Pharmacology

Anthelminthic Resistance – An Overview

Team Pashudhan Praharee

April 24, 2022

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Anthelminthic Resistance – An Overview

Dr. Shivani Mamane

Veterinary officer, Veterinary Dispensary Belur, Hulsoor taluka, Bidar district

Department of Animal Husbandry and Veterinary Sciences, Karnataka, India

Anthelminthic is a substance which expels or destroys the gastrointestinal tract worms

Ideal Anthelminthic traits includes the following-

Exhibit high level of toxicity to the target parasites
Should have high efficiency towards all the adults and juvenile stages of parasites including the arrested one
Wide Margin of safety to animal and the operator
No/less adverse effects on the environment
Easy to administer and cost effective
No severe pain or body reaction in animal should be encountered when administered
No residue in animal products
No stain should be produced in the animals tissue
Should have high therapeutic index

AR against the GI nematode is a major concern for the veterinarians as all the major classes of anthelminthics have developed the resistance. AR and it’s control strategies should be of major concern irrespective of country or host species. Overuse and misuse of anthelminthics have lead to this Anthelmintic Resistance in the animals. First Anthelminthic Resistance (AR) was identified in 1957 for Phenothiazine. First nematode to develope AR is Heamonchus contortus

Most commonly adopted diagnostic definition for AR (recommended by World Association for the Advancement of Veterinary Parasitology, WAAVP) is failure of a drug to reduce the faecal nematode egg counts by atleast 95 %. Technically AR is a resistance wherein genetically determined decline in the efficiency of an Anthelminthic against a population of parasites which was susceptible to that drug earlier.

Types of anthelminthic resistance

Side resistance- Here the parasite which shows resistance to a drug also shows the resistance with other drug of same group having same mechanism of action
Cross resistance – Parasite develops resistant against two drugs which are not belonging to same group or having same mechanism of action
Multiple resistance – Parasites shows resistance to 2 or more drugs which are not chemically related
Single resistance – here in this a single spp is resistant to single drug in a farm whereas many spp of parasite being resistant to single drug in a farm is termed as multi generic AR
Dual resistance -Here in a farm the different spp of worms are resistant to different group of anthelminthics
Reversion-It shows reversal of susceptibility to an anthelminthic by an original resistant strain of parasite

Phases of Antheminthic Resistance

First Phase – phase of susceptibility where the no. of resistant individuals within the parasite population is low

Intermediate Phase – With continuous exposure of same drug group the frequency of heterozygous resistant individual within the population increases

Final Phase – Sustained selection pressure results in resistant phase wherein homozygous resistant individuals predominate within population

Antheminthic Resistance development in brief

It is pre-adaptive phenomenon in nematode which results in the existence of resistant genes/ individuals in the normal population before deworming. AR is genetically inherited and evolution of resistance depends on ecological factors. In nematodes resistant genes are heterozygous and thus they are able to withstand the selective pressures of anthelminthic drugs. The AR is governed by the genes, which is complex and depends on the dominant and recessive genes. The effect of drug is same on homozygous susceptible SS with that on the population with heterozygous RS as the resistant R gene is recessive so resistance is not expresses. Whereas the homozygous RR genotype has R as dominant and the resistance is expressed. This R gene in RS genotype is recessive, aids in slow developement of resistance and is poor survival. On the contrary the R gene in RR genotype is dominant, which acts as catalyst for AR to achieve rapidly.

AR mechanisms – Resistance is mediated by multiple genes

Benzemidazoles resistance is due to mutation in beta tubulin gene of nematode, that has been correlated with a phenylalanine to tutoring substitution at the position 200 of H. contortus beta tubulin isotope I (microtubule molecule)

nACH receptor agonist like levamisole, tetramisole, Morental, pyrantel shows AR due to loss/chnage of nACH receptors

Macrocyclic lactones like Avermectins shows resistance due to reduced sensitivity of glutamate /GABA gated chloride channels

Predisposing factors for Antihelminthic resistance

Antihelminthic drench frequency – this is directly proportional to the AR. This implies if the same antihelminthic used on regular basis results in faster AR emergence. It holds good with respect to the Benzemidazoles resistance in H. contortus. It becomes important to consider epidemiology and ecology of parasite before planning the worm control strategies.
Selection of Antihelminthic and dosing-Under dosing helps in setting up of the AR. It was found that the parasite were found resistant to drugs which they were never exposed to due to borrowing of resistant worms. So proper rotation of drug annually help to delay AR
Population dynamics on pasture and timed treating – Refugia plays important role in slowing down AR development rate. Treating during the extreme climatic conditions increase the resistance as it will dilute the free living susceptible worms and results in large proportion of offspring with anthelminthic resistance.

Besides above factors like worm biology, host parasite relationship, climate, persistant antheminthics, route of drug administration, host spp, borrowing of resistant worm introduced from one farm to another through animal purchase or by grazing on pastures shared by several farm flocks.

Antheminthic Resistance detection techniques

It is first indicated by the failure of clinical response after judicious anthelmintic treatment by farmer. This can be achieved in the labs/institutions by in vivo and in vitro techniques. In vivo methods such as faecal egg count reduction test (FECRT), controlled anthelinthic efficacy test are bioassays applicable for all types of anthelminthics with low precision, whereas in vitro methods namely egg hatch assay, egg embryonation assay, larval paralysis assay, larval development assay, tubulin binding assay, larval motility assay are rapid, sensitive and considerably more economical.

The WAAVP has recommended FECRT and egg hatch assay as field tests to detect AR in ruminants and monogastric animals.

Faecal Egg Count Reduction Test

This test recommends the counting of faecal eggs from animals before and after treatment usually 10-14 days post treatment with exception in levamisole where faecal egg count is done at 7-10 days post treatment. This is ideal method to detect AR on field and holds good for all the anthelminthics. The FECRT data calculation according to Coles et al (1992) WAAVP method is

FECRT %= 1-(Xt/Xc)x 100 where, X is the arithematic mean EPG 10-14 days post treatment, t is the treated and c is the control group.

Tackling of Anthelminthic Resistance

Administration of correct dose of anthelminthics- deworming should be of therapeutic rather than for prophylactic purpose. Underdosing results in heterozygous individuals increasing their chance of producing resistant off springs. This even includes faulty administration of the drug.
Avoid introduction of resistant worms into the farm – this can be done by maintaining parasites in refugia which are not exposed to drug this is the key point in controlling and delaying the development of resistance wherein susceptible genes are preserved.

Avoid wrong usage of anthelmintic-the status of that particular agro climatic zone wrt resistance is known then choosing the correct anthelminthic becomes easier. Slow rotational use of different class of anthelminthic is must.

Regularly AR should be monitored by FECRT in field conditions to know the resistance status of the farm.
Use of combination of drugs delays resistance by providing extended protection against worms. eg- benzimiazoles + levamisole.
Rearing of parasitic resistant breeds improves the natural immunity of the herd.

Pasture management – avoid grazing large flocks in the mixed grazing farm where the resistant worms are present.
Use of non chemical methods includes nematode trapping fungi Duddingtona flagrans and Anthrobotrys oligospora

Conclusion

Anthelminthic resistance is an inevitable consequence of use of Anthelminthic.To delay the development of Anthelminthic resistance it is important for us to know the epidemiology and high incidence of the parasites and then strategically use the drugs at the full therapeutic dose instead of under dosing or over dosing the animals. Rotation of the anthelmintic drug type and avoid introducing resistant genes into the farm. Feeding of copper oxide wire particles (COWP) where copper released inside rumen destroys Haemonchus. Also inclusion of tannins in feed aids in destruction of microtubule of the parasite.

Integrated managemental strategies should be considered along with the novel concepts such as targeted selective treatment (TST) wherein only the animals which are harboring more worms need to be drenched instead of deworming the whole flock , this can be achieved by egg per gram. TST can also be achieved by using FAMACHA chart wherin based on the mucous membrane colour the animals with pallor mucosa are exposed to drug. Another method of deworming in small ruminants includes five point check wherein the nose, jaw, eye, back, tail in sheep and eye, jaw, back, skin/hide, tail in goats are thoroughly checked for the indication of worm and anthelmentic is administered if required. Reduction in AR can also be done by various safe pasture management techniques like rapid rotational grazing, alternate grazing.