Donkeys are subjected to a wide array of parasitic infections. Due to the lack of commercial vaccines, anthelmintic drugs constitute a fundamental tool in the control and prevention of parasitic infections in donkeys. Currently available anthelmintics include: macrocyclic lactones (eg ivermectin and moxidectin), benzimidazoles (eg fenbendazole and mebendazole) and tetrahydropyrimidines (eg pyrantel). The challenges to curing infections with parasitic helminths or worms, especially small strongyles (also known as cyathostomins), have increased in an era where there are dwindling anthelmintic choices for drug-resistant parasites.
Resistance status of donkey strongyles
The emergence of drug-resistant parasite variants is always a concern because it could compromise the usefulness of current therapeutics. Our understanding of drug resistance in donkey parasites has increased with accumulating evidence of limited efficacies of pyrantel, fenbendazole, iver-mectin and moxidectin in curing cyathostomiasis (caused by cyathostomins) in donkeys (Trawford et al., 2005; Peregrine et al., 2014; Lawson et al., 2015; Buono et al., 2018). Some of the factors that lead to the development and spread of anthelmintic resistance (AR) are widely accepted; eg the heavy reliance on anthelmintic treatment and the extra-label use of anthelmintics licensed for horses and ruminants, without optimisation of dosing regimens and determination of pharmacological properties of these drugs in donkeys.
Tackling anthelmintic resistance
To maximise the efficacies of current anthelmintic drugs, careful attention to the appropriate use of drugs is necessary. Veterinarians should balance between choosing anthelmintic treatment for donkeys with suspected strongyle infection and utilising anthelmintics in a judicious fashion. Although providing effective treatment and improving anthelmintic utilisation may seem opposing goals, there are strategies to accomplish both.
Anthelmintic stewardship can provide an efficient mechanism to implement these strategies and support the clinician’s effort in improving treatment outcomes and combating AR in donkeys. Veterinarians need to be sensible in anthelmintic use and should be open-minded to revise treatment dose intervals, because excessive anthelmintic use is a key factor in the development of AR. The Danish model of restricting anthelmintic drugs to prescription-only usage started two decades ago, and was later adopted by other European countries and Quebec in Canada.
Evidence-based and targeted treatment
To effectively manage resistant worms in donkeys and guide treatment choices, veterinarians should have better knowledge of local parasite epidemiology and follow the best possible practice in anthelmintic use. Also, they should monitor the development of AR using an early indicator, such as egg reappearance period (ERP) or faecal egg count reduction test (FECRT). Standardisation of resistance detection methods is essential to avoid discrepancies in the interpretation of the diagnostic results.
The practice of FEC-directed treatment and treating high strongyle egg shedders has been recently promoted as a potential approach for reducing anthelmintic treatment frequency because egg excretion (Figure 1) can be highly dispersed among individual animals. An earlier study suggested that increasing the threshold for treatment to 1,000 eggs per gram of faeces (epg) can minimise the emergence of resistance and prolong the use of anthelmintics, such as pyrantel (Lawson et al., 2015).
Combination therapy
Combination therapy, such as pyrantel combination drugs, has been suggested as a possible approach to improve treatment outcome. This approach may also slow down the progression of resistance by utilising different mechanisms of action and extend the spectrum of treatment by providing more coverage for potential parasites causing the infection. With the development of resistance to monotherapy (eg individual anthelmintics), efficacy can be partly restored by using a combination of different anthelmintics.
Despite the intuitive appeal of this approach, and although combination therapy may, in some situations such as handling resistant parasites, seem better than monotherapy, it is a temporary solution. Convincing data supporting combination anthelmintic therapy have not been confirmed in clinical trials as yet. Lessons should be learned from the situation in Australia, where resistance has been observed in sheep parasites against major classes of anthelmintics, including combination products (Wrigley et al., 2006).
Alternative solutions
The search for alternative, non-chemical treatments has gained momentum and many researchers have delved into the search for approaches as complementary and alternative solutions to better manage AR in donkey parasites.
Sound grazing management
Donkeys acquire infection by ingestion of infective third-stage larvae (Figure 2) when grazing in pastures. Therefore, pasture hygiene has been recognised as one of the most effective means of controlling helminths. Faecal removal from pasture at intervals frequent enough to prevent third-stage larvae developing can reduce nematode transmission, and removal of faeces twice a week alone was even more effective than anthelmintic therapy in reducing pasture levels of strongyle larvae.
The management of pastures by rotational grazing can be effectively practised, as well as lowering animal numbers, increasing grazing pasture size and keeping animals out on pasture for longer intervals. The use of different/alternative species such as small ruminants to mop up strongyles and other worms from the pastures can remove a substantial proportion of the larval population on pasture over time.
Nematodes are generally species-specific; therefore, good pasture management can be reasonably effective, with the exception of some helminths, such as Trichostrongylus axei and Fasciola hepatica, which can be transmitted between equines and small ruminants.
Refugia versus resistant populations
There is always a subpopulation of strongyle worms that has not been exposed to treatment and this is thought to be key in influencing the process of AR development. This refugia subpopulation (Van Wyk, 2001) is made up of parasite stages not exposed to the drug at the time of treatment, such as the encysted larvae, and larval stages in the environment: L1, L2 and L3. They escape the effects of the drug and are not under selection for resistance.
The amount of refugia in donkeys can be large and will dilute those parasites which can survive due to resistance. Therefore, lack of refugia means that the parasites containing the allele for resistance will slowly build up, creating a resistant population within the host. Refugia may not only impede the building of a resistant population but also can dilute the same resistant worm population and delay its proliferation, allowing the effectiveness of anthelmintic treatment to be prolonged.
Biological means of control
There has been some levels of success using the nematophagous fungus Duddingtonia flagrans as a biological control in equines. When D. flagrans is fed to an animal, usually in multi-nutritional pellets, results showed a reduction in cyathostomin larvae. This indicates that D. flagrans would be especially valuable when handling potentially resistant strains by reducing pasture contamination. However, despite its success, no attempt has been made as yet to develop D. flagrans into a commercial product.
In Australia, dung beetles have been promoted as a biological tool to reduce parasite larval population breeding in the dung. However, anthelmintic treatments can have deleterious effects on dung beetles themselves, further demonstrating the need for reducing the use of chemical drugs.
More traditional botanical products, such as garlic and papaya latex, have been investigated with the hope to discover more natural means of parasite control. Ingestion of plants containing secondary metabolites, such as tannins, has been shown to reduce parasite burden, providing a natural alternative and/or complementary antiparasitic treatment in a group of Miranda donkeys under a free-ranging system in Portugal. Whether these natural products can rescue donkeys affected with resistant parasites remains to be investigated.
Conclusions
In the last two decades, drug resistance caused by the overuse of anthelmintic drugs has gone from an interesting scientific observation to a reality of enormous veterinary importance. Current therapy for resistant parasites is limited to a few options, such as ivermectin and pyrantel. However, there have been reports of therapeutic failures of these drugs to control infection with strongyle resistant strains. The limited therapeutic options left for these parasites present a host of challenges for veterinarians. While the therapeutic values of anthelmintics to control parasite burden in donkeys and other animal species are acknowledged, additional complementary methods of parasite control are being investigated.
