23 Feb 2015
Louise Silk
Job Title
A dual active anthelmintic contains two different classes of anthelmintic with similar spectrums of activity.
An example would be two classes of anthelmintic that target nematodes, such as a levamisole (2-LV) and a macrocyclic lactone (3-ML). These must be distinguished from combination anthelmintics that contain anthelmintics with very different spectrums of activity – for example, a flukicide and a product that targets nematodes, such as triclabendazole and a 3-ML.
The principle behind a combination anthelmintic product is to broaden the range of worm species targeted. The aim of a dual active is to provide effective worm control in the face of anthelmintic resistance as well as to slow the rate of anthelmintic resistance to the component chemicals.
Dual and multiple actives have been used for many years in some parts of the world – particularly in the southern hemisphere. They make up 50 per cent of the sheep wormers available on the market in New Zealand and are also available for cattle. They include a multitude of combinations of anthelmintic classes such as benzimidazole (1-BZ) plus levamisole (2-LV), 2-LV plus 3-ML, as well as 1-BZ plus 2-LV plus 3-ML. This type of product was not available in the UK until 2012 when a new dual active product containing derquantel and abamectin was launched. This product is only available as a POM-V.
Derquantel is from a new anthelmintic class known as the 5-SI or spiroindoles (purple wormers). It is only available in a dual active product, combined with abamectin, a 3-ML (clear wormer). Derquantel is a nicotinic cholinergic antagonist with a novel action that blocks neuromuscular transmission, inducing flaccid paralysis in nematodes. Abamectin acts on glutamate-gated chloride channels and gamma-aminobutyric acid (GABA) neurotransmission sites in nematodes, blocking inter-neuronal stimulation of inhibitory motor neurones, also leading to flaccid paralysis.
There are two justifications for using dual active products. These are:
When resistant alleles are rare the number of parasites in the population with resistant alleles to two unrelated products is exceedingly low. Using a dual active will therefore remove all, or nearly all, of the resistant alleles from the exposed population and keep the resistant alleles very rare (SCOPS, 2012). This will result in a lower number of parasites with resistance to each of the component classes surviving within the population and, therefore, reduce the number available to reproduce and form part of the next generation, thus slowing the rate of resistance development.
Studies on insects in relation to resistance to pesticides has produced a number of prerequisite conditions required to slow the rate of resistance development when using more than one active (Leathwick et al, 2009, cited in Bartram et al, 2012). These are as follows:
Following on from this, computer modelling of sheep nematode populations has been used to indicate the ability of multiple actives to slow the rate of anthelmintic resistance development, provided certain criteria are met. The most important criteria appear to be the opportunity for survival of susceptible nematodes in refugia and the pre-existing levels of resistance to each anthelmintic in the product (Bartram et al, 2012). Unfortunately, data to support these computer models have proven difficult to generate given the slow population dynamics and the lack of genetic markers for resistant traits (Gilleard and Beech, 2007, cited in Bartram et al, 2012).
Ideally, dual active products should only be used when resistant alleles are at a very low frequency and, therefore, all the anthelmintics in the product are still fully effective. If resistance is relatively common to each active then the use of both together may provide improved clinical response for a few years if used carefully, through the additive effect described in Panel 1 (SCOPS, 2012).
In the UK, the frequency of 3-ML-resistant alleles within the gastrointestinal (GI) nematodes may be quite low on some farms; however, resistance is certainly on the rise, particularly with the increasing use of 3-ML products in the control of sheep scab. This means it is particularly important to integrate the new dual active product into worm control plans now. It is also essential the Sustainable Control of Parasites in Sheep (SCOPS) principles are followed to maintain the efficacy of this product for as long as possible. These include using management practices, such as correct dose calculation and administration, which seek to maximise efficacies, as well as maximising the benefits from the in refugia dilution effect.
If it is possible to reduce the number of resistant worms that remain within a worm population after treatment (by using a more effective wormer), there will be maximum benefit achieved by the use of the in refugia dilution effect. The example in Panel 2 indicates this in more detail.
Panel 2 shows how for less effective wormers the impact of the in refugia worm population on diluting resistant worms will be much reduced. It is therefore extremely important to utilise the principle of the in refugia dilution effect even when the wormers used are still highly effective on a particular farm. This will help to reduce the rate of resistance development to those wormers, thus keeping those wormers useful on that farm for longer.
A number of studies have been carried out to confirm efficacy of the new dual active against anthelmintic-resistant GI nematodes in sheep. It is important to bear in mind these studies have been designed and funded, and the data was analysed by the animal health company that developed this product, although the company was not involved in actual data collection.
Concerns over the use of dual or multiple actives include:
SCOPS is an industry-led body formed to develop sustainable strategies for parasite control in sheep, in response to the ever-increasing threat of anthelmintic resistance to the future heath and profitability of the UK sheep industry.
With the earlier reports of resistance to the new 4-AD group of anthelmintics in the Netherlands, SCOPS is urging vets, advisors and farmers to follow its advice regarding the integration of the newer classes of wormer (including the dual active containing derquantel) into their worm control programmes. SCOPS advice regarding the use of new wormers has been and remains as follows:
The situation on every farm in terms of management practices and anthelmintic resistance status varies enormously. As a result there can never be a blueprint formula for how and when to use a particular anthelmintic product. However, it is essential when formulating a worm control plan for a particular farm, the advisor has a good working knowledge of the management practices and resistance status specific to that farm, as well as a clear understanding of the products available.
One final word would be that to ensure safety, quality, efficacy and legal compliance, it is important only licenced products containing more than one active are used and that mixtures of more than one anthelmintic are never prepared on farm (Bartram et al, 2012).
With the rise in anthelmintic resistance, the author says it is important to integrate dual active products into worm control plans and follow the Sustainable Control of Parasites in Sheep principles.
IMAGE: The Kennel Club.
