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| This article will appear in a forthcoming issue of Trends in Parasitology. | |
Abstract
Drug resistance in gastrointestinal nematodes of livestock is a growing global problem that is unlikely to be overcome, at least in the short term, by the development of new anthelmintics [1]. With a limited choice of effective compounds on the market and a dearth of new compounds likely to become available, existing drugs must be used in ways that will maximize their impact on the parasite population, while avoiding or delaying the emergence of resistance. Such recommendations have also been made by the WHO in the context of large-scale chemotherapy programmes to control human nematode infections, where the threat of drug resistance could jeopardize current global initiatives [2,3]. This concern must also apply to parasites of pets, where commercial forces and marketing practices might be important factors in the emergence of resistance.
Treating Pets for Parasites
Until recently, the development of anthelmintic resistance in helminths of dogs and cats seemed unlikely in the view of the less-frequent applications of targeted treatments, of which each treatment was specific to particular parasites (e.g. the use of different drugs for controlling Toxocara, hookworm and cestode infections such as echinococcosis and dipylidiasis). However, the increasing and regular use of broad-spectrum anthelmintic combinations, or Allwormers, could create an environment for anthelmintic resistance to emerge [4].
The use of targeted strategic treatment for parasites such as Toxocara canis and hookworm, where owners can associate treatment with a particular parasite and its consequences both for the pet and possibly people, are much more likely to be successful and will lessen the possibility of the development of anthelmintic resistance. In Australia, a reduction in the prevalence of T. canis in dogs might reflect the awareness by dog owners about the need for strategic treatment designed to prevent worms reaching patency (when helminths commence egg production), thus limiting public health risks associated with environmental contamination with T. canis eggs. This is something that veterinarians have successfully educated pet owners about in Australia over the past 20 years [4]. By contrast, the tendency to advocate the use of regular anthelmintic treatment of dogs regardless of their ages, without an association with a particular parasite or strategy (for example see reference 5), is likely to hasten the appearance of drug resistance, a situation which has occurred in livestock [6] and for which there is emerging evidence in humans [7,8]. Although Allwormer drug formulations are successful in terms of marketing, the use of such drug formulations obviates the necessity for veterinarians to discuss specific targeted worming treatments with their clients. As a consequence, an important vehicle for educating the public has been lost.
The Lessons from Livestock
There has been some controversy about whether the situation in livestock and humans is analogous in terms of the potential for antihelmintic resistance to develop in pets [9]. However, the situation with pets is similar to that in livestock, in that the movement and behavior of host animals are largely controlled by a human agency, and there is a developing trend for parasite treatments to be given prophylactically at fixed time intervals. Furthermore, not only are drug combinations given regularly, but often there is no evidence of parasitism, and drug preparations of sub-optimal efficacy are used. For example, when five commercially available canine anthelmintic products containing different drug combinations were tested on dogs naturally infected with Ancylostoma caninum, three of these compounds reduced mean worm numbers by 76% or less [10]. The authors of that study considered that such poor performance made those compounds unsuitable for therapeutic use when A. caninum is present in clinically important numbers. However, the authors did not discuss the potential for these compounds to select for drug resistance.
The potential for the selection for parasites resistant to chemotherapy depends on the population dynamics of the host and parasite species, in addition to the epidemiological effects of the treatment. Clearly, the population dynamics of domestic pets are different to those of either humans or livestock and exhibit considerable variation. Many pets are kept in isolation from other animals of the same species, or in small groups; and their habitat is often quite different from the natural one in which host-parasite relationships might have evolved. In addition, pet owners usually regulate the mating and breeding behavior of their pets; this removes some of the opportunities for parasite transmission but could provide new parasite transmission routes. Consider this example: a breeding facility or kennel where dogs are regularly treated for helminths. If a population of resistant parasites were allowed to develop, then the animals sold from this facility could harbor their own sub-population of resistant worms, particularly if the dogs were given a final treatment of anthelminthics before dispatch to their new owners. If one of these dogs was subsequently introduced to an environment that had previously been free of larval helminths, the dog would soon establish its own isolated parasite community, all of which would be resistant to chemotherapy. Hence, a population of parasites resistant to chemotherapy would be founded. This mechanism is analogous to the "founder effect" observed when exotic host species are introduced to a new territory and could concurrently found a parasite community.
The "founder effect" would not be so profound if the animal were introduced to an environment that is already contaminated with eggs or larvae from the same parasite species. The presence of free-living stages that are susceptible to chemotherapy would serve to dilute the resistant population, which has been observed with parasites of livestock. Where the resistance mechanism is monogenic (controlled by a single gene), this would result in mating between different genotypes, thus resulting in more heterozygous than homozygous resistant parasites. This would then increase the susceptibility of the parasite population to drug treatment. The situation is similar when a pet animal is regularly treated for parasites and prevented from accessing larvae by strict hygiene measures. If a resistant genotype is present, the parasite burden in the animal might become small; however, the remaining parasites would be resistant to treatment. Any subsequent breakdown or relaxation of environmental hygiene measures would result in an increase in the parasite numbers, all of which would be resistant to chemotherapy. An example would be a dog that was previously regularly exercised away from its home, now being confined to and defecating on the property of the owner. The development of anthelmintic resistance in a parasite population associated with a single host animal has been modeled by Smith [11]. In particular, the effects of applying two different anthelmintics (either alternately or as a mixture) were compared. Treatment with the mixture was found to be more effective in delaying the onset of resistance, a conclusion similar to that reached for parasite control in livestock [12]. These results could indicate that the application of Allwormers for parasite control in domestic animals is to be recommended.
The reported low efficacy of some Allwormer preparations [10] should be viewed with concern in the light of a large body of opinion that under-dosing with such drugs leads to the development of resistance to chemotherapy. The basis of this belief is the paradigm that under-dosing might remain effective against susceptible homozygous parasites, but allow the survival of the heterozygotes [13]. Smith et al. have examined this logic by using a model based on parasites of livestock [14]. The results determined that the dose levels that killed only susceptible homozygotes were most dangerous when the initial frequency of the allele conferring the drug resistance was low. Other authors have also shown that, when anthelmintic resistance is in the process of developing and the gene frequency for resistance is small, the efficacy of the treatment against the heterozygote is the primary determinant for the rate of selection [15]. However, Smith et al. [14] found that the general belief that under-dosing promotes resistance is simplistic and that a more detailed knowledge of the epidemiological parameters and drug characteristics is necessary for determining the potential outcome. The relevant parameters for parasites of pets might be quite different to those for livestock. Hence, although low-efficacy worm treatments will select for resistance when the initial gene frequency is low, the range of numerical values that are classed as low must be determined for each situation. The same study also examined the paradigm that chemoprophylactic strategies promote resistance at a higher rate than chemotherapeutic strategies and found that this question requires a more detailed knowledge of the parasite population dynamics [14]. Hence, although frequent prophylactic use of Allwormers breaks two rules for the avoidance of anthelmintic resistance, these rules were suggested for livestock, and it has been shown that, even in livestock, further examination of both questions is needed before definite conclusions could be reached.
Conclusion
There are clear advantages in using drug combinations for anthelmintic control. However, the cynical could remark that, once resistance to a mixture of all available treatments in the arsenal has evolved, further control would be impossible. In this respect, there is a clear need for research to be undertaken on the occurrence of anthelmintic resistance in populations of pet parasites. There is also a need to ensure that such drug combination products are formulated to ensure optimal efficacy of all drugs in the mixture and that they are used in a strategically sensible way. It is also important that, by advocating the use of Allwormers, veterinarians do not lose sight of the importance of educating pet owners about specific parasites, particularly when strategic, targeted treatment is important, as with Toxocara, where parasites have public health significance. Despite extensive studies of nematode parasites of livestock, there is still much disagreement over which strategies will maintain parasite control and will reduce selection for resistance. The epidemiology of parasites of pet animals has been subjected to far less scrutiny; hence the strategies to be used require careful evaluation if they are to lead to the longterm sustainable control of parasites.
