In terms of their mode of action the current broad-spectrum wormers fall into three classes of drugs.

The table at the end of the newsheet details a selection of the broad-spectrum anthelmintics available for sheep and goats. Resistant worms have been recorded to all three drug classes in sheep and goats. These selected isolates usually show 'side resistance' (i.e. resistance to other drugs within the same category/class). 'Multiple resistance' also occurs (worms showing resistance to two or more drugs from different categories/classes).

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Although most farmers will be familiar with the term selection as a process to seek beneficial traits in their animals, the same process can also produce disadvantageous traits such as the selection of the genes related to drug resistance in worms. Resistance arises when there is a change in the susceptibility of the worm population to the drug or drugs used to control them. The gene or genes that are associated with anthelmintic resistance (AR) occur naturally at very low frequencies within the parasite population. When a drug is first introduced then the vast majority of the worm population is fully susceptible (homozygous susceptible) to the drug, a small proportion carries some of the genes that confer resistance (heterozygous resistant) and a tiny number of worms may be fully resistant (homozygous resistant). When worms are exposed to anthelmintics then only those individuals that carry the AR gene(s) will survive and pass these resistant genes onto their offspring. As resistance increases a greater proportion of the worm population will carry these genes and be able to survive treatment. Because anthelmintic resistance arises through selection the rate at which it develops on a farm will vary according to the frequency of resistance genes within the treated population and the selection pressure applied to that population.

At any given time only a small percentage of the total parasite population is normally resident within the host, the majority of the population being present on grass as worm eggs, developing larvae and infective larvae. Each time animals are treated with an anthelmintic only highly resistant worms (homozygous resistant individuals) survive and for about three weeks after treatment (the time that it takes for reinfection and maturation within the host to occur) only resistant eggs are passed onto the pasture. In this way the proportion of resistant individuals within the population increases very slightly but if treatments are well spaced out the rate of selection will be sufficiently slow to be virtually negligible. However, if we treat frequently (every 3-4 weeks) then we exert a high selection pressure and resistance may develop quite quickly.

Underdosing animals also increases the rate of selection simply by enabling worms that carry some of the genes (heterozygous resistant individuals) that confer resistance to survive. The manufacturer's recommended dose rate for a drug are set so that it kills all of the heterozygous and homozygous susceptible worms. If animals are underdosed then some of the heterozygous resistant individuals survive and thus increase the frequency of resistance genes within the total population. In this way underdosing exerts a strong selection pressure and can lead to the rapid development of resistance. The proportions of homozygous, heterozygous and susceptible individuals in the parasite population within the host and on pasture will, until some selection pressure is placed on the population, be relatively stable.

Normally the free-living population on pasture, which usually comprises the bulk of the population, provides a reservoir of susceptibility. However, under certain circumstances, the majority of the parasite population may be resident within the host rather than on the pasture. If treatments are given at such times then resistant populations may be selected rapidly, simply because the worms that survive treatment and carry the genes that confer resistance will re-populate the pasture. These conditions occur naturally in many tropical/subtropical countries where seasonal changes in climate ensure that the majority of the free-living population on pasture dies out. A similar situation exists in the UK when animals are moved post-treatment onto clean pasture or for those parasite species that cannot survive over winter on pasture.

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The free-living stages of roundworm parasites on the pasture have a limited capacity for migration and thus for practical purposes each farm represents a relatively closed environment, any movements of resistant strains being most likely to occur as a result of livestock movements.

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Selection pressure inevitably induces a change in the target population as illustrated by the selection of drug resistance. The process whereby the target population gradually moves back towards susceptibility, in cases where the selecting drug is withdrawn, is known as reversion. Reversion can occur only if the selected (resistant) population is in some way less fit to survive than the unselected (susceptible) population. Long-term studies conducted at Moredun over 15 years have addressed this question. A strain of Ostertagia was isolated in 1983 on the Institute farm which exhibited resistance to the benzimidazoles (white drenches). Since this time no benzimidazoles have been used on the farm, control of roundworms being achieved by an annual rotation between levamisole and ivermectin. The isolate was checked in 1998 for its susceptibility to benzimidazoles using a controlled efficacy test in lambs. The anthelmintic was only about 27 per cent effective at removing worms indicating that there had been no reversion to susceptibility over a 15 year period in the absence of a selecting drug. Therefore, once resistant worms are present on the farm they can be considered permanent for all practical purposes. For this reason it is important to limit the rate of development of resistance and not to allow resistance to be imported onto a farm.

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The first reports of anthelmintic resistant roundworms in the UK were published in the 1980s, since which time there have been a number of reports and surveys. In the early 1990s a detailed random survey was conducted in England and Wales. The results indicate that anthelmintic resistance is increasing in sheep flocks in England with a higher incidence of white drench (benzimidazole) resistance (44%) being recorded in the south west of England than in the North East (15%). A selective survey in Scotland indicated an overall prevalence of benzimidazole resistance of 24%. Recent surveys in England and Scotland have shown that the prevalence of benzimidazole resistance is higher in non-dairy goats (65 - 70%). All of these reports suggest that Ostertagia is the worm most commonly implicated in anthelmintic resistance in the UK with Haemonchus present on some farms, particularly in the more southern counties of England. Recently there have been reports which indicate that the range of gastrointestinal parasites showing resistance in the UK is increasing.

At present resistance is mainly confined to the benzimidazole group although there have been reports of levamisole resistance and ivermectin resistance in goats and cattle. Multiple resistance, resistance against two or more drug families, has been reported in the UK in cashmere and angora goats.

Although the total number of goats in the UK is small compared to sheep goats can play a significant role in the selection and transmission of anthelmintic resistance since the same parasites will infect both hosts.

Goats are particularly susceptible to roundworms and do not mount the same level of immune response as infected sheep; consequently goat management systems often rely heavily on frequent anthelmintic treatments. Goats also tend to be treated at the same dose rates as sheep and, because they metabolise and clear anthelmintics more rapidly than sheep, goats are often underdosed. Both increased frequency of treatment and underdosing are factors which increase the rate of selection of resistant genes and have led to the high incidence of AR in goats in the southern hemisphere.

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1. Underdosing
The drench needs to be administered accurately to obtain maximum efficacy against the worms as the dose is calculated as a volume per Kg liveweight. The manufacturers instructions should always be followed, Underdosing can lead to selection of worms which are partially resistant OM (heterozygotes) to an anthelmintic. It is important therefore to weight representative groups of sheep and then dose to the heaviest animals within the group being treated. It is better to slightly overdose than underdose. Regularly cheek that the drenching gun is delivering the correct volume of wormer (use a measuring cylinder to calibrate).
2. Increasing the Efficacy of the Drench
It is important when dosing lambs to ensure that the drench is given over the back of the tongue and not just into the mouth. The reason for this is that in a proportion of lambs an anthelmintic given into the mouth may result in the drug going down the oesophageal groove into the abomasum (4th stomach) rather than passing direct into the rumen (1st stomach) which occurs with 'over the tongue' drenching. Passage of drug directly into the abomasum can result in reduced drug uptake and lower efficacy against the worms (see Figure 1 below).

Figure 1 - The effect of rumen bypass on drench concentration

Research suggests that some oral anthelmintics work for longer in the gut if the animals rumens are relatively empty before dosing. An improvement in the efficacy of some oral anthelmintics (I-BZ; 3-AYclasses) can be obtained by short-term withdrawal of feed(see Figure 2 below). This has the effect of reducing rumen-fill which will slow the passage of the drug in the digesta and improve its uptake. Studies have shown an increase in efficacy of up to 40% for the white drenches. Try to withhold feed for 12-24 hours before drenching and for about 3 hours afterwards. This simple procedure should improve the efficacy of orally administered benzimidazoles or ivermectin. However, ewes in late pregnancy should not have their feed withheld due to the risk of inducing pregnancy toxaemia.

Figure 2 - The effect of reducing rumen fill on drench concentration

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Careful consideration needs to be given to the best options available for each farm in order to reduce anthelmintic inputs. Consult with your veterinary surgeon or sheep advisor who is familiar with the management of your farm in order to explore the potential that you have for reducing treatment frequency. It is possible on farms which have land available for conservation and/or cropping, or have sufficient cattle to operate a clean or alternate grazing system to produce 'safe' or 'clean' grazing. On farms where animals are set stocked and alternative hosts and/or land for conservation/cropping is limited the situation is more difficult. Farmers operating under these circumstances in New Zealand have monitored the faecal egg counts of their animals as a means of determining when treatments are required and thus have managed to reduce treatment frequency.

Our current understanding of the selection, transmission and prevalence of anthelmintic resistance has led to the development of a series of ground rules which should serve to minimise the selection pressure for the development of resistance.

• Reduce the frequency of drenching Consult your veterinary surgeon or sheep adviser for advice to ensure that you use the optimum number of drenches per season. Frequent suppressive drenching has been shown to increase the rate of selection for anthelminitic resistance as it allows only resistant worms to pass eggs onto the pasture.
• Adopt a rotation of anthelmintic classes Resistance to an anthelmintic is more likely to occur if the class of wormer is used year after year without any change. It is considered good policy to adopt an annual rotation (not more frequently) between the 1-BZ, 2-LV and 3-AV classes of drugs to reduce the selection pressure for development of resistance and also to maximise the potential for reversion. However, recent evidence from studies on modelling anthelmintic resistance suggests that an annual rotation may not confer additional benefit from changing the classes of drug at less frequent intervals. Within an annual rotation it may be necessary to use specific drugs for the control of tapeworm infections or sheep scab at certain times of the year.
• Ensure that you use the correct dose rates: Follow the manufacturer's instructions and do not mix different wormers together.
• Check that your drenching equipment is accurate and calibrate regularly to ensure delivery of the correct volume.
• Check stock bodyweights and dose for the heaviest animal within the group being treated.
• Use grazing strategies to reduce pasture contamination/host exposure: Provision of 'clean' or 'low-risk' pastures such as new leys or aftermaths and grazing using adult non-lactating ewes or cattle can reduce the parasite population on pasture and hence the requirement for frequent drug treatment.
• Avoid importing resistant worms: Since most anthelmintic resistance in the UK is against the benzimidzole class of drugs treat all purchased stock on arrival on your farm using drugs from the other two classes (2-LV or 3-AV) of anthelmintics. If possible hold new stock in a yard for at least 24 hours after dosing before turning out onto pasture to reduce contamination of grass with worm eggs
• Where resistance is suspected: Seek assistance to check the efficacy of your drench. Your veterinary surgeon can organise a simple faecal egg count reduction test to check the efficacy of your anthelmintic. It is worth noting that continued scouring after treatment may indicate that other infections such as coccidia could be a contributory factor.

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The best practices in cases where anthelmintic resistance is confirmed are as follows:

• Discontinue the use of the class of drenches to which resistance has been demonstrated.
• Alternate annually between the remaining effective drench classes.
• Periodically test that these products are still effective.
• Use management strategies which minimise the number of treatments per season.

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Anthelmintic resistant strains of roundworms (mainly to the white drenches) are present on an increasing number of sheep farms in the UK but by taking appropriate action the situation should be manageable. It is essential to reduce the selection pressure for development of drug resistance by adopting some of the practical recommendations highlighted in the News Sheet. It is apparent that the development of sustainable control strategies will depend upon integrating different approaches to control since this combined approach employs several elements each of which should exert minimal selection pressure rather than a single element exerting a high selection pressure. In this way the efficacy of the current broad-spectrum wormers on the market will be conserved.

Appendix: Broadspectrum Anthelminties for Sheep and Goats 1-BZ class of anthelmintics (Benzimidazoles /Probenzimidazoles)

Oral Drenches

Key to Symbols:

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