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Back to Journal »Infection and Resistance» Volume 14

Resistance to helminthiasis and its mechanism: a review

Author Fissiha W, Kinde MZ

Published on December 15, 2021, the 2021 volume: 14 pages 5403—5410

DOI https://doi.org/10.2147/IDR.S332378

Single anonymous peer review

Editor approved for publication: Professor Suresh Antony

Workye Fissiha, 1 Mebrie Zemene Kinde2 1 Department of Epidemiology and Public Health, School of Veterinary and Animal Sciences, Gondar University, Gondar, Amhara Region, Ethiopia; 2 Department of Veterinary Biomedical Sciences, School of Veterinary and Animal Sciences , Gondar University, Gondar, Amhara State, Ethiopia Ethiopia Amhara State Tel +251918518866 Email [email protected] Abstract: Worms are a different type of parasite that affects animals in different parts of the world Cause major health problems. The control of helminthiasis relies heavily on the use of drug repellents. Unfortunately, the massive use of anthelmintics has resulted in severe and significant resistance to helminths. Anthelmintic resistance is the heritable loss of anthelmintic susceptibility in parasite populations that were sensitive to the same anthelmintic in the past. The development of resistance to worms is obvious for different worms of almost all animal species and different anthelmintic groups on several continents. Frequent treatment, insufficient dosage, inheritance of parasites, and the goal and time of large-scale treatment are the predisposing factors for antihelminthics. Up-regulation of cell efflux mechanisms, increased drug metabolism, changes in drug receptor sites that reduce drug binding or the functional consequences of drug binding, and reduction of drug receptor abundance by reducing the expression of parasites in parasites are anti- The main mechanism of helminth drug resistance. In vivo methods such as fecal egg count reduction test and in vitro methods such as egg incubation test, larval movement test, larval development test and PCR can be used to detect worm drug resistance. The correct use of anthelmintics, the use of combined anthelmintics and the application of other alternatives are important strategies to slow down the development of resistance to antihelminthics. Anti-helminth drug resistance is a severe challenge worldwide. Existing anti-helminth drugs should be appropriately used to reduce dependence on anti-helminth drugs to reduce its challenges. Keywords: insect repellent, development, worms, mechanism, resistance

Worms are a group of worms that cause major health problems to animals all over the world. Although controlling livestock farms can reduce the impact of parasites, these technologies are not sufficient to eliminate these parasites. The control of helminthiasis relies heavily on the use of anthelmintics, which account for the largest portion of animal health expenditures in many countries. 1

At present, anthelmintics are the basis for the treatment of infections caused by veterinary worms, and due to the general lack of anti-parasitic vaccines, this may still be the case in the future. In the past 50 years, the chemical control of parasites in animals has been very successful, because of its remarkable effect, reducing more than 95% of parasites, overall good safety margin, broad spectrum of anti-worm drugs and reasonable cost. Sadly, the intensive use of anthelmintics resulted in severe and significant anti-helminth resistance (AR), mainly gastrointestinal nematodes in cattle, sheep, goats, and horses. 2 The increasing development of AR in domestic animal parasites is threatening animal health and production worldwide. 3 At present, three types of anthelmintics are most commonly used by small ruminants: benzimidazole (BZ), macrolide (ML) and cholinergic agonists (especially levamisole; LEV). AR has been reported in all types of anthelmintics. 2 The time from the introduction of an anthelmintic to the development of resistance seems to be less than 10 years. 4

The development of AR is a highly multifaceted process, which is affected by hosts, parasites, types of repellents and their use, animal management, and climatic characteristics. Therefore, it increases the challenge of developing control and preventive measures, which may vary from animal production system to animal production system. The participation of multiple factors, the challenge of developing new anthelmintics, and the difficulty of reversing drug-resistant strains into susceptible strains are very important factors in the development of AR. 5 Although AR has increased from time to time and has become a major challenge due to a large number of applications so far, no effective alternative strategies have been established to control worm infections. Therefore, regular AR testing and understanding of the predisposing factors and mechanisms of resistance to worms are very important for slowing down the spread of resistant parasites. Therefore, the main purpose of this review is to highlight AR and its predisposing factors, development mechanisms, detection methods, and strategies to delay AR development.

AR is the hereditary loss of anthelmintic susceptibility in parasite populations susceptible to the same anthelmintic in the past. When the proportion of individual parasites in a population is higher than that of the normal population of the same species, when it loses sensitivity to a certain dose of anthelmintic, AR is considered to exist, and it will be passed on from generation to generation. 6

According to Nipane et al., 7 there are three types of AR, namely cross-resistance, side-resistance, and multiple resistance. Cross-resistance is the first type of resistance, in which the parasite strain can tolerate therapeutic doses of antihelminthic drugs, which are chemically unrelated, or anthelmintic drugs with different mechanisms of action. The second type of resistance is lateral resistance, which is resistance to an insect repellent due to the selection of another insect repellent with a similar mechanism of action. The resistance between benzimidazole anthelmintics is considered an example of side effects. It has been reported that strains resistant to levamisole can also have side effects on Morantie. Resistance to two or more repellents with similar or different mechanisms of action due to independent selection or side resistance of each group is the third type of resistance, called multiple resistance.

The development of AR is obvious to different worms of almost all animal species and different anthelmintic groups on several continents. 8 In Europe, the results of many scientific studies have shown to varying degrees that worms have increased resistance to the well-known anti-worm viruses. A group of anthelmintics, they are benzimidazole, tetrahydropyrimidine, imidazothiazole and macrolides. A cross-sectional study conducted by Mickiewicz et al. showed that Polish goat farms have AR against BZ, ML, and LEV. Among them, resistance to BZ and ML is widespread, while resistance to LEV is at a low level. Potârniche et al. 2 also reported on the resistance of Romanian goat gastrointestinal nematodes to MLs and BZs. This is the first report in the country. In addition, individual reports have shown that worms have developed resistance to recent types of anthelmintics (for example, Haematococcus contortus has developed resistance to monepantet, C and aminoacetonitrile derivatives). 10 Investigations showed that some sheep and goat farms were closed due to anti-worm drugs shortly after the market was launched, and even in some countries. 11 The time from the introduction of anti-worm drugs to the development of resistance seems to be less than 10 years. In sheep, the development of resistance to imidazothiazoles, tetrahydropyrimidines, and avermectin milbemycins occurs within three to nine years. The severity and scope of this problem, especially the multi-drug resistance of nematode populations, is expected to increase. 4 Some authors have reported the widespread incidence of benzimidazole, imidazolethiazole, and macrolides in the multi-drug resistant populations of Haematococcus contortus, Teladorsagia, and Trichostrongylus in sheep across Europe. 12

With the widespread use of anthelmintics in many tropical and parasite endemic countries, the severity of parasite resistance has been exaggerated. The trend of animal overuse also poses a threat to public health. Government agencies either lacked understanding or underestimated the mechanism of this emerging problem. 13 The broad-spectrum anthelmintics most commonly used in Ethiopia to treat gastrointestinal worm infections in livestock belong to three anthelmintic families, namely benzimidazoles (such as albendazole and triclabendazole). ), imidazothiazole (such as tetraimidazole and levamisole) and macrolides (such as ivermectin). Irregular and inappropriate use of anthelmintics has led to failure to eliminate parasites in the gastrointestinal tract of livestock, and instead led to AR in various nematode parasites in different geographic regions of Ethiopia. 14 Wondimu and Bayu15 from Haramaya, Ethiopia, reported the presence of multidrug-resistant gastrointestinal parasites. Nematodes in goats resist albendazole, tetrachlorazole, ivermectin and tetraimidazole, among which Trichostrongylus spp., Teladorsagia spp. and Haemonchus spp. It is a genus commonly identified in cultures after treatment. In Limpopo Province, South Africa, Mphahlele et al. reported a high prevalence of AR against gastrointestinal nematodes infecting sheep. 16

The efficiency of modern anthelmintics on vulnerable strains is about 99%. A few tolerant parasites are the most resistant component of the population. These surviving parasites are discarded into the environment and contaminate pastures, leading to the development of most resistant generations, and the development of AR due to selective pressure. The development speed of AR is affected by many factors, of which treatment frequency is the most important. 17

This is an important factor that determines the speed of AR development. When anthelmintics are used more frequently for treatment, resistance to anthelmintics will develop faster. The basic principle for choosing AR is that treatment provides surviving parasites with advantages in reproduction and replication over susceptible parasites within about two to three weeks after the application of the anthelmintic. 18

It has been shown that the provision of large-scale preventive treatment contributes to the development of AR in worms. However, handling approximately 80% of the flock can delay the development of resistance. 17

Incorrect and inappropriate application of insect repellent dosage is one of the main factors that may cause AR. Visual weight estimation is the most commonly used method to determine the dose rate of anthelmintics, especially the dose rate of general drugs in veterinary medicine. This is usually inappropriate and may lead to insufficient doses. In turn, this insufficient dosage allows the survival of heterozygous resistant worms, thus helping to select resistant strains. 19

Resistant parasites pre-exist in the parasite population. AR is currently considered to be a pre-adaptation phenomenon in which resistance alleles are present in the parasite population before being discovered for the anthelmintic under study. In the absence of anthelmintics, natural selection retains resistance alleles at a low frequency because resistance alleles make worms that carry them less suitable for survival than completely susceptible worms. However, the introduction and continuous use of insect repellents gives anti-worms a survival advantage. This allows them to reproduce at a faster rate than susceptible worms, leading to an increase in the frequency of worms with resistant phenotypes in the population. Eventually, the frequency of worms with a resistant phenotype has risen to the point where resistance to worms is said to have emerged or developed. When anti-worm drugs are a recessive feature of worms, only homozygous worms can tolerate appropriate doses of anthelmintics. Insect repellents can kill heterozygous parasites​​. 1

Understanding the mechanism of drug resistance can help researchers better predict the rate of emergence of drug resistance and provide tools for studying parasite biology and therapeutic targets. Antihelminth drug resistance mechanisms usually include (1) upregulation of cell efflux mechanism, (2) increased drug metabolism, (3) changes in drug receptor sites, reducing drug binding or the functional consequences of drug binding, or (4) Decrease the abundance of drug receptors by reducing expression or another way of down-regulation. The link between the aforementioned changes and resistance is different between worm species. 20

Macrolide resistance includes resistance to individual drugs in this category (such as ivermectin). The terms abamectin and milbemycin resistance are often used to denote populations of macrolide-resistant worms because of their long history of use. The most likely target of ML therapy is ligand-gated chloride channels, and it has been suggested that mutations in genes encoding these proteins may cause AR. The occurrence of GluClRs mutations was first reported in a paper on the mechanism of ivermectin resistance in parasitic worms. The alleles of the GluCla subunit gene were found more frequently in ivermectin and moxidectin-resistant Haemophilus contortus isolates, which means that mutations in this gene are related to ML resistance. 21,22

Protein transporters, especially P-glycoprotein (Pgps), act as an efflux mechanism to transport molecules across the cell membrane, thereby reducing their intracellular concentration. This prevents the drug from reaching its target site. According to reports, Pgps-related ivermectin resistance is in H. contortus. PGP-2 is the most consistent Pgp associated with ML resistance. 22 Enzymes involved in drug metabolism are another non-specific mechanism most likely to cause macrolide resistance. Recently, Yilmaz et al. 23 reported that the expression of CYP34/35 was increased in multidrug-resistant strains of Tortobacter compared with susceptible strains.

The mechanism of benzimidazole antihelminthic drugs has been clearly related to the change of ß-tubulin. The resistance to BZ may be caused by the change of phenylalanine 200 tyrosine in the isoform I ß-tubulin. twenty four

Even a single amino acid mutation in tubulin can cause benzimidazole binding to be blocked in resistant nematodes. The BZ-resistant gastrointestinal nematode (GIN) species is associated with three non-synonymous single nucleotide polymorphisms (SNPs) in the isoform 1-tubulin gene. The most common SNP results in the substitution of phenylalanine at position 200 with tyrosine (F200Y), while other SNPs result in the substitution of phenylalanine at position 167 with tyrosine (F167Y) or the substitution of glutamic acid at position 198 with alanine ( G198Y) (E198A) 25.

The function of nicotinic acetylcholine receptors (nAChRs), especially the L-type subgroup of these receptors, is preferentially activated by levamisole and pyrant, and has been the focus of research on the causes of drug resistance to nicotinic agonists. 26 When these L-nAChRs are activated, they cause neuromuscular depolarization and spastic paralysis. In different species of Trichostrongylus nematodes, there are some indications that the change of the target site in the nematode may be the mechanism of resistance to levamisole and pyrone. The decreased expression levels of genes encoding nACh subunits that constitute receptors are related to levamisole and pyranto resistance of H. contortus and A. caninum, respectively. In the isolates of H. contortus, T. colubriformis and T. circlecincta, there are two shortened forms of receptor subunits (acr-8b as the truncated form of acr-8a, and unc-63b as the truncated form of unc-63a Form)) is also related to resistance. 27,28

Before determining the AR diagnosis, many criteria must be considered. First, remember that a range of diseases may cause similar clinical indications related to parasites. Second, deworming treatment may not be able to control nematodes due to reasons other than resistance. Failure in these situations is usually attributed to problems such as failure of the wet equipment or insufficient dosage due to incorrect weight estimation. With the rise of AR, there is an increasing demand for reliable and standardized detection methods. In vivo and in vitro methods are used to detect and monitor AR.29

The worm egg counts of the animals before and after treatment are compared to determine the deworming effect of the chemicals. The test has been fully standardized and can be widely used. According to FECRT, when two requirements are met, the resistance is obvious: the percentage of egg reduction is less than 95%, and the lower limit of its 95% confidence range is equal to or less than 90%. The number of eggs after treatment with benzimidazole should be counted 10-14 days after delivery of the anthelmintic. Since deworming treatment can temporarily prevent egg laying without killing adult nematodes, it is a good idea to use it. 30 If the interval between treatments is less than 10 days, egg production may decrease, leading to an overestimation of the repellent effect of benzimidazole. Therefore, it is recommended to collect stool samples 10-14 days after treatment. If levamisole resistance is suspected, a stool sample should be collected within 7 days after treatment. Therefore, depending on the anthelmintic group, the duration between treatment and the second egg number is different: 7-10 days for benzimidazole; 3-7 days for tetrahydropyrimidines and imidazothiazoles; macrocyclic inner The ester needs 14-17 days. 12

Benzimidazole anthelmintics can prevent the embryonic development and hatching of nematode parasite eggs. This technique has been established to detect resistance to this group of insect repellents. This test is not suitable for the use of tetrahydropyrimidines, imidazothiazoles and macrolides, because they do not have an ovicidal effect. In the experiment, put fresh eggs into each well of a 24-well plate, incubate at 27°C for 48 hours and add several concentrations (0.5, 1, 2, 3, 5 ppm) of benzimidazole, and the remaining eggs and Count the hatched larvae and calculate the LD50 value. This is a more feasible test method for benzimidazole resistance. 31

The test is based on the larvae's ability to survive and develop under different concentrations of anthelmintic. The development of larvae under different doses of anthelmintic was examined in a larval development test (eggs from fresh fecal samples pooled in a subgroup of chickens). Cultivation can be carried out on liquid or solid nutrient medium (agar). Use this method to detect AR for the main Anthelminthidae. Depending on the time of infection, the test reports changes in LD50 (50% of the larvae die), especially when macrolides (ML) are used. Some veterinary offices and regional veterinary laboratories provide this test. 32

The three larvae were incubated with different concentrations of drugs in the dark at 25°C for 24 hours. They were then exposed to light for 20 minutes to stimulate those who were not paralyzed. Then, calculate the proportion of the number of non-motor larvae to the total larvae at each drug concentration. 33

Using this PCR-based technique can genotype resistant (rr) or susceptible (rS and SS) adults or larvae. By using four primers in the same reaction mixture, worms can be genotyped to identify mutations in β-tubulin residue 200 (phenylalanine to tyrosine), which are related to BZ resistance. 34

In the past five years, the use of insect repellents in the management of livestock worms has led to the development of resistance to each major repellent category. The development of new anthelmintics to control resistance is a slow and expensive process. Therefore, it is extremely important to use existing insect repellents in a way that minimizes the effects of AR. 20

In order to prevent parasite infection and/or maintain low infection pressure, various management strategies such as pasture management and shelters. These will reduce the need for the use of anthelmintics that may help delay the development of AR. The important actions required to slow the progress of AR are to use insect repellents appropriately, reduce dependence on insect repellents, avoid introducing resistance to farms by handling purchased livestock during the post-arrival quarantine period, and keep people susceptible to worms against worms and worms. Test anti-worm drugs regularly. 32

When the helminth parasite population is exposed to anthelmintics, it is considered that there is a risk of AR. Surprisingly, the risk of developing resistance increases during periods of insufficient dosage and very frequent application of anthelmintics classified in the same category. It has been suggested to rotate the types of anthelmintics to slow the development of resistance. Applying reliable diagnosis to determine the type of worm, using diagnostically effective anthelmintics, and following label instructions for correct dosage and administration are very important strategies for delaying anthelmintic resistance. 35

The prevention of drug resistance must focus on slowing down the accumulation of drug resistance alleles, and strategies to slow the development of drug resistance must be implemented in the early stages of the evolution of drug resistance and before clinical evidence of reduced drug efficacy appears. This is best achieved by following a policy of ensuring adequate refuge; a term used to express the proportion of the parasite population that has not received a specific treatment, and therefore avoid selecting resistance. 1 Worm resistance is inherited in the worm population. Once resistance is established, it will not reverse or lose resistance. By protecting susceptible individuals to dilute the offspring of resistant parasites that survive the treatment, the refuge limits the development of resistance. As the size of the refuge becomes larger, the evolution of resistance slows down. 36

As a way to slow down the development of AR, it is recommended to use combination anthelmintics with relevant activity spectrum but different modes of action. Due to the development of resistance to imidazole thiazole and tetrahydropyrimidine, recently, the use of a combination of different repellent classes to control the presence of resistant nematodes has increased interest and slowed the development of the number of resistances. 37

Reducing the frequency of use of anthelmintics is very useful for reducing the incidence of AR. Applying better grazing management is a possible and useful way to reduce the frequency of anthelmintic use. Reducing the grazing rate and grazing time, and implementing mixed grazing between different animal species are key factors in improving grazing habits. Application of biological control is also an extraordinary technology to reduce the use of anthelmintics. The main principle of biological control is to use natural enemies that can eat/kill parasites to reduce the level of infection in the pasture. 38 These treatments do not attempt to eliminate the free-living larval stage, but reduce them to the point where they are already infected. Minimal clinical or subclinical impact, while promoting acquired immune response. 39 Selecting animals that are less genetically vulnerable is an attempt to reduce the burden of animal parasites. 40

The development of effective vaccines against intestinal parasites will reduce the frequency of use of antiparasitic drugs. Although numerous attempts have been made to develop vaccination to protect grazing animals from worm infections, only one vaccine against placental larvae is currently available on the market. 41

The extensive use of anthelmintics for the management of livestock worms has led to the development of AR, which is a highly multifaceted process that is affected by the treatment of animals, parasites, types of anthelmintics and their use. The abuse of insect repellents, such as insufficient dosage, treatment of all animals on the same farm at the same time, continuous use of the same insect repellent, substandard quality, and frequent use of insect repellents are all important factors that lead to the occurrence of AR. Up-regulation of cell efflux mechanism, increase of drug metabolism, changes in drug receptor sites that reduce drug binding or the functional consequences of drug binding, and reduction of drug receptor abundance by reducing the expression of parasites in parasites are anti-drug receptors. The main mechanism of worm drug resistance. Today, there is no effective way to control parasitic worms except for the application of anthelmintics. In addition, the development of new anthelmintics to manage AR is a slow and expensive process. Therefore, it is very important to use existing anthelmintics in a way that minimizes the impact of AR, such as the appropriate and combined use of anthelmintics to reduce dependence on anthelmintics. It is also important to regularly detect and monitor the development of AR.

The authors report no conflicts of interest in this work.

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