Anthelmintic resistance : A burning havoc to veterinarians and animal owners

Dr Mangsatabam Norjit Singh *

Introduction

Gastrointestinal (GI) nematodes are of major economic importance in domesticated animals throughout the world. They are responsible for blood loss, depression of appetite, impaired GI functions, alterations in protein, energy and mineral metabolism, change in water balance, increased mortality, decreased live weight gain, wool growth / yield, fertility and milk production, rejection of carcasses or organs for human consumption and predisposing to other diseases.

For many decades use of anthelmintics has been central in the control programs of these parasites. Three broad spectrum anthelmintic classes are currently used to control gastro-intestinal nematode infections of animals viz. benzimidazoles, imidazothiazole/ tetrahydropyridines and macrocyclic lactones.

The extensive use of anthelmintics for control of GI nematodes has resulted in the development of resistance to one or more of the widely used anthelmintics in many countries.Anthelmintic resistance has been defined as “the ability of parasites to survive doses of drugs that would normally kill parasites of the same species and stage”.

It has been observed that frequent usage of the same group of anthelmintic; use of anthelmintics in sub-optimal doses, prophylactic mass treatment of domestic animals and frequent and continuous use of a single drug have contributed to the widespread development of anthelmintic resistance.

In recent years, the problem of anthelmintic resistance (AR) has reached new heights where it can no longer be ignored as a major issue in the control of parasites of livestock. At present, resistant nematode populations are detected in all our naturally grazing species; sheep, goats, cattle and horses. No new anthelmintics with different modes of action are expected on the market in the near future. So, the maintenance of the efficacy of existing anthelmintics is, therefore, essential for continuing animal productivity and welfare.

Factors contributing to development of anthelmintic resistance

i. Drench frequency:Frequent use of anthelmintics of the same class for a long period of time results in the development of anthelmintic resistance. The alternation of the anthelmintic family may slow down the selection of resistant worms during the early steps of resistance development.

ii. Managemental factors:Managemental factors are found responsible for emergence of anthelmintic resistance at a higher rate.

iii. Harbouring anthelmintic resistant nematodes or grazing on common pastures: Anthelmintic resistance may be introduced from one farm to another through animal purchase or by grazing on pastures shared by flocks from several farms.

iv. Under-dosing: Under-dosing occurs when a host is administered ”a weight-dependent dose that is less than that recommended by the manufacturer”. It results from a mis-estimation of body weight. Under dosing is considered as an important factor in the development of anthelmintic resistance because sub therapeutic doses might allow the survival of heterozygous resistant worms.

v. Environmental factors: The climatic conditions of an area determined the type of parasites prevalent and its propagation. During the raining season, there is heavy worm burden in the pasture which may require higher anthelmintics intervention and this can select rapidly for resistance.

vi. Mass treatment: Prophylactic mass treatments of domestic animals have contributed to the widespread development of anthelmintic resistance. Computer models indicate that the development of resistance is delayed when 20% of the flock is left untreated.

vii. Time of treatment:It is a common feature to treat animals before turnout to pastures and in some cases, during housing. This strategy favours a high and efficient selection pressure on worms. In such a scheme, animals that are turned out on pastures at the beginning of the grazing season only harbour adult worms that survived the anthelmintic treatments.Pastures are then contaminated by the eggs laid by resistant worms. The role played by these resistant eggs depends on the proportion of infective larvae that overwintered in the grass/soil.

Methods for detection of anthelmintic resistance:

Different methods, both in vivo and in vitro methods, have been used to detect and monitor AR. Faecal Egg Count Reduction Test (FECRT) is the most commonly used in vivo method and gives an estimation of the efficacy of the drug by comparing the egg counts pre and post treatment. The accuracy of the method depends on a correlation between egg counts and worm burdens which is not always present.

Another test i.e. controlled test is the most reliable method but is rarely used because of high costs. This test uses untreated control groups and the parasitized animals are euthanized about 10 days post treatment and a necropsy is subsequently performed.

Different in vitro methods like Egg Hatch Assay (EHA) is mostly used for the detection of possible BZ resistance in sheep and horses.The larval development assay (LDA) uses the ability of the anthelmintic to arrest the normal development from eggs to L3 larvae. By observing the proportion of L3 larvae developed in different concentrations of an anthelmintic, a LC50 value can be determined.

Molecular techniques like PCR, Allele specific PCR, Real time PRC, etc.can be used for detection of AR with high sensitivity and specificity.The molecular basis of anthelmintic resistance is only known for the benzimidazoles where it is caused by a mutation in â-tubulin, which involves a phenylalanine to tyrosine mutation at residue 200 of the isotype 1 â-tubulin gene.

However, in addition a similar mutation at codon 167 and other changes like transport of the drug out of the parasite may be involved in BZ resistance in nematodes. Allele specific PCR (AS-PCR) is an effective method to identify point mutation. Recently, real time PCR on isotype 1 of â-tubulin, strains of the main species of trichostrongylids (T. circumcincta. H. contortus and T. vitrinus) that are susceptible and resistant to BZ were differentiated.

Management strategies to delay the development of resistance

There are several management strategies to prevent parasitic infestation and or to keep the infestation pressure low, i.e. pasture management and refugia which will result in reduced use of anthelmintics and subsequently delayed in resistance development.

a) Correct use of anthelmintics at optimum dose: Repeated under-dosing and/or too frequent use of anthelmintics belonging to the same class will increase the risk for selection of resistance. Optimum weight-dependent anthelmintic dose as per manufacturer should be given and proper check must be done for calibration of the drenching device.

b)Reduction in frequency of treatment: Selection occurs at a faster rate with increasing frequency of treatment due to high selection pressure.

c) Rotational use of anthelmintic: Use of single an¬thelmintic or those with the same class for a longer period of time results in the rapid development of anthelmintic resistance. Therefore, rotation of the anthelmintic class may slow down the selection of resistant worms during early steps of resistance development.

d) Use of multiactive anthelmintic products: A treatment strategy to delay resistance development may include the use of products (so called multiactive anthelmintic prod¬ucts) containing two or more substances with activity against the same target parasite but with a different mode of action. However, there are also concerns that the use of multi active anthelmintics could potentially lead to the selection of multiple resistance to different anthelmintic classes particularly when livestock grazes low contamina¬tion pasture with insufficient refugia population.

e) Regular monitoring of anthelmintic resistance: Regu¬lar annual testing with in vivo or in vitro test is required on farm to monitor the status of drug efficacy of anthelmintics.

f) Use of clean or safe pastures: Safe pastures means the pasture which are not contaminated with the worm larvae and clean pastures means the pasture which has not been grazed by sheep or goats for the past 6 to 12 months but by horses or cattle.

g) Pasture rest and rotation: Resting period varied from 2 months (semi-arid) to 6 months (cool moist climate) but 60-65 day rest period is sufficient. In a rotational grazing system ideally, sheep/goats should not be returned to the same pasture for 2-3 months.

h) Alternate grazing system/ Graze multiple species: Grazing between different age groups of different species taking each species has different grazing behavior that complements one another. Cattle/horse act as vacuum cleaner to the pasture if grazed before or after sheep/goat. Pastures grazed by cattle and horses are safer for sheep/ goats.

i) Targeted selective treatment (TST): Targeted selective treatment can be defined as any system that selects ani¬mals on an individual basis for treatment, using logical specific criteria on which this selection is made. One in which only those animals that will most benefit from treatment are given anthelmintic. In the TST group, only 20% of the flock required treatment at any one time and moreover 88% of the animals that were given anthelmintic showed a positive response in performance following treatment.

j) Use of bioactive forages: The pasture plants contain¬ing condensed tannins have anthelmintic properties. Condensed tannins (CT) are not only included in certain plants, a lot of plants have CT content but only those with higher levels are referred to as ‘bioactive forage’. Some examples of bioactive forages are Chicory, Birdsfoot Tre¬foil, Sulla, Sainfoin, Quebracho etc.

k) Use of herbal anthelmintic: Plants or plant parts with anthelmintic activity are used in folk veterinary medicine, but it is necessary to investigate and scientifically validate low-cost phytotherapeutic alternatives for future use to control GI nematodes in animal by farmers. Indigenous plants like Areca catechu, Artemisia vulgaris, Calotropis procera, Calotropis procera, Melia azedarach, Chrysanthe¬mum spp., Carica papaya, Heracleum spp., Azadirachtaindica, Allium sativum, Hedysarum Coronarium, Artemisia maritime, etc showed potential an¬thelmintic activities against nematode parasites.

l) Integrated pest (parasite) management (IPM): It in¬volves the use of a combination of techniques and monitoring to achieve pest control and maintain chemical susceptibility. In addition, in the context of veterinary parasitology, IPM schemes must manage chemical use because of concerns about chemical residues in meat, eggs, wool and milk. In controlling animal parasitism, IPM would work by improving host resistance using non-chemical means to control parasites, using chemicals judiciously, improving monitoring of infection and resist¬ance and understanding the host-parasite relationship.


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