Prescription-Only Anthelmintic Drugs

Over the past decade, evolved resistance to freely available and widely used anthelmintic drugs for controlling parasites of livestock has gone out of control. In the majority of the most important parasite species of sheep, goats, cattle, and horses, multiple-drug resistance is the new status quo ( Kaplan and Vidyashankar 2012 ). The situation is the most severe in goats, in which resistance to all available anthelmintics is now commonplace. However, anthelmintic resistance in other major livestock species worsens each year and now threatens the control of parasites on many farms. There have been no new classes of anthelmintics introduced into the US livestock market in the past 32 years. Consequently, resistance is redefining how parasite control should be practiced and how anthelmintics should be used. What should be done to slow the tide of resistance? We know a great deal about the major risk factors that drive it ( Leathwick et al. 2009 ). There are evidence-based, sustainable parasite-control strategies that can be implemented now that would have an immediate impact. Only by using these strategies can we ensure that the few anthelmintic drugs that we have available will remain efficacious. Putting veterinarians in the driver's seat, by restricting anthelmintics to prescription use, is the single best step toward achieving this. The control of nematode parasites is a fundamental requirement for maintaining the health and productivity of livestock. Although there are a number of different management strategies that can be employed, the use of anthelmintic drugs is by far the easiest and most effective. Beginning in the 1960s with the introduction of thiabendazole (a benzimidazole drug), a major shift occurred in the way the veterinary and livestock industries viewed parasite control. This was closely followed by the development and marketing of the nicotinic agonist class of anthelmintics, exemplified by levamisole, and the macrocyclic lactone class, exemplified by ivermectin. It quickly became obvious that these highly effective, broad-spectrum drugs improved the health and welfare of livestock, as well as the profitability of livestock farming. It became common practice to treat (healthy) horses with anthelmintic drugs every 2 months, year round, and to treat sheep and goats at 1–2-month intervals during the grazing season. Cattle were treated less frequently; even so, anthelmintic use became routine. In almost all cases, the administration of anthelmintic drugs was prophylactic. Horse owners and livestock producers could buy anthelmintics in the feed store—and, later, over the Internet—much more cheaply than through a veterinarian, and pharmaceutical companies marketed their drugs directly to livestock producers and horse owners, so veterinarians became less and less involved in parasite-control decisions. For several decades, this arrangement seemed to work. Parasitic disease became less common, although the fear of parasites was continually reinforced in magazine articles and pharmaceutical company advertisements. But, predictably, reports of resistance to anthelmintic drugs quickly followed the introduction of each new drug class. Over time, the geographical range and the prevalence of resistance increased, as did the spectrum of resistant parasites. Not surprisingly, this went largely unnoticed by the anthelmintic drug—using public for quite a long time, illustrating the point that many or most treatments were unnecessary. Parasitologists agree that near-complete reliance on frequent anthelmintic treatments to control parasites (I have called it global worming ) must change. Anthelmintics must be viewed as an important tool of an integrated parasite-management program rather than the sole component. Old habits are hard to break, however, and evidence-based, sustainable integrated parasite management that relies less on anthelmintics is more complicated and difficult to implement ( van Wyk et al. 2006 ). Anyone intending to deliver an anthelmintic agent should address a long list of questions before the proper drug can be selected, including the following: Which species of parasites are the most important to control in the type and age class of the animals of interest? Which stages of those parasites are most likely to be present? Which drugs (or drug classes) provide the proper spectrum of activity against the parasite species and the stages being targeted? What are the host—parasite dynamics that are most relevant to the control of those species? Which animals in the herd require anthelmintic treatment, and which do not? And, finally, are those drugs still effective against the particular parasite species or stages being targeted at this site (or are the parasites resistant to that drug or class of drugs)? Clearly, these issues are complex. Most lay individuals cannot determine the answers and so are unable to implement optimal strategies for parasite control. The reality is that only veterinarians possess the necessary breadth of knowledge. Diagnostic surveillance of parasite infection levels and testing of the efficacy of anthelmintics should be done on every farm ( Kaplan and Nielsen 2010 ), but this is rarely done in the United States (or in most other countries). One exception is Denmark, where, in 1999, legislation was passed making anthelmintics available only on a prescription basis ( Nielsen et al. 2006 ). More recently, prescription-only restrictions on anthelmintic drugs have been implemented in Sweden, the Netherlands, Finland, and the Canadian province of Quebec ( Nielsen 2009 ). It is too soon to judge the effects, but in Denmark, surveys of horse owners and equine veterinarians have indicated a major change in how parasite control is approached. In 2004 (5 years after the enactment of the legislation), Danish equine veterinarians who were surveyed demonstrated a dramatic change in practices and had become heavily involved in parasite-control programs. Parasite surveillance and drug efficacy testing is now the new normal, and the result has been a more-than-50-percent decrease in the frequency of anthelmintic treatment, with no concomitant increase in the diagnosis of parasitic disease in Danish horses. Anthelmintic resistance is, of course, closely connected to the antimicrobial resistance that is becoming more prevalent worldwide and is now recognized as a major threat to public health. Multiple-resistant strains of bacteria are responsible for significant morbidity and mortality, as well as for large increases in medical costs. Few new classes of antibiotics are being developed. The medical and veterinary communities now largely agree that antibiotics should be used in a targeted, limited way in both humans and animals to slow the evolution of resistance. One major difference is that the drug-resistant parasites of livestock are not zoonotic: They do not pose a threat to human health (if they did, the public health community would long ago have demanded a major change in how anthelmintic drugs are used). But this is beside the point. To approve a veterinary anthelmintic, the US Food and Drug Administration quite properly requires proof that it is safe to the animals receiving it; that the product is effective in killing the parasites for which it is making efficacy claims; and, in the case of drugs for food animals, that it has established meat and milk withdrawal times (to prevent residues' finding their way into food). Yet it is now accepted in the veterinary literature that these drugs no longer achieve the levels of efficacy required for the label claims on many or even most farms. Given the high levels of parasite drug resistance and the small number of anthelmintic drug classes, it seems almost certain that development of anthelmintic resistance will outpace the introduction of new drug classes. Indeed, most parasitologists now regard anthelmintics as a limited resource that must be conserved. Why, then, are these important drugs still sold over the counter, with no requirement that the user know how to administer them appropriately and responsibly?

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