinations is not permitted in many regions (Geary et al., 2012), but they have been widely

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adopted in Australasia, largely as a response to the high prevalence of resistance, but also in many cases because they provide a resistance management benefit. It will be interesting to see whether over time, combination anthelmintics have a major impact on resistance development in countries where they are used extensively, in comparison to those where they are not available. However, as with all anthelmintics, there are potential disadvantages with the use of combinations, and these have recently been reviewed by Geary et al. (2012). Briefly, in the absence of an adequate level of refugia of unselected parasites, the use of combination anthelmintics has the potential to select for the development of resistance to several actives simultaneously, hence reducing the range of anthelmintic options. It is, therefore, essential that use of combinations is not seen as a sole solution to anthelmintic resistance, and that their use is part of an integrated package of resistance management strategies. Unfavourable pharmacokinetic or pharmacodynamic interactions between constituent actives or excipients are possible and must be considered, however, these can largely be addressed as part of the product registration process. The possibility of a shared mechanism for resistance between the benzimidazole and macrocyclic lactone classes of anthelmintics has been suggested, and used as an argument against using these actives in combination (Mottier and Prichard, 2008). However, if there is a shared resistance mechanism between these, or any other classes of anthelmintic, then it will impact on the development of resistance regardless of how the actives are used. To address this issue, Leathwick (2012) modelled a scenario where resistance to each of two actives was polygenic, with one of the genes conferring resistance to both. In this study, using the two actives in combination was still superior at slowing the development of resistance than using each active separately in an annual rotation. This kind of analysis is important because, unfortunately, new actives come to market without a detailed knowledge of the resistance mechanisms and decisions about how best to use them are invariably made without access to these data. Finally, both modelling (Leathwick, 2012) and field trials (Leathwick et al., 2012) indicate that combinations lose their ability to delay the development of resistance as the frequency of resistance genes increases (Leathwick et al., 2009), although the extent to which this occurs appears to be influenced by the size of the population in ‘refugia’. This latter point may be relevant to recent experiences on New Zealand sheep farms which indicate that a total reliance on the use of combinations, in conjunction with other resistance management practices aimed at retaining refugia of susceptibility, does not increase the severity of resistance, even when overt resistance to multiple anthelmintic classes is already present (Leathwick, unpublished data). 6.4. Strategic use of new anthelmintic classes One of the opportunities presented by the development and registration of new anthelmintic classes (e.g. monepantel and derquantel) is to use them strategically to help preserve, where this is still feasible, efficacy of the older

classes. In New Zealand, a strategy has been developed where a single treatment with a new active, as part of a programme of 5–7 preventive treatments to lambs (Lawrence et al., 2007), has the potential to slow the emergence of resistance to the anthelmintic(s) used for the routine treatments (Leathwick and Hosking, 2009). Because most adult worms live much longer than the 28–30-day drenching interval, resistant worms surviving treatment with one or more of the older classes can accumulate over the course of this programme. A single treatment with an anthelmintic from a new class at the beginning of autumn should prevent any accumulated resistant worms from passing eggs onto pasture at a time when conditions are favourable for development to the infective larval stage. This will minimise their contribution to future generations of worms and slow the development of resistance (Leathwick and Hosking, 2009). This practice has been widely promoted in New Zealand and has been adopted by a proportion of farmers.

7. Prevention of the introduction of resistant nematodes The potential for importing resistant genotype parasites with brought in stock is intuitively obvious and requires little empirical justification. As the prevalence of resistance has increased around the world, so too has the probability that animals transferred between farms will introduce anthelmintic-resistant worms. “Quarantine” treatments for introduced stock have been widely advocated (Prichard et al., 1980; Coles and Roush, 1992), with the aim of completely removing the worm burden. High anthelmintic efficacy is obviously essential and may require a combination of available anthelmintics. Because any surviving worms are likely to be resistant to several anthelmintic groups, treated animals should then be grazed on nematode-contaminated pastures to allow maximum dilution of any surviving resistant genotypes. Analysis of data from two surveys conducted in New Zealand indicated that sheep farms which had introduced large numbers of purchased stock were significantly more likely to test positive for ivermectin resistance than those that did not have such introductions (Lawrence et al., 2006; Hughes et al., 2007). Similarly, Suter et al. (2004) linked the prevalence of ivermectin resistance in Western Australia with the failure of farmers to quarantine-treat stock after purchasing a farm. These data support the view that failure to adequately quarantine-treat livestock is responsible for the transfer of anthelmintic-resistance problems between sheep farms, and it must be expected that this also inadvertently occurs between cattle properties. Surprisingly, survey data shows that a large proportion of sheep farmers throughout the world continue to import stock onto their farms with no quarantine treatment (Suter et al., 2004; Lawrence et al., 2007; Morgan et al., 2012). The failure by many livestock owners to adopt the relatively simple quarantine strategy implies that convincing them to implement more complex resistance management measures is likely to be challenging (Besier and Love, 2012).

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8. Implementation of recommendations Experiences with sheep farmers in both New Zealand and Australia indicate that acceptance and implementation of resistance management practices on farm is relatively easy as long as the need to do so is clear and the recommended practices meet the farmer’s criteria for practicality (Bath, 2006; Kahn and Woodgate, 2012). For example, in New Zealand the concept of leaving a proportion of adult sheep untreated as a source of refugia is easy for farmers to understand and implement and most are willing to do so (Leathwick, pers. obsn.). In contrast, leaving lambs untreated is unlikely to be accepted on the large hill country farms typical of New Zealand sheep farms, or in Australia, both on practicality grounds and due to the risk of productivity loss. Hence, for New Zealand and Australian sheep farmers, the key to ensuring adoption of resistance management practices appears to be in having good supporting evidence for recommended changes, and in promoting changes which a farmer can implement without significant disruption. 9. Conclusions On sheep farms throughout Australasia anthelmintic resistance is the status quo rather than the exception, and the majority of farmers are aware of the need to take appropriate action. Field trials have measured the direct cost in lost income from using an anthelmintic product which is less than fully effective due to resistance to be about 10% of product value, and this occurred despite few visual signs of parasitism. This magnitude of loss far exceeds the cost of routinely testing anthelmintic efficacy, yet the proportion of farmers who test, even on an irregular basis, remains surprisingly small. Many years of research into the development and management of anthelmintic resistance in sheep parasites has resulted in a portfolio of strategies for minimising resistance development. Although much of the early understanding of resistance management was derived from modelling studies many of the strategies promoted to farmers today have been validated in field trials. This validation gives confidence that the advice given to farmers is sound, and supports a greater likelihood that farmers will implement recommendations with a sound empirical basis. A major difference between Australasia and many other countries is the availability and widespread acceptance of combination anthelmintics as a resistance management tool. Few sheep farmers in either country would not accept combinations, and in New Zealand the use of combinations in cattle is also common. It will be interesting to see in the future whether there are measureable consequences for resistance development which can be attributed to this difference in approach. The current situation in cattle and horses in many countries indicates a failure to learn the lessons from resistance development in small ruminants. Despite research in sheep and goats over several decades in Australasia, the cattle and equine industries have remained generally oblivious to the issue of anthelmintic resistance and the need to take pre-emptive action. As in other countries,

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a perception was held that resistance in cattle parasites would develop very slowly, if it developed at all. Clearly such preconceptions are incorrect and anthelmintic resistance must be considered a threat in all countries, situations and host species, where anthelmintics are used routinely to control parasites. The challenge ahead for the cattle and equine industries will be to maximise the advantages for resistance management from the extensive body of research and experience gained in small ruminants. Conflict of interest statement The authors declare that they have no conflict of interest relating to this paper. Acknowledgements We thank Ian Sutherland for helpful comments on a draft manuscript and Alan Marchiondo and his colleges for organising this special journal issue on this important subject. References Barger, I.A., 1982. Helminth parasites and animal production. In: Symons, L.E., Donald, A.D., Dineen, J.K. (Eds.), Biology and Control of Endoparasites. Academic Press, Sydney, Australia, pp. 133–155. Barnes, E.H., Dobson, R.J., Barger, I.A., 1995. Worm control and anthelmintic resistance: adventures with a model. Parasitol. Today 11, 56–63. Bartram, D.J., Leathwick, D.M., Geurden, T., Taylor, M.A., Maeder, S.J., 2012. The role of combination anthelmintic formulations in the sustainable control of roundworms of sheep. Vet. Parasitol. 186, 151–158. Bath, G.F., 2006. Practical implementation of holistic internal parasite management in sheep. Small Rumin. Res. 62, 13–18. Besier, R.B., 2007. New anthelmintics for livestock: the time is right. Trends Parasitol. 23, 21–24. Besier, R.B., 2008. Targeted treatment strategies for sustainable worm control in small ruminants. In: Tropical Biomedicine (25 (Supplement): Proceedings of the 5th International workshop; novel approaches to the control of helminth parasites of livestock, Ipoh, Malaysia, 26–29th February, pp. 9–17. Besier, R.B., 2012. Refugia-based strategies for sustainable worm control: factors affecting the acceptability to sheep and goat owners. Vet. Parasitol. 186, 2–9. Besier, R.B., Hopkins, D.L., 1988. Anthelmintic dose selection by farmers. Aust. Vet. J. 65, 193–194. Besier, R.B., Love, S.C.J., 2003. Anthelmintic resistance in sheep nematodes in Australia: the need for new approaches. Aust. J. Exp. Agric. 43, 1383–1391. Besier, R.B., Love, S.C.J., 2012. Advising on helminth control in sheep: it’s the way we tell them. Vet. J. 193, 2–3. Besier, R.B., Moir, D., Holm-Glass, M., 1995. The dollar cost of drench resistance. Proc. Aust. Sheep Vet. Soc. (Melbourne), 154–157. Besier, R.B., Palmer, D.G., Woodgate, R.G., 2001. New recommendations for sustainable strategic drenching. Proc. Aust. Sheep Vet. Soc. (Melbourne) 11, 32–36. Besier, R.B., Love, R.J., Lyon, J., van Burgel, A.J., 2010. A targeted selective treatment approach for effective and sustainable sheep worm management: investigations in Western Australia. Anim. Prod. Sci. 50, 1034–1042. Borges, F.A., Almeida, G.D., Heckler, R.P., Lemes, R.T., Onizuka, M.K.V., Borges, D.G.L., 2013. Anthelmintic resistance impact on tropical beef cattle productivity: effect on weight gain of weaned valves. Trop. Anim. Health Prod. 45, 723–727. Bousquet-Mélou, A., Mercadier, S., Alvinerie, M., Toutain, P.-L., 2004. Endectocide exchanges between grazing cattle after pour-on administration of doramectin, ivermectin and moxidectin. Int. J. Parasitol. 34, 1299–1307. Bousquet-Mélou, A., Jacquiet, P., Hoste, H., Clément, J., Bergeaud, J.P., Alvinerie, M., Toutain, P.L., 2011. Licking behaviour induces partial anthelmintic efficacy of ivermectin pour-on formulation in untreated cattle. Int. J. Parasitol. 41, 563–569.

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G Model VETPAR-7072; No. of Pages 11 10

ARTICLE IN PRESS D.M. Leathwick, R.B. Besier / Veterinary Parasitology xxx (2014) xxx–xxx

Brunsdon, R.V., 1980. Principles of helminth control. Vet. Parasitol. 6, 185–215. Brunsdon, R.V., Kissling, R., Hosking, B.C., 1983. A survey of anthelmintic usage for sheep: a time for change? N. Z. Vet. J. 31, 24–29. Busin, V., Kenyon, F., Laing, N., Denwood, M.J., McBean, D., Sargison, N.D., Ellis, K., 2013. Addressing sustainable sheep farming: application of a targeted selective treatment approach for anthelmintic use on a commercial farm. Small Rumin. Res. 110, 100–103. Cawthorne, R.J.G., Whitehead, J.D., 1983. Isolation of benzimidazole resistant strains of Ostertagia circumcincta from British sheep. Vet. Rec. 112, 274–277. Cleale, R.M., Hart, K.B., Hutchens, D.E., Johnson, E.G., Paul, A.J., Smith, L.L., Tucker, C., Yazwinski, T.A., Doscher, M.E., Grubbs, S.T., WulsterRadcliffe, M., Amodie, D.M., 2004. Effects of subcutaneous injections of a long-acting moxidectin formulation in grazing beef cattle on parasite fecal egg reduction and animal weight gain. Vet. Parasitol. 126, 325–338. Coles, G.C., Roush, R.T., 1992. Slowing the spread of anthelmintic nematodes of sheep and goats in the United Kingdom. Vet. Rec. 130, 505–510. Cringoli, G., Rinaldia, L., Veneziano, V., Mezzino, L., Vercruysse, J., Jackson, F., 2009. Evaluation of targeted selective treatments in sheep in Italy: effects on faecal worm egg count and milk production in four case studies. Vet. Parasitol. 164, 36–43. Dobson, R.J., le Jambre, L.F., Gill, J.H., 1996. Management of anthelmintic resistance: inheritance of resistance and selection with persistent drugs. Int. J. Parasitol. 26, 993–1000. Dobson, R.J., Barnes, E.H., Tyrrell, K.L., Hosking, B.C., Larsen, J.W.A., Besier, R.B., Love, S., Rolfe, P.F., Bailey, J.N., 2011a. A multi-species model to assess the impact of refugia on worm control and anthelmintic resistance in sheep grazing systems. Aust. Vet. J. 89, 200–208. Dobson, R.J., Hosking, B., Besier, R.B., Love, S.C.J., Larsen, J., Rolfe, P.F., Bailey, J.N., 2011b. Minimising the development of anthelmintic resistance, and optimising the use of the novel anthelmintic monepantel, for the sustainable control of nematode parasites in Australian sheep grazing systems. Aust. Vet. J. 89, 160–166. Forsyth, B.A., Gibbon, A.J., Pryor, D.E., 1983. Seasonal variation in anthelmintic response by cattle to dermally applied levamisole. Aust. Vet. J. 60, 141–146. Gaba, S., Cabaret, J., Sauve, C., Silvestre, A., 2010. Experimental and modeling aproaches to evaluate different aspects of the efficacy of targeted selective treatment of anthelmintics against sheep parasitic nematodes. Vet. Parasitol. 171, 254–262. Gasbarre, L.C., Smith, L.L., Lichtenfels, J.R., Pilitt, P.A., 2009. The identification of cattle nematode parasites resistant to multiple classes of anthelmintics in a commercial cattle population in the US. Vet. Parasitol. 166, 281–285. Geary, T.G., Hosking, B.C., Skuce, P.J., von Samson-Himmelstjerna, G., Maeder, S., Holdsworth, P., Pomroy, W., Vercruysse, J., 2012. World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.) Guideline: anthelmintic combination products targeting nematode infections of ruminants and horses. Vet. Parasitol. 190, 306–316. Gogolewski, R.P., Rugg, D., Allerton, G.R., Kawhia, D., Barrick, R.A., Eagleson, J.S., 1997. Demonstration of the sustained anthelmintic efficacy of a controlled-release capsule formulation of ivermectin in ewes under field conditions in New Zealand. N. Z. Vet. J. 45, 163–166. Gokbulut, C., Cirak, V.Y., Senlik, B., Aksit, D., Durmaz, M., McKellar, Q.A., 2010. Comparative plasma disposition, bioavailability and efficacy of ivermectin following oral and pour-on administration in horses. Vet. Parasitol. 170, 120–127. González, A., Sahagún, A., Diez, M.J., Fernández, N., Sierra, M., García, J.J., 2009. The pharmacokinetics and metabolism of ivermectin in domestic animal species. Vet. J. 179, 25–37. Gopal, R.M., West, D.M., Pomroy, W.E., 2001. The difference in efficacy of ivermectin oral, moxidectin oral and moxidectin injectable formulations against an ivermectin-resistant strain of Trichostrongylus colubriformis. N. Z. Vet. J. 49, 133–137. Greer, A.W., McAnulty, R.W., Gibbs, S.J., 2010. Performance-based targeted selective anthelmintic treatment regime for grazing dairy calves. In: Proc. 4th Aust. Dairy Sci. Sym, pp. 385–389. Greer, A.W., Kenyon, F., Bartley, D.J., Jackson, E.B., Gordon, Y., Doonan, A.A., McBean, D.W., Jackson, F., 2009. Development and field evaluation of a decision support model for anthelmintic treatments as part of a targeted selective treatment (TST) regime in lambs. Vet. Parasitol. 164, 12–20. Höglund, J., Dahlström, F., Sollenberg, S., Hessle, A., 2013. Weight gain-based targeted selective treatments (TST) of gastrointestinal nematodes in first-season grazing cattle. Vet. Parasitol. 196, 358–365.

Hoste, H., Le Frileux, Y., Pommaret, A., 2002. Comparison of selective and systematic treatments to control nematode infection of the digestive tract in dairy goats. Vet. Parasitol. 106, 345–355. Hughes, P.L., Dowling, A.F., Callinan, A.P.L., 2007. Resistance to macrocyclic lactone anthelmintics and associated risk factors on sheep farms in the lower North Island of New Zealand. N. Z. Vet. J. 55, 177–183. Jackson, R., Rhodes, A.P., Pomroy, W.E., Leathwick, D.M., West, D.M., Waghorn, T.S., Moffat, J.R., 2006. Anthelmintic resistance and management of nematode parasites on beef cattle-rearing farms in the North Island of New Zealand. N. Z. Vet. J. 54, 289–296. Kahn, L.P., Woodgate, R.G., 2012. Integrated parasite management: products for adoption by the Australian sheep industry. Vet. Parasitol. 186, 58–64. Kaplan, R.M., 2004. Drug resistance in nematodes of veterinary importance: a status report. Trends Parasitol. 20, 477–481. Kaplan, R.M., Vidyashankar, A.N., 2012. An inconvenient truth: global worming and anthelmintic resistance. Vet. Parasitol. 186, 70–78. Kenyon, F., Jackson, F., 2012. Targeted flock/herd and individual ruminant treatment approaches. Vet. Parasitol. 186, 10–17. Kenyon, F., McBean, D., Greer, A.W., Burgess, G.S., Morrison, A.A., Bartley, D.J., Bartley, Y., Devin, L., Nath, M., Jackson, F., 2013. A comparative study of the effects of four treatment regimes on ivermectin efficacy, body weight and pasture contamination in lambs naturally infected with gastrointestinal nematodes in Scotland. Int. J. Parasitol. Drugs Drug Resist. 3, 77–84. Laffont, C.M., Bousquet-Mélou, A., Bralet, D., Alvinerie, M., Fink-Gremmels, J., Toutain, P.-L., 2003. A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle. Vet. Res. 34, 445–460. Lawrence, K.E., Rhodes, A.P., Jackson, R., Leathwick, D.M., Heuer, C., Pomroy, W.E., West, D.M., Waghorn, T.S., Moffat, J.R., 2006. Farm management practices associated with macrocyclic lactone resistance on sheep farms in New Zealand. N. Z. Vet. J. 54, 283–288. Lawrence, K.E., Leathwick, D.M., Rhodes, A.P., Jackson, R., Heuer, C., Pomroy, W.E., West, D.M., Waghorn, T.S., Moffat, J.R., 2007. Management of gastrointestinal nematode parasites on sheep farms in New Zealand. N. Z. Vet. J. 55, 228–234. Leathwick, D.M., 2004. Long-acting drenches and drench resistance. In: Proc. 34th Sem., Sheep Beef Cattle Soc., N.Z. Vet. Assoc, pp. 41–52. Leathwick, D.M., 2012. Modelling the benefits of releasing a new class of anthelmintic in combination. Vet. Parasitol. 186, 93–100. Leathwick, D.M., 2013. Sustainable control of nematode parasites—a New Zealand perspective. Small Rumin. Res., http://dx.doi.org/10.1016/ j.smallrumres.2013.12.020. Leathwick, D.M., Sutherland, I.A., 2002. Heads or tails—which drench do i choose? In: Proc. 32nd Sem. Soc. Sheep and Beef Cattle Soc., N.Z. Vet. Assoc, pp. 115–127. Leathwick, D.M., Hosking, B.C., 2009. Managing anthelmintic resistance: modelling strategic use of a new anthelmintic class to slow the development of resistance to existing classes. N. Z. Vet. J. 57, 203–207. Leathwick, D.M., Miller, C.M., 2013. Efficacy of oral, injectable and pouron formulations of moxidectin against gastrointestinal nematodes in cattle in New Zealand. Vet. Parasitol. 191, 293–300. Leathwick, D.M., Vlassoff, A., Barlow, N.D., 1995. A model for nematodiasis in New Zealand lambs: the influence of drenching and grazing management on the development of anthelmintic resistance. Int. J. Parasitol. 25, 1479–1491. Leathwick, D.M., Sutherland, I.A., Vlassoff, A., 1997. Persistent drugs and anthelmintic resistance—part III. N. Z. J. Zool. 24, 298–299. Leathwick, D.M., Pomroy, W.E., Heath, A.C.G., 2001. Anthelmintic resistance in New Zealand. N. Z. Vet. J. 49, 227–235. Leathwick, D.M., Miller, C.M., Atkinson, D.S., Haack, N.A., Alexander, R.A., Oliver, A.-M., Waghorn, T.S., Potter, J.F., Sutherland, I.A., 2006a. Drenching adult ewes: Implications of anthelmintic treatments preand post-lambing on the development of anthelmintic resistance. N. Z. Vet. J. 54, 297–304. Leathwick, D.M., Waghorn, T.S., Miller, C.M., Atkinson, D.S., Haack, N.A., Oliver, A.-M., 2006b. Selective and on-demand drenching of lambs: impact on parasite populations and performance of lambs. N. Z. Vet. J. 54, 305–312. Leathwick, D.M., Miller, C.M., Atkinson, D.S., Haack, N.A., Waghorn, T.S., Oliver, A.-M., 2008. Managing anthelmintic resistance: untreated adult ewes as a source of unselected parasites, and their role in reducing parasite populations. N. Z. Vet. J. 56, 184–195. Leathwick, D.M., Hosking, B.C., Bisset, S.A., McKay, C.H., 2009. Managing anthelmintic resistance—is it feasible in New Zealand to delay the emergence of resistance to a new anthelmintic class? N. Z. Vet. J. 57, 181–192. Leathwick, D.M., Waghorn, T.S., Miller, C.M., Candy, P.M., Oliver, A.M.B., 2012. Managing anthelmintic resistance—use of a combination

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anthelmintic and leaving some lambs untreated to slow the development of resistance to ivermectin. Vet. Parasitol. 187, 285–294. Leigh, J., Hunnam, J., 2013. The effect of ML resistant Cooperia in healthy cattle. In: Proc. N. Z. Vet. Assoc. Conf, pp. 247–251. le Jambre, L.F., Dobson, R.J., Lenane, I.J., Barnes, E.H., 1999. Selection for anthelmintic resistance by macrocyclic lactones in Haemonchus contortus. Int. J. Parasitol. 29, 1101–1111. Lifschitz, A., Virkel, G., Imperiale, F., Sutra, J.F., Galtier, P., Lanusse, C., Alvinerie, M., 1999. Moxidectin in cattle: correlation between plasma and target tissues disposition. J. Vet. Pharmacol. Ther. 22, 266–273. Lifschitz, A., Virkel, G., Ballent, M., Sallovitz, J., Imperiale, F., Pis, A., Lanusse, C., 2007. Ivermectin (3.15%) long-acting formulations in cattle: absorption pattern and pharmacokinetic considerations. Vet. Parasitol. 147, 303–310. Lloberas, M., Alvarez, L., Entrocasso, C., Virkel, G., Lanusse, C., Lifschitz, A., 2012. Measurement of ivermectin concentrations in target worms and host gastrointestinal tissues: Influence of the route of administration on the activity against resistant Haemonchus contortus in lambs. Exptl. Parasitol. 131, 304–309. Martin, P.J., 1989. Selection for thiabendazole resistance in Ostertagia spp. by low efficiency anthelmintic treatment. Int. J. Parasitol. 19, 317–325. Martin, P.J., le Jambre, L.F., Claxton, J.H., 1981. The impact of refugia on the development of thiabendazole resistance in Haemonchus contortus. Int. J. Parasitol. 11, 35–41. McKellar, Q.A., Gokbulut, C., 2012. Pharmacokinetic features of the antiparasitic macrocyclic lactones. Curr. Pharma Biotech. 13, 888–911. McKenna, P.B., 2010. Update on the prevalence of anthelmintic resistance in gastrointestinal nematodes of sheep in New Zealand. N. Z. Vet. J. 58, 172–173. McMahon, C., McCoy, M., Ellison, S.E., Barley, J.P., Edgar, H.W.J., Hanna, R.E.B., Malone, F.E., Brennan, G.P., Fairweather, I., 2013. Anthelmintic resistance in Northern Ireland (III): Uptake of ‘SCOPS’ (sustainable control of parasites in sheep) recommendations by sheep farmers. Vet. Parasitol. 193, 179–184. Michel, J.F., 1985. Strategies for the use of anthelmintics in livestock and their implications for the development of drug resistance. Parasitology 90, 621–628. Miller, C.M., Waghorn, T.S., Leathwick, D.M., Candy, P.M., Oliver, A-M.B., Watson, T.G., 2012. The production cost of anthelmintic resistance in lambs. Vet. Parasitol. 186, 376–381. Molento, M.B., 2009. Parasite control in the age of drug resistance and changing agricultural practices. Vet. Parasitol. 163, 229–234. Morgan, E.R., Hosking, B.C., Burston, S., Carder, K.M., Hyslop, A.C., Pritchard, L.J., Whitmarsh, A.K., Coles, G.C., 2012. A survey of helminth control practices on sheep farms in Great Britain and Ireland. Vet. J. 192, 390–397. Mottier, L., Prichard, R.K., 2008. Genetic analysis of a relationship between macrocyclic lactone and benzimidazole anthelmintic selection on Haemonchus contortus. Pharmacogenet. Genom. 18, 129–140. Nielsen, M.K., 2012. Sustainable equine parasite control: perspectives and research needs. Vet. Parasitol. 185, 32–44. Nielsen, M.K., Kaplan, R.M., Thamsborg, S.M., Monrad, J., Olsen, S.N., 2007. Climatic influences on development and survival of free-living stages of equine strongyles: Implications for worm control strategies and managing anthelmintic resistance. Vet. J. 174, 23–32. Pech, C.L., Doole, G.D., Pluske, J.M., 2009. Economic management of anthelmintic resistance: model and application. Aust. J. Agric. Res. Econ. 53, 585–602. Playford, M.C, Smith, A.N., Love, S., Besier, R.B., Kluver, P., Bailey, J.N. Prevalence of anthelmintic resistance in sheep nematodes in Australia 2009-2012. Aust. Vet. J. (submitted 2013). Pomroy, W.E., 2006. Anthelmintic resistance in New Zealand: a perspective on recent findings and options for the future. N. Z. Vet. J. 54, 265–270. Prichard, R.K., Hall, C.A., Kelly, J.D., Martin, I.C.A., Donald, A.D., 1980. The problem of anthelmintic resistance in nematodes. Aust. Vet. J. 56, 239–251. Rogers, C.W., Gee, E.K., Firth, E.C., 2007. A cross-sectional survey of Thoroughbred stud farm management in the North Island of New Zealand. N. Z. Vet. J. 55, 302–307.

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Sallovitz, J.M., Lifschitz, A., Imperiale, F., Virkel, G., Larghi, J., Lanusse, C., 2005. Doramectin concentration profiles in the gastrointestinal tract of topically-treated calves: Influence of animal licking restriction. Vet. Parasitol. 133, 61–70. Sargison, N., Wilson, D., Scott, P., 2009. Relative inefficacy of pour-on macrocyclic lactone anthelmintic treatments against Cooperia species in Highland calves. Vet. Rec. 164, 603–604. Stafford, K.A., Morgan, E.R., Coles, G.C., 2009. Weight-based targeted selective treatment of gastro-intestinal nematodes in a commercial sheep flock. Vet. Parasitol. 164, 59–65. Suter, R.J., Besier, R.B., Perkins, N.R., Robertson, I.D., Chapman, H.M., 2004. Sheep-farm risk factors for ivermectin resistance in Ostertagia circumcincta in Western Australia. Prev. Vet. Med. 63, 257–269. Sutherland, I.A., Leathwick, D.M., 2011. Anthelmintic resistance in nematode parasites of cattle: a global issue? Trends Parasitol. 27, 176–181. Sutherland, I.A., Brown, A.E., Leathwick, D.M., Bisset, S.A., 2003. Resistance to prophylactic treatment with macrocyclic lactone anthelmintics in Teladorsagia circumcincta. Vet. Parasitol. 115, 301–309. Sutherland, I.A., Bailey, J.N., Shaw, R.J., 2010. The production costs of anthelmintic resistance in sheep managed within a monthly preventive drench program. Vet. Parasitol. 171, 300–304. Taylor, M.A., Hunt, K.R., 1989. Anthelmintic drug resistance in the UK. Vet. Rec. 125, 143–147. van Wyk, J.A., 2001. Refugia—overlooked as perhaps the most potent factor concerning the development of anthelmintic resistance. Onderstepoort J. Vet. Res. 68, 55–67. van Wyk, J.A., Bath, G.F., 2002. The FAMACHA system for managing haemonchosis in sheep and goats by clinically identifying individual animals for treatment. Vet. Res. 33, 509–529. van Wyk, J.A., Hoste, H., Kaplan, R.M., Besier, R.B., 2006. Targeted selective treatment for worm management—how do we sell rational programs to farmers? Vet. Parasitol. 139, 336–346. Van Wyk, J.A., Riley, D.G., 2009. Genetic parameters for FAMACHA© score and related traits for host resistance/resilience and production at differing severities of worm challenge in a Merino flock in South Africa. Vet. Parasitol. 64, 44–52. Waghorn, T.S., Leathwick, D.M., Rhodes, A.P., Jackson, R., Pomroy, W.E., West, D.M., Moffat, J.R., 2006a. Prevalence of anthelmintic resistance on 62 beef cattle farms in the North Island of New Zealand. N. Z. Vet. J. 54, 278–282. Waghorn, T.S., Leathwick, D.M., Rhodes, A.P., Lawrence, K.E., Jackson, R., Pomroy, W.E., West, D.M., Moffat, J.R., 2006b. Prevalence of anthelmintic resistance on sheep farms in New Zealand. N. Z. Vet. J. 54, 271–277. Waghorn, T.S., Leathwick, D.M., Miller, C.M., Atkinson, D.S., 2008. Brave or gullible: testing the concept that leaving susceptible parasites ‘in refugia’ will slow the development of anthelmintic resistance. N. Z. Vet. J. 56, 158–163. Waghorn, T.S., Miller, C.M., Oliver, A-M.B., Leathwick, D.M., 2009. Drenchand-shift is a high risk practice in the absence of refugia. N. Z. Vet. J. 57, 359–363. Waghorn, T.S., Reynecke, D.P., Oliver, A-M.B., Miller, C.M., Vlassoff, A., Koolard, J.P., Leathwick, D.M., 2011. Dynamics of the free-living stages of sheep intestinal parasites on pasture in the North Island of New Zealand. 1. Patterns of seasonal development. N. Z. Vet. J. 59, 279–286. Waller, P.J., 1994. The development of anthelmintic resistance in ruminant livestock. Acta Trop. 56, 233–243. Waller, P.J., 2006. From discovery to development: current industry perspectives for the development of novel methods of helminth control in livestock. Vet. Parasitol. 139, 1–14. Woodgate, R.G., Besier, R.B., 2010. Sustainable use of anthelmintics in an Integrated Parasite Management Program for sheep nematodes. Anim. Prod. Sci. 50, 440–443. Woodgate, R.G., Love, S., Knox, M.R., Besier, R.B., le Jambre, L.F., 2012. WormKill to WormBoss—can we sell sustainable sheep worm control? Vet. Parasitol. 186, 51–57. Young, R.R., 1983. Populations of free-living stages of Ostertagia ostertagi and O. circumcincta in a winter rainfall region. Aust. J. Agric. Res. 34, 569–581.

Please cite this article in press as: Leathwick, D.M., Besier, R.B., The management of anthelmintic resistance in grazing ruminants in Australasia—Strategies and experiences. Vet. Parasitol. (2014), http://dx.doi.org/10.1016/j.vetpar.2013.12.022