Anthelmintic Drug Resistance in Livestock: Current Understanding and Future Trends

Abstract

Anthelmintic, ectoparasiticides (insecticides, acaricides), and antiprotozoal chemotherapeutic drugs target parasites. Chenopodium oil like alkaloids, arsenic compounds, cupric sulfate, nicotine, and cupric silicate were used to destroy nematodes. Unfortunately, these chemicals were less effective and less safe for livestock. The four major groups of broad-spectrum antinematodal compounds are macrocyclic lactones such as milbemycins/ivermectin, benzimidazole/pro-benzimidazole, tetrahydro pyrimidines such as morantel, pyrantel tartrate, and imidazothiazoles such as tetramisole and levamisole. The various factors responsible for gastrointestinal (GI) parasitism make it difficult to develop effective control measures, to the best of our knowledge. Hence, an effective strategy for the control of parasitic diseases that do not solely rely on anthelmintic therapies needs to be developed at the regional level, based on the epidemiology of the disease. This book chapter aims to elaborate on the various other ways to control parasitic diseases due to Anthelmintic drug resistance.

1. Introduction

Antiparasitic chemotherapeutics can be categorized as anthelmintics, ectoparasiticides (insecticides and acaricides), and antiprotozoals. Anthelmintics are those agents used to destroy worms and are used as anticestodal, antinematodal, and antinematodal agents [1].

The use of chemical agents against nematodes traced back to the 1990s and those agents were having less effectiveness. Chemicals used for nematode destruction were arsenic compounds, cupric sulfate, nicotine, Chenopodium oil like alkaloids. These chemical compounds were found less effective and more toxic for livestock. Synthetic drug phenothiazine antinematodal characteristics were first reported in the United States and were used as broad-spectrum medicine for nematode treatment in horses, ruminants, and chickens. Phenothiazine is removed from the therapeutic inventory in many countries [1].

From that time scientists were trying to produce an ideal anthelmintic drug that could be used as broad-spectrum dewormers and result in the use of organophosphorus compounds, imidazoles, and tetrahydro pyrimidines. Thiabendazole (TBZ) was developed in 1961 after two decades, and this drug is having high efficiency and safety and broad-spectrum. It was the first-generation benzimidazole group and used against a wide range of hosts, i.e., goats, poultry, sheep, cattle, pigs, horses, and humans against gastrointestinal nematodes, and it shows ovicidal, larvicidal, and adulticidal activities. After TBZ’s success, it was planned to structurally modify it toward evolving drugs with excellent properties. Levamisole was discovered in 1966 and was marketed with the name of hydrochloride (HCL) salt having broad-spectrum antinematodal activities and immunomodulator effects [2].

Macrocyclic lactone derivatives including ivermectin (IVM) were discovered in 1981 broad-spectrum insecticidal activities. After this in 2009 after 28 years, monepantel was commercially released [3]. Broad-spectrum antinematodal synthetic compounds are divided into four major groups, i.e., macrocyclic lactone derivatives including milbemycins/ivermectin, benzimidazole/pro-benzimidazole group, tetrahydro pyrimidines group including morantel, pyrantel tartrate, and imidazothiazoles group including tetramisole and levamisole [1].

Commonly used chemotherapeutic groups are briefly reviewed in this review.

2. Benzimidazoles/pro-benzimidazoles and their mode of action

Compounds of this group are metabolized in the body and activate BZ metabolites. Members of this group are oxfendazole, ricobendazole, albendazole, thiabendazole, mebendazole, triclabendazole, oxibendazole, cambendazole, and other chemicals belonging to pro-benzimidazole, i.e., thiophanate, febantel, and netobimin [1].

Benzimidazole is effective against adult nematodes in ruminants and also has ovicidal and larvicidal activities. Some benzimidazole also exhibits anti-trematode and anticestodal activities. They are used in various hosts such as bovine, canine, equine, ovine, feline, reptiles, caprine, birds, and human species. In the case of humans, thiabendazole, mebendazole, and albendazole are used. They are having low toxicity and in some cases can be drenched 10 times than the calculated standard dose rate [2, 4].

All members of this group are having the same mode of action and disturb the energy metabolism of parasitic nematodes through binding with tubulin protein (alpha and beta molecules). This protein is present in plasma and microtubules and forms heterodimers and constructs blocks in polymeric microtubules [1]. Microtubules formation is a dynamic process affected by tubulin ring polymerization and depolymerization. Microtubules play an important role in cell division, energy metabolism, shape, and transport of substrate and protein assemblage. Benzimidazole group members bundle with β-tubulin, and this complex integrates at the propagating ends of the microtubules and inhibits the assemblage of extra microtubules. This whole process is known as capping [5, 6, 7].

They cause parasite undernourishment (due to failure in glucose uptake, the proliferation of microtubules, and protein secretion), reduction in acetylcholinesterase enzyme secretion, reduction in carbohydrate catabolism through fumarate reductase enzyme. Histological investigation of benzimidazole pharmacodynamics also reports their role in disturbance of microtubule aggregation in nematodes at those concentrations that do not influence mammalian cells (Figure 1) [1, 6, 8].

Figure 1.

Illustration of four different mechanisms of action by benzimidazoles against GI parasites.

3. Imidazothiazoles and their mode of action

Imidazothiazoles consist of two drugs, i.e., tetramisole and levamisole HCL (LEV). Levamisole is a Levo isomer and has true antinematodal activity while tetramisole is a mixture of Levo and destroys forms. That is why the calculated dose of levamisole is half that of tetramisole.

Levamisole is mostly used in goats, sheep, swine, and cattle while in the case of horses, it is contraindicated. This drug is having potency against both mature and immature stages. That’s why the calculated dosage of LEV is half that of tetramisole with a safety index of twice.

In sheep, goat, cattle, and swine, LEV is administrated, and in horses, mostly it is contraindicated. In several mature and immature stages of alimentary tract nematodes and lungworms, LEV has shown great potential. Whereas LEV is not anticestodal nor it is anti-trematode. LEV has not shown any ovicidal activity such as BZs. Whereas the remedial index of LEV is relatively lower than that of other antinematodal. LEV has also been found effective against hypobiotic larvae of the sheep parasitic nematode, H. contortus [1, 4].

The working mode of action of levamisoles has depicted that it works as a cholinergic agonist; it acts as nicotinic acetylcholine receptors on the surface of the nematode muscle cells along with neuromuscular junction. The antinematodal potential of LEV is mostly associated with its ganglion stimulant activity. It induces ganglion-like structure in somatic muscle cells of nematodes. The induction ultimately results in determining muscle contractions that are in line with the depolarizing barricades causing paralysis.

The pharmacodynamics of the compound plays an important role in the paralysis that leads to the elimination of helminths promptly through normal intestinal peristalsis (Figure 2) [1, 2].

Figure 2.

Illustration of the mechanism of actions of levamisole and ivermectin against GI parasites.

4. Macrocyclic lactones (avermectins/milbemycins) and their mode of action

Macrocyclic lactones have different commercialized products that show insecticidal activity against a broad range of parasitic nematodes and ectoparasites (ticks, mites, lice) that infest domestic animals [9, 10]. Avermectins that include doramectin, ivermectin, abamectin, and eprinomectin are the fermented products of actinomycete Streptomyces avermitilis. On the other hand, milbemectins including moxidectin and selamectin are the fermented products of Streptomyces cyanogriseus. On a chemical basis, avermectins differ based on the side chain of the lactone ring while milbemycins differ from each other because of the lactone skeleton [1].

The unequal larvicidal and adulticidal activity of IVM against Gastro-Intestinal Tract (GIT) roundworms and lungworms of ruminantia, porcine, and equine is its main factor of characterization [10, 11]. The control of microfilariae of canine heartworm Dirofilaria immitis is also achieved by the same chemical [1]. These chemicals do not have any anticestodal or antitrematodal activity nor are they ovicidal. Because of the nematicidal, acaricidal, and insecticidal activity of IVM, it is frequently used in sheep in different countries [4].

IVM along with other ML derivatives such as moxidectin is frequently used against haemonchosis in sheep due to its mode of action [1]. This increases their influence by binding to glutamate and GABA-gated chloride channel receptors in nematode and arthropod nerve cells. The whole process results in the opening of the channel and allows the entry of chloride ions (Cl⁻). This will lead to the paralysis of the body wall, pharyngeal muscles, and uterine muscles in nematodes [12]. It is stated that the sensitivity of dissimilar chloride channel subunits to MLs and expression location are variable characters, and it can be accounted for the paralytic effect of different concentrations of MLs on the neuromuscular systems. It is also stated that nematode paralysis and body wall muscle paralysis can be proved serious for prompt exclusion, also pharyngeal muscle paralysis is more sensitive [13]. It has also been revealed that MLs cause the flaccid paralysis of the pharynx of nematodes along with moxidectin and IVM as it is more sensitive than somatic musculature, which shows that the target is the nervous system of parasites. If the concentration of MLs drops, then the motility of the parasites can be recuperated. As compared with somatic muscles, the paralysis of the pharyngeal muscles, as well as consequential inhibition of nourishing, can be longer. The reason for the ineffectiveness of ML derivatives against trematode and cestode parasites is that these worms do not have receptors at their glutamate-gated chloride channel.

5. Anthelmintic resistance of GIT nematodes

Resistance development against anthelmintics consists of a certain phase, i.e., during first phase, number of parasites developing resistance against specific anthelmintics is less; there is a gradual increase, and heterozygous parasites develop resistance and lead to the final phase where individuals become resistant against those anthelmintics, and the population becomes homozygous parasites population. It is also observed that parasite resistance against a specific anthelmintic also brings resistance against some other anthelmintics groups [14].

Resistance is a drug tolerance ability of a worm and survives in the recommended doses of anthelmintics that are normally an effective dose [15]. Parasitic resistance was first described in 1957, and firstly studied anthelmintic agents were organophosphates, phenothiazine, rafoxanide, thiabendazole, and macrocyclic lactones [16]. Recently different GIT parasites especially H. contortus resistance are studied against different anthelmintics groups, i.e., rafoxanide, macrocyclic lactones, phenothiazine, organophosphates, levamisole, ivermectin, and thiabendazole in small ruminants [17]. It is also noted that resistance development started after a few years of drug development especially in H. contortus [18]. But, the resistance of the parasites against a broad spectrum of anthelmintics is increasing gradually within days; multiple factors are involved in developing resistance such as excessive and repeated use of the same anthelmintic, underdosing, poor management, etc. [19, 20]. Resistance of some GI parasites, specifically of H. Contortus against diverse groups of drugs, namely rafoxanide, organophosphates, phenothiazine, macrocyclic lactones (ivermectin), thiabendazole, and levamisole in small ruminants, has been reported worldwide [18]. Currently, numerous tests are available for the detection of anthelmintic resistance of GI parasites including in vitro egg hatch assay, fecal egg count reduction test, in vivo anthelmintic efficiency assay (AEA), and tubulin binding assay (TBA) [21]. The prominent anthelmintic classes reported for resistance of H. contortus in sheep [3, 22] have been presented in the Table 1.

Imidazothiazoles (Levamisole HCL)	Benzimidazoles (most members)	Tetrahydropyrimidines (Morantel and Pyrantel)
Common	Very common	Less common
Salicylanilides (Closantel)	Avermectines (Ivermectin and Moxidectin)	Amino acetonitrile derivatives (Monepantel)
Common	Common	Less common

Table 1.

The renowned anthelmintic classes (with drug examples) reported resistance [3, 22].

6. Geographic regions where resistance has developed

Initially, the development of resistance against nematicidal drugs was reported in the Southern hemisphere, and the most resistant was studied on H. contortusnematode. The development of resistance has differed geographically based on various factors such as weather conditions, species of parasite, mode of therapy, use of variable drugs, etc. The resistance rate is slightly lower in temperate zones in the Northern hemisphere [1, 23]. Prominently in the previous three decades, anthelmintic resistance is reaching its peak and becoming a great issue in livestock development, and the resistance is being reported around the globe including South Pacific, Australia, Latin America, North America, Africa, Eastern Union, and Southeast Asia [23]. Several studies reporting the occurrence of antinematodal resistance against various chemotherapeutic agents residing in sheep abomasa from different parts of the world are shown in Table 2:

Country	Anthelmintic drugs	Reference(s)
Argentina	BZs, LEV, IVM	[24]
Australia	Ops, BZs, LEV, TBZ, OXF, Closantel, Morantel	[19, 20]
Belgium	BZs	[25]
Brazil	BZs, LEV, IVM, Closantel	[24]
France	BZs, LEV	[26]
Germany	IVM,BZs, Pyrantel tarterate, FEN, Febantel, OXF, LEV, TBZ, ALB, MBZ	[27]
India	BZs, IVM, FEN, Morantel, Closantel, LEV, Thiophanate,	[28]
Kenya	BZs, LEV, RAF, FEN, IVM	[29]
Malaysia	BMZ, LEVS, IVM, Moxidectin, Closantel	[25]
Netherlands	OXFS, LEVS, BMZ, IVM	[30]
New Zealand	BMZ, LEVS, IVM	[18, 31]
Pakistan	OXFS, LEVS, ALB, IVM	[32, 33]
Paraguay	BMZ, LEVS, IVM	[34]
South Africa	BMZ, IVM, RAF, Closantel	[35]
Uruguay	BMZ, LEVS, IVM	[36]
United State of America	FEN, IVM, Pyrantel pamoate, LEVS, TBZ,	[37, 38]
Zimbabwe	RAF, BMZ, LEVS,	[39]

Table 2.

Geographical distribution of anthelmintic resistance developed by helminths in different parts of the world (selected references).

ALB = Albendazole, BM_Z = Benzimidazoles, FEN=Fenbendazole, IVM = Ivermectin, LEV_s = Levamisole, OXF_S=Oxfendazoles, RAF = Rafoxanide, and TB_Z = Thiabendazole.

Hence, the growing anthelmintic resistance is threatening livestock production, increasing the toxic level in the environment, and ultimately reducing the food availability for human beings [23, 40]. Therefore, the scientists and parasitologists are performing the duty to raise one’s hope by launching alternatives to overcome the developing resistance such as biological control (phytotherapy) [33].

7. Globally applicable gastrointestinal nematodes control measures/strategies

Control of gastrointestinal nematode parasite (GINP).

Numerous techniques and plans have been utilized to lower the gastrointestinal (GI) nematode parasites of small ruminants across the world. Some of the techniques and methods are appropriate, and a few of them have limitations. Moreover, new methods and new approaches are being evaluated and established. The prime methodologies that have been used routinely to reduce the burden of GI nematodes are reviewed here.

7.1 Chemical control methods

7.1.1 Chemotherapy (anthelmintic)

Anthelmintics are those drugs that kill the helminths and are playing a toxic role to the worms and can be achieved by exposing the nematodes to a higher concentration of anthelmintics. This higher concentration is for worms not for the host body cells. This higher concentration inhibits the vital metabolic processes of the worms and kills the worm either by starving it or paralyzing it [23]. Resistance is a reduction in the efficacy of certain anthelmintics against parasites that are susceptible to anthelmintics in normal conditions [41]. Chemotherapeutic application is a very common and primitive method (conventional) to control the GINP around the globe. The agents have been used for both therapy and prophylaxis. Benzimidazole, Ivermectin, and Imidathiazole are three major chemical groups that have been used frequently for decades.

Several reports are published that demonstrate the resistance generation of GI nematodes to these chemicals worldwide [23]. Few studies reported the higher level of resistance produced against the broad-spectrum anthelmintics and also reported the side effects at higher dose levels [41]. A higher level of resistance in H. contortus is developed in the endemic areas of haemonchosis. Nevertheless, the side effects and resistance produced by the excessive use urged scientists to adapt alternative GI nematode control methods to reduce the risk of environmental pollution. The consumer requested “clean and green” by-products that are free from residuals and growth promoters and cost-effective, and scientists were appealed to work for the launching of new and effective drugs and strategies [23]. Various factors such as frequent dosing of the same brand to infected and noninfected without discrimination, wrong choice, inappropriate administration massively involved in the development of resistance and reoccurrence of disease with re-exposure of the parasites [41]. H. contortus (roundworm) has been reported as resistant to all broad-spectrum families of anthelmintics [33, 35, 42].

Resistance is a global issue, and some regions are more exposed to it as compared with others, e.g., tropical and subtropical regions are more affected by the resistance of GI nematodes [33]. Soli et al., [40] reported multiple anthelmintic resistance in goats from Punjab Pakistan, and various other researchers also reported anthelmintic resistance in goats [33, 35, 42]. The most extensively used model for the control of nematode parasites is the use of chemical agents, and among these the most commonly used chemicals are benzimidazoles and avermectin. However, resistance development against these anthelmintics results in difficulty in the use of these chemicals as a control measure at the farm level [23]. High-degree resistance is reported in parasites against multiple chemical agents [43]. Along with H. contortus, some other nematode parasites develop resistance and are studied well, e.g., Trichostrongylus spp. and Ostertagia spp. [23]. Due to resistance development, the introduction of new administered drugs shows reduced efficacy [41].

Regions where haemonchosis is endemic and anthelmintic treatment is frequently used at the farm level are exhibiting more resistance in H. contortus. So, the use of alternative strategies is the necessity of time to control parasite burden at farm level, and also consumer demand is changed; they need cost-effective and residual-free strategies for control [23]. Some other methods are also used for the control of parasites in the animal industry, which are still underutilized and can be a more successful alternative against resistance development issues.

7.1.2 Copper oxide wire particles

In grazing ruminants, copper is administered along with diet as a feed additive to overcome the deficiency symptoms. The use of copper started in the 1900s, in various forms to minimize the worm load (SCSRPC). The use of copper oxide wire particles (COWPs) was found more successful in reducing nematodes, more precisely H. contortus [40, 43]. Following administration of COWP, it enters the abomasum along with the ingesta and sticks to the mucosal folds [44]. In the acidic conditions of the abomasum, stuck elements take several weeks to dissolve, and free copper is released slowly, which augments the soluble copper concentrations. Ultimately, copper reserve of the liver increases. The copper mode of action is yet to be understood, but researchers assumed that it alters the abomasum conditions that hinder nematode attachment and cause their death or expulsion. Following the COWP ingestion, an increase in packed cell volume (PCV) and a decline in EFC have been observed. The efficacy of COWP is higher against adult worms of abomasum but ineffective in the case of intestinal helminths [43]. Therefore, fecal culture is recommended to explore the higher population of H. contortus, before COWP administration [45]. The COWP is found to be equally effective against nematodes in both sheep and goats [40].

For administration in cattle, COWP boluses (Copasure©) of 12.5 and 25 g are available and for small ruminants, smaller dosages of 0.5–2 g are used [40, 43]. The recommended COWP dosage for cattle of weight above 227 kilograms was 12.5 g [45]. The sensitivity of sheep is higher against copper, and a little higher dosage may lead to toxicity although COWP is released slowly. Risk factors of copper toxicity that should be considered during administration are animal breed, age, health status, and other minerals deficiency such as molybdenum, poultry litter exposure [46]. Investigation on the use of COWP among exotic artiodactyls has been performed at Disney’s Animal Kingdom® Lodge. During the trials, four artiodactyl species included roan antelope, blesbuck, scimitar-horned oryx, and blackbuck. The corollary of their study indicated a marked reduction in EFC (above 90%) on day 7 post-COWP therapy. The animal species variations, liver health status, copper level, interaction level with other minerals, and history of copper supplementation should be considered before the implementation of the COWP GIN control program in exotic animals. Before the use of COWP in an integrated pest management program, the impact of COWP on reproduction, accumulation level, and sensitivity level among species should be investigated [45].

7.2 Nonchemical methods to control GI parasitism

7.2.1 Biological control

In this perspective, the naturally found pest antagonist organisms are used to control the pest population. Grønvold et al. [47] ascertain the role of fungi as nematophagous, earthworm, and dung beetle as anthelmintic [48], and these are potentially effective biological agents. Biological control is an effective way of overcoming the GI helminths. Mainly nematophagous fungus, Duddingtonia flagrans, is used to control the nematodes infesting GI tract. During the field trial, it shows encouraging results toward sheep and goats’ GI nematode parasite control [42]. The fungal spores are fed to animals along with a diet that passes through the GI tract without harming the gut mucosa. Fungus sporulates in animal feces and their hyphae kill the nematode larvae in fecal material; hence, diminished the pasture burden of nematodes larval stage [49, 50, 51, 52]. The use of nematophagous fungi is an effective alternative approach, but there is a limitation regarding delivery to animals and antagonist role of other drugs, namely benzimidazole as an antifungal agent. Duddingtonia flagrans also show their effectiveness toward the larvae that escape out after the COWP treatment, which proposes another application of biological control for helminths [43].

The biological control strategies were proposed to reduce the parasite population below the economic threshold and clinical level above that considerable production losses are there. High efficacy of D. flagrans was noticed against larval stages of various nematodes of cattle [47], sheep [53], and horses [52]. It has been proven by field trials that among grazing animals, daily fungal spores feeding for 3–4 months hinder the build-up of various larvae up to dangerous levels on pasture.

Sheep feeding supplemented with D. flagrans chlamydospores lowers the egg counts and improves animal weight gain in comparison with untreated animals [54]. For the application of nematode-trapping fungi against GINs of ruminants, a strategy was formulated [55]. D. flagrans can produce a large quantity of thick-walled chlamydospores, which makes them more effective against nematodes in comparison with other nematode-trapping fungi [56]. D. flagrans is used as a biological agent against nematode such as H. contortus in grazing animals [42].

7.3 Control through monitoring

7.3.1 Parasite monitoring strategies

Strategies for worm load investigation: FEC, larval developmental assays (LDA), FEC reduction test, and fecal larval culture (FLC) have proved valuable linkage with monitoring and control of worm infection. Mainly FEC is used for monitoring and management of GIN parasites. LDA is used for nematode species identification and to explore the resistance level [57]. FLC helps in identifying worm species, seasonal variation, and enclosure of GIN population. FECRT is the most authentic approach to determine anthelmintic resistance, but it is expensive and labor-intensive [57]. The demands for the exploration of alternative strategies toward helminth control have been augmented due to the lack of new anthelmintics. The applications of plants having condensed tannins, COWP, nematophagous fungi, and other biological approaches in combination with anthelmintics, animal management, control of ecological factors, and GIN level monitoring strategies could be effective to overcome GIN resistance in small ruminants.

7.3.2 FAMACHA chart and mac master technique

Among TST methods FAMACHA chart and McMaster are mainly used way to identify the worm-infected animals and require treatment. The former method is used to diagnose anemic animals by comparing their eye (conjunctiva) color with the chart. The latter method provides a real-time picture of parasite burden via egg counting in fecal material. In the McMaster method, fecal material is suspended in floatation solution and supernatants are taken on a specific glass slide (Mc Master chamber) and observed under a microscope for egg counting. For reducing anthelmintic resistance among GI parasites, selective therapy is highly effective. By using the aforementioned methods, medicinal cost of animals declines because they selectively purchase few anthelmintics and animals are responsive against these drugs. On the other hand, selective therapy is laborious and time-taking, farmers have to perform the FAMACHA check once a month. Routine-wise performance of McMaster is mandatory because sometimes with FAMACHA check animals found healthy while through McMaster they were found with high worm burden, and such animals should be treated because these animals may act as a source for others. The FAMACHA score system is found to be highly effective in the selection of worm-resilient animal breeds [58].

7.4 Control through management

7.4.1 Pasture management, grazing management, rotational grazing

For the control of GI nematodes infections, two most commonly used methods include the use of anthelmintics and pasture management; they are associated with reduction of production losses because of nematodes infections. Two ways of producing safe pastures and reducing the infectivity of pasture include rotational grazing and pasture spelling, this strategy is very [59]. In rotational grazing, it is assumed that significant larval mortality occurs because of break-in grazing. But, unfortunately, the period in between animal rotations makes the best use of available and nutritious forage coincides with the period during that high concentration of L3 becoming available for reinfection. In the United States, a study was conducted at a farm and reported that lambs raised under a rotational grazing system were highly infested with helminths in comparison with others. Most of them were infected with nematodes, H. contortus, and gained less weight in comparison with control (non-grazing). It is therefore concluded that rotational grazing is not a good option in sheep. In some situations, it is recommended to extend the periods between the rotations of (60–90 days) as it may significantly lessen the parasitic infection. Rotation of younger susceptible animals with highly resistant older animals may prove to be beneficial. But such a strategy may not be possible due to practical restraints [35].

7.4.2 Manipulating supplementation of nutrients

With the provision of a good and high level of nutrition, the productivity of animals can be improved with an increase in the immune response against parasites. With an increase in the level of proteins in the diet, an increase in the resistance and resilience of lamb against H. contortus has been observed [60]. The supplementation of a meal with sorghum and soybean for the grazing kids has shown increased resilience against helminth parasites [61]. Indeed, improvement in nutrition is an efficient strategy to lessen and compensate for the negative impacts of parasitic infection. Whereas approach to urea molasses increases both resistance and resilience in grazing East African goat kids in an environment overshadowed by H. contortus [62]. In a review by Hoste et al., [63], it has been discussed that the supplementary feeding to the goats has shown an increased response concerning resilience, whereas the effects on host resistance were less prominent.

7.5 Control through medicinal plants

In ethnoveterinary medicine, medicinal plants are used for the prevention and treatment of gastrointestinal parasitism. There is a wide range of medicinal plants or plant extracts that are used to treat almost every kind of livestock disease related to parasites. There are so many studies and available literature on the anthelmintic properties of plants and their extracts, which confirms the antinematodal effects of these plants [33, 42, 64, 65, 66, 67]. In comparison to synthetic drugs the herbal preparations are way cheaper and easily available and thus have been used for a long time in the therapy of livestock diseases of helminth parasites [68].

Many plants and herbs are used as control agents for human and veterinary endoparasites, and the efficacy of each plant depends upon the chemical composition and secondary metabolites composition. The composition of a plant is a variable character depending upon soil properties, climatic conditions, geographical variability, and environmental conditions. Anthelmintic activity of a plant is variable in different areas of the world and depends upon the harvest of the plant, plant parts, which are used as anthelmintics, storage of the plant, and combination of different plant extracts [68]. Choice of extraction solvent is also an important factor that affects the solubility of secondary metabolites of the target plants usually water and methanol are used as extraction solvents. Ethanolic extracts are considered a better choice as they can easily enter the body of the parasite through absorption [69].

To determine the plant properties, two different study types are used. i.e., in vitro and in vivo, and each study type has some merits and demerits. In vitro studies are cost-effective and can study a variety of plants at the same time, allowing the study of specific parasites and their lifecycle stages [70]. While in vivo studies are lengthy processes and can study a single plant at a time. Sometimes the result of the in vivo and in vitro can be different as the outcome of the study depends on the internal factor of the host and plant species, e.g., the digestive system of the host [71].

Till today 25% of modern pharmacopeia use plant-derived drugs and some semisynthetic using plant as prototype compound [72]. Anthelmintic efficacy of plants is derived from different parts, e.g., saponins (can cause teguments degradation and vacuolization), tannins, and polyphenols can form a protein complex in the rumen and increase the protein supply, interfere with energy generation, reduction in gastrointestinal metabolism, and ultimately death of the helminth and alkaloids (effect the transport of sucrose transfer from the stomach to the intestine and helminth glucose support is disturbed causing paralysis) [73].

7.5.1 Condensed tannins

Tannins are compounds that attach with proteins and other molecules and are used as a biological alternative against chemical anthelmintic; many plants naturally contain condensed tannins. There are two main groups in which tannins are divided: one is hydrolyzable tannins (HTs) and the other one is condensed tannins (CTs). Among the two of these groups, condensed tannins are more abundant and are naturally present in browse, legumes, plants, and forage. The concentration of CT, type of animal consuming CT, the plant itself, and the concentration of CT in the plant are the factors that stimulate the effects of CTs. The high concentration of CT can have negative effects, and the noticeable negative effect is reduced palatability that ultimately causes a reduction in intake and digestion, which exerts a negative impact on productivity [46]. There are several benefits of CT intake that include increased wool growth and growth rate, increased amount of bypass protein, reduced bloating, high milk production, as well as a high rate of ovulation.

The prominent and most important benefit of CTs is their positive impact on the GIN infection. It has been observed that CTs specifically H. contortus reduce the GIN infection, it also reduces the overall egg output through the reduction in female fecundity. In addition to this, there is also a decrease in the GIN egg hatchability and the development of larva in the feces. Concerning reduction in GIN infection, the most important and researched CTs include big trefoil, sericea lespedeza, sulla, and sanfoin [46]. When the animals are allowed to graze SL management benefits have been observed that are less exposure to GIN as the plant grows off the ground, and since there is also an increase in the level of proteins that causes a potential increase in the resilience and resistance.

7.5.2 Plants as nutraceuticals

The nutritional combination of animal feed affects the biodiversity of GIT fauna, which may affect the parasite fitness by altering the intestinal environment in which the parasites propagate [63]. Tannins, flavonol glycosides, sesquiterpene, and secondary metabolites are potential candidates for integrated nematode control at the farms level [63, 74, 75]. The plants having these properties are known as nutraceuticals, which are considered for both the nutritional value and as an anthelmintic. It has been reported that supplementation of bioactive plants to goats played role in the regulation of bionomics of resistant parasitic populations along with enhancing the ability of the goat to withstand negative effects of the pathophysiology of parasitic infections [63]. An increase in post-ruminal protein availability playing role in reducing the parasitic infections in large ruminants has also been reported, which may be attributed to the availability of condensed tannins (CTs) or proanthocyanidins and polymers of flavonoid units [48].

7.6 Control through immunological interventions

7.6.1 Vaccines (immunization and vaccination)

The most effective way of controlling infection is vaccination; therefore, demand for vaccine development against GI parasites rises. In disparity with vaccines of viral and bacterial pathogens, vaccine development against parasites did not gain similar success although parasitologists are working in this regard for the last 30 years. The vaccine has been developed against tapeworm and lungworm sheep and cattle respectively. Studies have been conducted in the identification of various antigens of nematodes as vaccine agents [76]. Gut-associated antigens have been reported as vaccine candidates, namely H-gal-GP and H11 of H. contortus [77]. Fecal egg count has been markedly declined in goat kids with the use of vaccine candidates. Secretory and excretory products of parasites have been found as effective vaccine candidates. It has been reported that the use of secretory and excretory antigens as vaccine candidates in infection of H. contortus results in enhancing the immunity of the host, thereby reducing the FEC and worm burden by 70% [78]. It has been reported that the use of H-11 and H-gal reduces 60–75% of worm burden and 80–90% FEC, and they can be good candidates for vaccine development [79]. Both of these candidates have been reported to induce protective immunity in terms of IgG production, PCV maintenance, FEC, and worm burden reduction in lambs and kids [77].

Traditional use of chemotherapeutic agents against infection of ectoparasites as well as endoparasites leads to the development of resistance against these therapeutic agents. It converges the scientists for exploring the nontraditional ways of controlling GI parasites; development of a resistant breed of the host through selective breeding, vaccine development, implementation of other control measures (alternate pasture grazing and rotational grazing), and synergistic use of anthelmintics [80].

In vaccines, acquired immunity plays a pivotal role in the protection of the host against pathogens, and it needs to be explored for the development of a vaccine. In the case of parasites, the role of acquired immune response is not fully explored. Therefore, vaccine development against GI parasites for protection remains ineffective [81].

Some fungi of Arthrobottrys spp. have been reported to attack and kill the larvae of nematodes in fecal pats, but these fungi are being killed by passage through the gut and therefore are of no great importance, but nowadays, a new fungus D. flagrans has been reported, which will grow and pass through the gut harmlessly and is active against larvae of nematodes in fecal pats [13].

8. Alternatives

Gastrointestinal nematode resistance to anthelmintics has been growing day by day, gaining currency to consider it for adopting control measures shortly of the domestic livestock industry. The use of chemical anthelmintics in combination with bioactive plants as nutraceuticals seems to be a potential strategy for parasitic control. Alternate strategies, i.e., use of plants containing condensed tannins, plant-based vaccines, COWP, and biological control through nematode-trapping fungi along with husbandry management may prove helpful in minimizing the mortality and morbidity of parasitic diseases in small ruminants. However, animal breeds selected based on their response to nematodes present in the gastrointestinal tract are an alternate control strategy toward minimizing gastrointestinal problems in goats [43].

8.1 Breeding for resistance

Identification of resistant individuals is necessary for the production of parasitic-resistant breeds. Two parameters are mostly reported for the selection of resistant breeds, i.e., FEC, which is an indirect parameter for measurement of the relative level of infection [82]. Hematocrit and PCV are being used for the identification of worm burden, especially in the case of H. contortus. In Australia, FEC both in natural and artificial infections has been used for many years to select the animals for parasitic resistance [83].

The researchers cannot divide the magnitude of resistance into discrete genetic units; therefore, the resistance is described in the form of heritability estimates [84]. The phenotype of quantitative traits is regulated by the additive effect of specialized genes [85], which are yet to be identified. The resulting resistance may be attributed to the effect of a combination of many small genes or a group of major genes that are being regulated not only by additive effects but also by the environmental effects [84].

8.2 Genetic and phenotypic parameters for worm resistance

Packed cell volume and fecal egg count are the most useful markers/parameters to estimate the response of host challenge and natural infection with nematodes present in GI in general and specifically H. contortus. Both PCV and FEC are heritable traits. Heritability of FEC ranges from 0.04 to 0.37. Morris et al. [86] described a heritability estimate of 0.05 in Saanen goats at the age of 12 months in New Zealand, and Woolaston et al. [87] described a heritability estimate of 0.04 and 0.08 in Fijian goats at 12 months of age in Fiji. [88]. Similar studies have been conducted in Kenya where they found FEC heritability estimates of 0.15, 0.16, and 0.12 in small East African goats at the age of 4, 5, 8, and 10 months, respectively. Some more studies have been conducted by Vagenas et al., [89] in Scotland, and they found 0.37 and 0.32 estimates of heritability for FEC in Scottish Cashmere goat’s breed.

8.3 Genetic and phenotypic correlation between resistant traits

Estimations of phenotypic and genetic correlation explained the amount to which genes affect two different traits and the phenotypic correlation guides the number of relations between two traits. Correlation evaluations are important in the measurement of the appropriateness of indicator traits as indirect criteria in programs related to breeding. Mandonnet et al., [88] under tropical conditions, stated positive (0.37–0.58) and negative (0.56–0.79) genetic correlations between FEC and PCV and eosinophil and FEC amount in goats. Costa et al., [66] in Brazil also describe a highly negative and significant relationship between changed PCV and FEC or hemoglobin −0.53 and − 0.45 in H. contortus infected goats. Very strong negative correlations between IgA activity and FEC have been found in Teladorsagia circumcincta infected Scottish Blackface lambs (−0.97, s.e. 0.11 and − 0.78, s.e. 0.18, respectively) and also in resistance-related traits and burdens of worms [90].

8.4 Genetic and phenotypic parameters for production traits

Host live weight is a production trait that has been considered as an important parameter while assessing the genetic resistances of the host toward GI nematode parasites. The heritability estimates of live weight (LWT) varied widely ranging from 0.13 in Australian Angora goats to 0.50 in Texan Angora goats [91]. Likewise, heritability estimates have been reported in South Africa goats breed as 0.29 and 0.35 [92]. It has been shown that resistance to infection by nematode parasites may not necessarily equate to resistance to the effects of the parasite challenge in grazing animals [86]. The association between FEC and productivity varies in magnitude and direction depending on the breed and the environment in which the evaluation was done. The genetic correlations between packed cell volume (PCV) and packed cell volume decline (PCVD) and production (live weight and wool growth) are either negligible or favorable [93].

Several studies around the globe have been conducted to assess the genetic potential of sheep and goats breeds that are resistant to gastrointestinal nematodes in the last three to four decades [82, 83, 87, 93]. The selection of breeds that are resistant to gastrointestinal nematode parasites is assuming the most promising alternate control method of gastrointestinal nematodes. Improved resistance toward nematodes control leads to reduced cost of anthelmintic treatment and diminished production losses associated with worm burden. Australia and New Zealand initiate programs on breeding for resistance and adopt them successfully by utilizing phenotypic markers [94]. Approximately 96% of the world’s goat population is kept by smallholders in developing countries, and genetic improvement programs are rare [95].

8.5 Phenotypic traits as indicators of GI resistance

Host selection for resistance has based mostly on quantitative measurement of phenotypic traits. These traits have been measured to check the response of the host being evaluated for resistance, which are biochemical, immunological, parasitological, and pathological features [84]. For the development of high-resistant breeds, it is necessary to identify the high-resistant individuals. Criteria for the selection of parasitic resistance are commonly based on two traits, i.e., packed cell volume, which indicates anemia, and fecal egg count, which measures the amount of infection. There is variation in the development of resistance between the animals of different breeds and within the same breeds, which is because of their genetic makeup. The scientists are working to investigate the cause of the development of resistance, and up to some extent they succeeded in finding some reasons while the others are under investigation [84].

9. Conclusion

According to the best of our knowledge about different factors that are responsible for GI parasitism, it is hard to develop control measures. So, the epidemiology of each parasitic disease is needed to be studied at the regional level to recommend an effective strategy for the control of parasitic diseases, which is not completely dependent on anthelmintic therapy [11]. Keeping in mind the subtropical and tropical areas in which dry seasons are more might be grazing management, rational use of anthelmintics, and use of resistant breeds.

Acknowledgments

The author wishes to thank all other coauthors for providing guidance and support.

Conflict of interest

The authors declare that they have no conflict of interest.