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Resistance to Anthelmintics

By Jozef Vercruysse, DVM, Ghent University ; Edwin Claerebout, DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University

The development of nematode and trematode resistance to various groups of anthelmintics is a major problem. Compared with development of antibiotic resistance in bacteria, resistance to anthelmintics in nematodes has been slower to develop under field conditions. However, resistance is becoming widespread, because relatively few chemically dissimilar groups of anthelmintics have been introduced over the past several decades. Most of the commonly used anthelmintics belong to one of three chemical classes, benzimidazoles, imidazothiazoles, and macrocyclic lactones, within which all individual compounds act in a similar fashion. Thus, resistance to one particular compound may be accompanied by resistance to other members of the group (ie, side-resistance).

In nematodes of small ruminants, and especially in Haemonchus contortus, resistance to all classes of broad-spectrum anthelmintics has reached serious levels in many parts of the world. Resistance also has been found in Trichostrongylus spp, Cooperia spp, and Teladorsagia spp in sheep and goats. Reports of multiple resistance to most major classes of anthelmintics are increasing. Recently, resistance to monepantel has occurred in the field (New Zealand) in at least two nematode species (Teladorsagia circumcincta and Trichostrongylus colubriformis) after being administered on 17 separate occasions to different stock classes and in <2 yr of the product first being used on the farm.

Resistance to benzimidazoles is widespread in cyathostome nematodes of horses. Parascaris equorum resistance to macrocyclic lactones (ivermectin and moxidectin) has been reported in many countries. Macrocyclic lactone resistance in cyathostomes is only occasionally suspected, however, and the problem is still not considered to be serious.

There are limited reports of resistance against levamisole, pyrantel, and benzimidazoles in Oesophogostomum dentatum in pigs.

Multidrug (benzimidazoles and macrocyclic lactones) resistance in cattle nematodes has been documented on farms in New Zealand, the Americas, and Europe, and this will probably become more widespread. In most cases of resistance against macrocyclic lactones, Cooperia spp were identified as the resistant worm species, but macrocyclic lactone resistance is also emerging in Ostertagia ostertagi. The full extent of anthelmintic resistance in cattle nematodes is unknown.

The development of significant levels of resistance seems to require successive generations of helminths exposed to the same class of anthelmintic. However, evidence suggests that genes for resistance are invariably present, at a low frequency, for any given anthelmintic. Selection for resistance simply requires the preferential killing of the susceptible parasites and survival of the parasites with the resistance genes. Side-resistance is frequently seen between members of the benzimidazole group because of their similar mechanisms of action; control of benzimidazole-resistant parasites by levamisole can be expected because of its different mode of action. Although there is no evidence for cross-resistance between levamisole and benzimidazoles, this does not mean that worms resistant to both kinds of drugs will not evolve if both types of anthelmintics are used frequently. Nematodes resistant to levamisole are cross-resistant to morantel because of the similarities of their mechanisms of action. When resistance to the recommended dose rate of an avermectin appears in some species of nematodes, a milbemycin, at its recommended dose rate, may still be effective. However, there is side-resistance among the avermectins and the milbemycins, which are within the same class of anthelmintics, and continued use of either subgroup will select for macrocyclic lactone resistance.

Recently, it was demonstrated in Haemonchus contortus and Onchocerca volvulus that macrocyclic lactone anthelmintics can affect β-tubulin, although no mechanistic explanation for this has been published. However, it suggests that macrocyclic lactone use may select for benzimidazole resistance, because benzimidazole resistance appears to be largely due to a single polymorphism being selected. However, benzimidazole resistance was widely reported before the commercial use of macrocyclic lactones. Ivermectin resistance has usually been reported in areas of the world where benzimidazole resistance is already widespread. In using anthelmintic combinations or rotations, consideration should be given to the genetic interactions in the parasite between benzimidazole and macrocyclic lactone anthelmintics in terms of selection for the alleles that confer benzimidazole resistance.

Every exposure of a target parasite to an anthelmintic exerts some selection pressure for development of resistance. Therefore, management practices designed to reduce exposure to parasites and to minimize the frequency of anthelmintic use should be recommended. The development of an anthelmintic resistance problem may theoretically be delayed by rotating chemicals with different modes of action annually between dosing seasons. Drug combinations may be another appropriate choice, provided the anthelmintics used in the combination are both effective and select for different resistance mechanisms.

In parasite control, economic benefit is best obtained by careful management practices. Planned (or targeted) treatment of a whole flock or herd should be based on the biology, ecology, and epidemiology of the parasite(s), with particular reference to climatic conditions. There is a trend among parasitologists to recommend replacing current practice for worm control involving repeated dosing of whole groups of animals with “targeted selective treatments” in which only individual animals showing clinical signs or reduced productivity are given drugs.