Different classes of anthelminthic classes in use for treating helminth infections in Zimbabwe, mech
QUESTION
Describe the different classes of anthelminthic classes in use for treating helminth infections in Zimbabwe, mechanism of action, levels of resistance in the field and strategies which could be employed to delay resistance?
Anthelmintics are a type of medicine that kills helminths. Helminths are worm-like parasites such as flukes, roundworms, and tapeworms. Anthelmintics are used to treat people who are infected by helminths, a condition called helminthiasis. These drugs are also used to treat infected animals. There are several classes of anthelmintic and these include benzimidazoles and probenzimidazoles, salicylanilides and substituted phenols, imidazothiazoles, tetrahydropyrimidines, organophosphates, macrocyclic lactones and, more recently introduced, the amino-acetonitrile derivatives, the cyclic octadepsipeptides, and the spiroindoles.The major classes used in Zimbabwe being the benzimidazoles, tetrahydropyrimidines/imidazothiazoles ,ogranophosphates and macrocyclic lactones.
Anthelmintics must be selectively toxic to the parasite. This is usually achieved either by inhibiting metabolic processes that are vital to the parasite but not vital to or absent in the host, or by inherent pharmacokinetic properties of the compound that cause the parasite to be exposed to higher concentrations of the anthelmintic than are the host cells. While the precise mode of action of many anthelmintics is not fully understood, the sites of action and biochemical mechanisms of many of them are generally known. The pharmacologic basis of the treatment for helminths generally involves interference with the integrity of parasite cells, neuromuscular coordination, or protective mechanisms against host immunity, which lead to starvation, paralysis, and expulsion or digestion of the parasite
Benzimidazoles target a protein called tubulin, which has a major role in maintaining cell structure. The destruction of cell structure results in the death of the worm. Importantly, the drug is selectively toxic to worms, because even though tubulin is found in all cells (worm and mammalian), the drug binds more strongly to the worm tubulin.Examples include albendazole, fenbendazole, oxfendazole.
The tetrahydropyrimidines/imidazothiazoles act on the nervous system of the parasite. Muscle cell surfaces contain ion channels which control the chemical composition inside the cell. This drug class binds to a receptor on a particular type of ion channel. This causes paralysis of the worm muscle and results in worm expulsion. The drugs affect the worm but not the host because they are uniquely shaped for binding to worm receptor only.An example of tetrahydropyrimidines/imidazothiazoles is the Levamisole.
The macrocyclic lactones include Ivermectin, perhaps the most well known of this class of drug, as it is used to treat onchocerciasis (river blindness) in humans. Ivermectin binds to and disrupts a different type of ion channel in the worm cells, causing paralysis and inhibiting feeding and reproduction. Much like the earlier two classes of drug, the macrocyclic lactones also have a selective effect on worms because the specific ion channel is absent in the mammalian hosts.
Organophosphates inhibit many enzymes, especially acetylcholinesterase, by phosphorylating esterification sites. This phosphorylation blocks cholinergic nerve transmission in the parasite, resulting in spastic paralysis. The susceptibility of cholinesterases by host and parasite varies, as does the susceptibility of these different species to organophosphates.
Helminthic diseases are treated with a variety of drugs including macrocyclic lactones, benzimidazoles, imidazothiazoles and praziquantel. In animals, resistance to anthelmintics occurred rapidly after their introduction. There is considerable debate about the definition of resistance, and ‘tolerance’ is used to describe the stage between success and failure of drug treatment. Anthelmintic resistance is a major concern for farmers and veterinarians in Zimbabwe. Such resistance in livestock is a persistent and growing issue in all parts of the world and requires immediate attention. The development of anthelmintic resistance poses a large threat to future production and welfare of grazing animals. Development of variable degrees of resistance among different species of gastrointestinal nematodes has been reported for all the major groups of anthelmintic drugs. 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 helminthes. The degree and extent of this problem especially with respect to multidrug resistance in nematode populations is likely to increase.
In Zimbabwe, there are various ways in which farmers and veterinarians attempt to reduce the levels of resistance and these include an adoption of strict quarantine measures, a combination drug strategy are two important methods of preventing of anthelmintic resistance, good feeding strategies, alternative strategies for genetic improvement and a good pasture management. The farmers and veterinarians observed that the development of anthelmintic resistance suggests that modern control schemes should not rely on sole use of anthelmintics, but employ other, more complex and sustainable recipes, including parasite resistant breeds, nutrition, pasture management, nematode-trapping fungi, antiparasitic vaccines and botanical dewormers. Most of them reduce reliance on the use of chemicals and are environmental friendly.
In Zimbabwe, effective management strategies to prevent development of anthelmintic resistance are worthless if producers purchase resistant worms residing in breeding stock. Therefore, strict quarantine procedures should be instituted for all new additions. The current recommendation is to quarantine (on dry lot where feaces can be removed) every new addition, dose with triple-class anthelmintic therapy, and perform fecal egg count reduction tests. Feed should be withheld for 24 hours before treatment, then moxidectin, levamisole, and albendazole should be administered consecutively (do not mix drugs together) at the appropriate dose for sheep or goats. Fourteen days later, treated animals should be evaluated by fecal egg count and fecal flotation techniques. The fecal egg count should be zero, and flotation should yield very few or no eggs. Furthermore, after receiving this treatment, animals should be placed on a contaminated pasture. Never should an animal be placed onto a clean pasture after a triple anthelmintic class treatment regimen is administered, because any surviving worms will be triple resistant and there will be no refugia on pasture to dilute the future transmission of any eggs that are shed.
Treating simultaneously with 2 drugs from different anthelmintic classes is another method of preventing the development of anthelmintic resistance in Zimbabwe. A computer based model has documented that if this strategy is used when the drugs are first introduced, before there is any selection for resistance to either drug, appreciable resistance will not develop for over 20 years. However, once resistance alleles accumulate in worm populations, this strategy will probably not be successful. Compared with individual drug effects, anthelmintics of different chemical classes administered together induce a synergistic effect, resulting in clinically relevant increases in the efficacy of treatment. This synergistic effect is most pronounced when the level of resistance is low. Once high-level resistance to both drugs is present, the synergistic effect is unlikely to produce acceptable levels of efficacy. In contrast, the same model indicated that rotating drugs with each treatment, using annual rotation or a 5- or 10-year rotation resulted in high-level resistance within 15 to 20 years. Thus, the common recommendation of annual rotation must be challenged.
Another method that is under study are alternate strategies for genetic improvement. There is considerable evidence that part of the variation in resistance to helminths infection is under genetic control. Resistance is most likely based on inheritance of genes that play a principal role in expression of host immunity. There are several breeds of sheep and cattle around the globe that are known to be relatively resistant to infection. Using such breeds exclusively or in crossbreeding programs would certainly lead to improved resistance to worm infection, but some level of production might be sacrificed. Although such a strategy may be acceptable to some, selection for resistant animals within a breed also is a viable option. Within a breed, animals become more resistant to infection with age as their immune system becomes more competent to combat infection. Some animals within such a population do not respond well and remain susceptible to disease; therefore, the majority of the worm population resides in a minority of the animal population. It would make sense to encourage culling practices where these minority ‘‘parasitized’’ animals were eliminated, thus retaining more-resistant stock.
Nutrition is another method by which farmers, veterinarians and parasitologists attempt to reduce the levels of resistance. The strongest link between nutrition and parasitism has been illustrated between protein intake and resistance to gastrointestinal nematode infection. Immunity is closely related to protein repletion. Gastrointestinal nematodes increase the demand for amino acids by the cattle and sheep. Supplementation with phosphorus has been shown to prevent worm establishment. Cobalt deficiency also has been associated with reduced immunity to gastrointestinal nematodes. Adequate copper values are necessary for development of immunity to gastrointestinal nematodes.
Good pasture management is another method of reducing the levels of resistance. Reducing exposure of susceptible hosts in control programs is paramount. The goal of pasture management is to provide safe pastures for grazing. Pastures should be subdivided into smaller lots to allow longer periods before regrazing. Pastures that have become heavily contaminated because of mismanagement can be tilled and reseeded. Stocking rate is an important consideration in parasite control as it affects exposure to infective larvae and contamination of the pasture. It is impossible to make a general recommendation on stocking rate as this will vary according to type of pasture, time of the year, current weather conditions, and type of animal being grazed.
In the early spring or at the onset to the rainy season, reduced pasture contamination is the most important aspect of control. Strategic deworming to remove arrested or recently emerged larvae before they contaminate the pasture will reduce pasture contamination. Treatment 2 weeks after a rain that removes recently acquired worms before they can begin passing eggs also will decrease pasture contamination. When plants high in condensed tannins are grazed, there is evidence that the incoming larvae are adversely affected as well as providing bypass protein for the host. If animals are allowed to browse, their chances of acquiring larvae diminishes as the distance from the ground increases. Most infective larvae are found within 2 inches (50 mm) of the soil surface.
Increasing evidence suggests that resistance is often the result of changes in genes other than the immediate drug target, including transporters and drug metabolism. From a clinical standpoint, it is important to appreciate that resistance is a genetic trait that only becomes expressed phenotypically once allele frequencies of resistance genes reach fairly high levels. Benzimidazole resistance could not be detected using phenotypic-based assays (e.g., egg hatch or fecal egg count reduction tests) until 25% of the gastrointestinal nematodes were resistant. Therefore, prevention of resistance must be aimed at reducing the rate with which resistance alleles accumulate, and strategies designed to slow the development of resistance must be in integrated early on in the process of resistance evolution, before there is any clinical evidence of reduced drug effect. This is accomplished best by following practices that ensure maintenance of an adequate level of refugia; a term used to describe the proportion of a parasite population that is not exposed to a particular drug, thereby escaping selection for resistance.
Most parasitologists now consider levels of refugia as the single most important factor contributing to selection for anthelmintic resistant parasites. Worms in refugia provide a pool of genes susceptible to anthelmintics, thus diluting the frequency of resistant genes. As the relative size of the refugia increases, the rate of evolution toward resistance decreases. In gastrointestinal nematodes of small ruminants, which have a direct life cycle, refugia are supplied by: 1) stages of parasites in the host that are not affected by the drug treatment, 2) parasites residing in animals that are left untreated with a particular drug, and 3) free-living stages in the environment at the time of treatment. For many years, parasitologists and veterinarians have recommended that all animals should be treated with an anthelmintic at the same time. However, this strategy has turned out to be unsustainable, and parasitologists now favor a selective approach where only animals in need of treatment actually receive medication. This selective approach is highly compatible with host parasite dynamics; parasite burdens are highly aggregated in hosts, with 20–30% of animals harboring 80% of the worms.
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