Resistance to Anthelmintics in Animals

The development of nematode and trematode resistance to various groups of anthelmintics is a major problem. Compared with development of antimicrobial resistance in bacteria, resistance to anthelmintics in nematodes has been slow to develop under field conditions. However, resistance is becoming widespread because relatively few chemically dissimilar groups of anthelmintics have been introduced during the past several decades.

Most 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 group members (ie, side resistance).

The table Anthelmintic Resistance provides an overview of nematode genera/species in different host species for which resistance has been reported against different anthelmintics or anthelmintic classes.

Once a genetic modification confers a survival advantage on a parasite, the organism becomes resistant to a given drug class and transfers that resistance to its progeny. Resistance mechanisms include decreased uptake or active efflux of the anthelmintic drug and alterations in target receptors or enzymatic cascades within the parasite. 

In nematodes of small ruminants, resistance to all classes of broad-spectrum anthelmintics has reached serious levels in many parts of the world. Multiple resistance to all major classes of anthelmintics has been identified in all of the economically important GI nematodes of small ruminants:

• Haemonchus contortus

• Teladorsagia circumcincta

• Cooperia spp

• Nematodirus battus

• Trichostrongylus colubriformis

Resistance to monepantel has occurred in the field in at least 3 nematode species (Teladorsagia circumcincta, T colubriformis, and H contortus) in different countries.

Resistance to benzimidazole is widespread in cyathostome nematodes of horses, and resistance of cyathostomes against pyrantel has also been reported. Macrocyclic lactone resistance in cyathostomes is only occasionally suspected, and the problem is still not considered to be serious. However, a shortened egg reappearance period after macrocyclic lactone treatment has been documented, which is indicative of developing resistance.

Parascaris spp resistance to macrocyclic lactones (ivermectin and moxidectin) is widespread. Reports also show treatment failure of pyrantel against Parascaris in North America, Europe, and Australia and of fenbendazole in Australia and Saudi Arabia. 

Treatment failure against Oxyuris equi has also been reported; however, it is unclear whether this truly is resistance or merely confirms the incomplete oxyuricidal efficacy of broad-spectrum equine anthelmintics.

Limited reports exist of resistance against levamisole, pyrantel, and benzimidazole in Oesophagostomum dentatum in pigs.

Although less prevalent than in small ruminants and horses, anthelmintic resistance is also emerging in cattle. In most cases of resistance against macrocyclic lactones, Cooperia spp were identified as the resistant worm species. Resistance against macrocyclic lactones, benzimidazole, and levamisole in Ostertagia ostertagi and benzimidazole resistance in Cooperia oncophora has also been demonstrated. Multidrug (benzimidazole and macrocyclic lactone) resistance in cattle nematodes has been documented on farms in New Zealand, South America, and Europe and will probably become more widespread. The full extent of anthelmintic resistance in cattle nematodes is still unknown.

Development of notable 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 susceptible parasites and survival of parasites with resistance genes.

Side resistance is frequently observed 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 benzimidazole, 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 due to the similarities of their mechanisms of action. When resistance to the recommended dose of an avermectin appears in some species of nematodes, a milbemycin may still be effective. However, side resistance exists among the avermectins and the milbemycins, which are within the same class of anthelmintics, and the continued use of either subgroup will select for macrocyclic lactone resistance.

FAMACHA card for parasite detection in small ruminants

Image

Courtesy of Dr. Edwin Claerebout.

In parasite control, long-term economic benefit is best obtained by careful management practices. To slow down anthelmintic resistance, a sufficiently large refugium (ie, the proportion of the worm population that is not exposed to anthelmintics and, consequently, is not under selection pressure for development of resistance) should be maintained.

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. Targeted treatment decisions can be supported by diagnostics, eg, Ostertagia- or Fasciola-specific antibody levels in bulk tank milk in dairy cattle.

Current practice for worm control emphasizes targeted selective treatment, in which only individual animals showing clinical signs, decreased productivity, or increased fecal egg counts are given drugs. For example, in regions where H contortus is the predominant nematode species in small ruminants, the FAMACHA color chart is used to identify animals that have parasite-induced anemia and require treatment, while other animals in the flock are left untreated to maintain a refugium.

Other examples of treatment decision parameters in sheep are the dag score and the body condition score. In horses, targeted selective treatment based on individual fecal egg counts is routinely performed in some countries.