Could pet deworming regimen fuel parasite resistance?

Veterinarians ponder implications for heartworm and gut worm infections

Photo courtesy of Dr. Mark Kittleson A postmortem of an infected dog reveals adult heartworms in the pulmonary arteries. The horrific nature of heartworm disease has led the veterinary profession to advocate routine use of heartworm preventives in dogs. Now some worry that the liberal use of anthelmintics may backfire by promoting drug-resistant parasites. A postmortem of an infected dog reveals adult heartworms in the pulmonary arteries. The horrific nature of heartworm disease has led the veterinary profession to advocate routine use of heartworm preventives in dogs. Now some worry that the liberal use of anthelmintics may backfire by promoting drug-resistant parasites.

As a veterinarian working in companion animal medicine, Dr. Chiara Switzer knows that her profession widely recommends treating dogs and cats routinely with drugs to prevent infestations of heartworm and intestinal parasites.The approach is meant not only to keep the pets healthy but to minimize the risk of animals transmitting parasites to their human families — a compelling consideration, Switzer says. At the same time, she worries that this highly touted regimen might do harm in the long run.“I have a couple of concerns,” she said: “One, that the wide-ranging shotgun approach to tackle all parasites at one time, regardless of the risk for those parasites and whether or not you realistically need protection from them, will lead to parasites developing resistance to these drugs.“Two,” she continued, “that this approach is designed out of a fear of liability — regarding zoonotic (disease transmission) concerns — rather than actual sound medical advice.”A number of veterinary researchers are raising the same concerns.Since the 1980s, anti-parasitic drugs have been widely used in the routine care of both livestock and household pets. Now, increasing evidence of drug resistance in livestock and horse parasites known as helminths — parasitic worms that include intestinal worms and canine heartworm — has veterinary practitioners and scientists alike questioning the automatic use of such drugs in household pets.In fact, emerging evidence points to the existence of strains of canine heartworm that appear to be resistant to anthelmintic drugs known as macrocyclic lactones, the class of drugs used in monthly heartworm preventives.Byron Blagburn, a parasitologist at Auburn University who has examined the efficacy of commercially available heartworm prevention drugs, is cautious about using the term “resistance” with canine heartworm. He puts it this way: “There is enough laboratory research to strongly suggest that in limited geographic regions there are isolates that are not responding to preventative drugs as they did when those preventatives entered the market.”Other experts in the field express concerns more bluntly.“Panaceas on wheels” is what Dr. Craig Reinemeyer, a past president of the American Association of Veterinary Parasitologists, calls broad-spectrum products that target fleas, ticks and internal parasites in one dose.“In recent years, the pharmaceutical industry has preferred a shotgun approach to parasite control — single products that kill hookworms, whipworms, ascarids, tapeworms, and simultaneously control heartworms and fleas. I don’t think such an extreme approach is necessary, certainly not for each and every pet. Most adult dogs, for example, don’t have ascarids,” said Reinemeyer, referring to intestinal worms. “This is an example of marketing and commercial interests trumping scientific evidence.”Reinemeyer, whose expertise is in equine parasites, has the same discomfort with the practice of giving dogs anthelmintics every month to stave off heartworm. “I don’t think anyone will come right out and say we’ve got resistant heartworms, but if we were seeing some of the same things in horses that practitioners are seeing in dogs, we’d call it resistance,” he said.Dr. Andrew Peregrine, a professor of clinical parasitology at the University of Guelph, Ontario Veterinary College, has a similar perspective. He compares the monthly parasite prevention routine for dogs and cats to the tradition in the horse world of deworming foals monthly for their first year of life.A decade ago, resistance in foal roundworm was considered unlikely. But since 2002, multiple cases of ivermectin-resistant foal roundworms have been reported. Peregrine said that in every case of resistant roundworms he has investigated since then, he’s found that the farm dewormed its foals every four weeks.“Frequency of dosing is one of the things that selects for resistance,” he said.Dr. Patrick Meeus, immediate past president of the American Association of Veterinary Parasitologists and head of Global Therapeutic Research, Parasitology, for Pfizer Animal Health, said much the same thing. “In general, the more a product is used,” he said, “the more likely it is resistance will develop.”Selection for resistance through drug use works like this: When exposed to the drug, the organisms vulnerable to the drug die, leaving those that are naturally resistant to survive and reproduce. Eventually, resistant organisms may dominate the population, rendering the drug ineffective over time.The evolutionary dynamic is at play whether the threat to the organism is a drug or other hazard. “Eventually, nature wins the day,” Peregrine said.Until the advent of modern drugs, parasite control in livestock and pets relied upon management techniques such as pasture rotation and removal of fecal material. Anti-parasitic drugs were available for severe cases but those drugs were difficult to administer and carried a high risk of toxicity to the animal.In the 1970s and '80s, the game changed. New anthelmintic drugs that were potent, safe and easily administered flooded the market. Louis Gasbarre, a parasitology researcher retired from the U.S. Department of Agriculture and a former president of the American Association of Veterinary Immunologists and the American Association of Veterinary Parasitologists, describes how the drugs were welcomed with gusto and used liberally by owners, producers and veterinarians alike:“(We) thought we could administer these drugs with impunity. We didn’t think that there would be a problem with drugs becoming ineffective. We began to devise what were markedly more effective control programs. We also forgot management."What users apparently forgot, Gasbarre said, is that parasites reproduce swiftly and with a high potential for genetic change. “We really fueled that system,” he said. “We exerted extraordinary selective pressure on parasites.”Although the concept of selection pressure exerted by drugs is straightforward, development of resistance in a given population is complex.Factors such as frequency of dosing, timing of the dose, the proportion of the parasite population exposed to the drug, and the life cycle of the parasite can influence whether and how quickly resistance develops.Further, the existence of resistance itself may be difficult to determine. Early clues are reports of loss of efficacy of a drug or drugs that were known previously to effectively kill the target organisms.In Australia and New Zealand, resistance to some classes of anthelmintic drugs quickly developed in sheep parasites; resistance was recognized in the 1980s. Since then, it’s become clear that many anthelmintic drugs have lost efficacy against a variety of parasites in multiple animal species around the globe.“Essentially every single livestock host has multiple species of parasites that have resistance to multiple drugs, and this is true throughout the world,” said Dr. Ray Kaplan, a professor in the Department of Infectious Diseases at the University of Georgia College of Veterinary Medicine, speaking last March at a meeting hosted by the U.S. Food and Drug Administration, “ Antiparasitic Drug Use and Resistance in Ruminants and Equines .”While the problem is most severe in small ruminants such as goats and sheep, Kaplan said that horses, cattle, camelids and zoo animals are impacted, as well. In fact, acknowledging that the statement was off-topic to the FDA gathering, Kaplan commented that “anthelmintic resistance is also a major concern in human parasites and in Dirofilaria immitis, the dog heartworm, as well.”“The bottom line,” he said, “is that the anthelmintic resistance is an inevitable consequence of using ... anthelmintic drugs.”The idea that resistance is inevitable isn’t universally accepted.Dr. Michael Murray, technical director for pet parasiticides at Merial Animal Health, told the VIN News Service via email: “With regard to prevention of canine heartworm disease, the development of resistance leading to widespread product failure has not happened and is not inevitable. There are many factors that contribute to the development of resistance, and these cannot be generalized across products, active ingredients, or target organisms.”Meeus, the parasitology research head at Pfizer Animal Health, said he largely agrees. At the same time, referring to reports concentrated in the Mississippi Delta region of loss of efficacy in heartworm prevention products, Meeus acknowledged that “there is something going on. ... There are strains (of heartworm) out there that don’t seem to be affected (by the drugs).”It’s possible, Meeus said, that those strains are naturally resilient — that is, less susceptible to the drugs from the outset, as opposed to having evolved resistance. While anti-parasitic drugs are tested against parasites in the laboratory and in the field to determine efficacy, the strains tested do not necessarily represent every strain present in nature. Meeus said researchers currently are looking into the resilience question.Blagburn, the Auburn University researcher, noted that any development of resistance in D. immitis would differ from that seen in gastrointestinal parasites because their life cycles are significantly different. For one thing, the canine heartworm parasite has a relatively long lifespan, so its generations turn over more slowly than intestinal worms. And it’s transmitted via mosquitoes rather than ingested through contaminated feces on the soil, as happens with intestinal worms.Another significant difference, Blagburn said, is that heartworm infects feral dogs and wild canids such as wolves, foxes and coyotes, which are not given preventive drugs. The presence of an untreated population of hosts reduces the selection pressure on the parasite. That’s because parasites that are susceptible to the drug can live in the untreated animals and reproduce, thereby diluting the resistant genes.Small animal anti-parasitic drugs target more than heartworm. Anthelmintics also act against gastrointestinal parasites such as hookworms (Ancylostoma caninum) and roundworms (Toxocara canus and Toxocara cati).While populations of canine hookworms displaying resistance to the drug pyrantel have been documented in Australia , it is generally accepted that resistance among small animal gastrointestinal parasites has not been conclusively demonstrated in the United States.These parasites more commonly affect young animals than adults, but many pets are given monthly deworming treatments regardless of age.Often, the chief concern regarding these parasites is not the health of the pet but the health of the pet’s human household. Hookworm and roundworm infections in people, while usually benign, can have devastating consequences, including tissue and organ damage, liver inflammation and blindness.Dr. Craig Datz, an adjunct associate professor in the Department of Veterinary Medicine and Surgery at the University of Missouri, believes the risks posed by intestinal worms are not tolerable for most pet owners. On a message board of the Veterinary Information Network (VIN), Datz wrote : “We … as humans have decided to domesticate animals and bring them into our houses, kitchens, and even on our beds. Veterinarians lead the way in promoting the human-animal bond. Therefore, we need to take measures to decrease (not eliminate, but decrease) direct spread of diseases from animals to people.”To use the occurrence of parasite drug resistance in horses and cows as a guide for managing parasites in dogs and cats is inappropriate, Datz argues.“Pets have a function to be companions,” he said in an interview. “If you ask any pet owner if they want their dog or cat to have some worms occasionally or to be worm-free, they would want (the pets) to be worm-free.”That begs the question: How great is the risk of acquiring a parasitic infection from an untreated pet?The answer is difficult to determine.Part of the problem is that the data are incomplete, according to Dr. J. Scott Weese, an authority on zoonotic disease and public health at the University of Guelph Ontario Veterinary College.The U.S. Centers for Disease Control and Prevention (CDC) reports that nearly 14 percent of the U.S. population has been infected with roundworm and that dog owners are more likely to be infected. But this figure may not reflect the true risk of disease, Weese said.“The numbers from the CDC are for seroprevalence,” he said, referring to the presence of Toxocara antibodies in the blood, “not infection.” In other words, the figure represents people who have been exposed to the parasite, but not necessarily pathologically infected.Weese recognizes that most people consider any risk of parasitic disease unacceptable. As he writes on a VIN message board , “It's an almost-impossible area to debate ... when you're dealing with a rare but potentially devastating disease. How many cases are 'acceptable'? Would additional deworming actually do anything to reduce human cases? What is the risk of contact with an animal that's been dewormed according to a specific protocol vs. an un- or 'inadequately'- dewormed animal? We don't know and it's going to be very, very hard to figure that out.”There’s another side to the argument that parasite prevention in pets is needed to protect people’s health, however. Peregrine, the University of Guelph clinical parasitologist, noted that some of his colleagues in pediatric medicine have raised concerns about drug-resistant Toxocara strains developing as a result of pressures applied by the use of veterinary drugs in pets. If roundworms become resistant to available drugs, that would limit the options for treating infected children.How can the competing concerns be balanced?Weese advocates a case-by-case approach. “I don't think anyone would suggest that we stop deworming small animals, or that we restrict deworming solely on the basis of concerns about resistance,” he wrote on VIN. “What I think we need to do, however, is to put the science back in our decisions. We need to make sure that we are making decisions based on evidence, not marketing or convenience. In some populations and individuals, monthly deworming may make sense. In others, it may not.”In an interview, Weese elaborated: “We need to look at the lifestyle of the animal. What’s the risk of exposure? Does it go to the public park every day or see another dog every couple of months? A puppy has a greater risk; after the initial series, you can back off.”Geographical risk is another consideration, Peregrine said. He explained: “The risk of (roundworm infection in people) in southern Ontario is a fraction of the risk in humans in some (parts of) the U.S. So, does that warrant the use of preventives year-round in every dog in Ontario? If the downside is that you are likely to select for resistance, is it warranted?”Switzer, the clinician in Toronto, said the individual approach makes a lot of sense to her but noted that it requires more work on everyone’s part.“I believe one size never fits all,” she said, “but I think that’s a harder sell because it takes more time and money for all concerned, and everyone likes easy answers and straight paths.”