Anthelmintic Resistance

WIKIDRUGS ANTHELMINTIC DRUGS

Anthelminitic resistance is starting to emerge in the UK as a significant problem and has already had huge effects in the southern hemisphere. It has mainly been seen in the nematode population and is now starting to appear in the trematodes. In the UK benzimidazoles seem to have the most resistance against them, especially in sheep and horses. Now ivermectin and levamisole resistance is starting to develop. It is a concern and prudent use of the current products needs to occur to halt the progression of resistance, with a shift of thinking towards parasite control that reduce the reliance upon chemicals.

Mechanisms of Resistance

This is still an area of research, but most methods of resistance seem to revolve around a reduced binding site affinity. For benzimidazoles it seems that there is less affinity to the tubulin binding site. Macrocyclic Lactones seem to have increased expression of a non-specific transmembrane efflux pump that can eject toxins out of the nematode.

Investigating Resistance

Any poor response to anthelminitic therapy is often viewed as resistance, this is not the case. Often there are other underlying reasons for the failure of the drug, here are some more come causes:

• Misdiagnosis
• Underdosing - usually resulting from underestimating the body weight of the animal
• Failure to follow drug instructions
• Poor maintenance of the dosing equipment
• Dogs and cats rejecting tablets and so the dose
• Not removing stock from, or reintroducing stock to heavily contaminated pastures
• Inappropriate choice of drug or dosing regime

If none of these reasons are discovered to hold true then an appropriate test must be performed to confirm resistance.

In Vivo Detection Methods

Faecal Egg-Count Reduction Test One compares the faecal egg-count before and 7-14 days after treatment. This is the simpliest and cheapest of all tests but has some limitations:

• Two on farm visits are necessary
• Low sensitivity
• Egg output doesn't always reflect worm numbers
• Different species of worm can dominate at different times of year
• False negatives are common especially if worms become temporarily infertile but aren't killed.
• False positives can occur if drugs have poor action against mucosal larvae (eg levamisole)

Controlled Test Worm free animals are infected, treated and then slaughtered and compared to an appropriate control. This is very reliable but also expensive.

In Vitro Detection Methods

These are cheap and very sensitive tests but their significance relies upon the validity of any standardisation procedures. They aren't predictive of clinical disease and also will reflect seasonal variations in species domination.

Egg Hatch Assay Eggs, from animals infected with suspected resistant worms, are incubated with serial concentrations of anthelmintic. The ED₅₀ is then determined. This works best for testing resistance of benzimidazoles.

Larval Development Test As above but larvae are incubated and there rate of development is recorded, this will take about a week. This is best used for investigating levamisole resistance.

Tubulin Binding Assay Best used for investigating benzimidazoles.

Molecular Techniques RFLP assay and a specific PCR-reaction have been made to test for benzimidazole resistance.

Development of Resistance

The rate at which resistance develops is dependent upon both genetic factors and also selection pressures. The following are some important factors that effect resistance:

• How many free-living parasites there are compared to parasitic stages
• How many species are present and what is there biotic potential
• How often anthelmintics are used
• What anthelmintic is used and how often the type of drug is changed
• What management strategies are in place
• What is the local climate (this will effect length of worm season and parasite generation time)
• What is the stocking rate

Delaying Resistance

The following can be implemented on farms to try and halt or delay the presence of resistance on the farm.

• Use an effective drug
• Give the correct dose, ie correct body weights used, follow all drug instructions and maintain equipment.
• Use the minimum possible number of doses at the appropriate times
• Change the chemical group of drug used each year
• Test the effectiveness of the drugs in use by regularly monitoring faecal egg-counts
• Education of the farm staff
• Use narrow spectrum drugs wherever possible
• Use the pharmacokinetic properties of the drugs to your advantage, ie you can reduce ruminant intake before dosing
• (Use a mixture of drugs with differing actions, this is a controversial method)

Other Control Strategies

• Regular faecal removal, especially with horses
• Select rams, used for breeding ewe replacements, for their low faecal egg-counts
• Enhance natural immunity and resilience by feeding suppliments such as by-pass protein
• Use feedstuffs with natural anthelminitic substances, such as condensed tannins
• Use nematophagous fungi to help reduce the number of infective larvae developing in faeces

For more information on managing parasites in sheep please look at the Sustainable Control of Parasites in Sheep (SCOPS) website; http://www.nationalsheep.org.uk/index.php?option=com_content&task=view&id=287&Itemid=68