The border collie puppy seen by Dr. William Feeman for a wellness appointment in January appeared healthy but tested positive for hookworms — not uncommon during a routine puppy exam. What was unusual, in Feeman's experience, happened later.
The doctor in Ohio prescribed standard dewormers, pyrantel and fenbendazole, in succession. But the intestinal parasites persisted. Over the next six weeks, the veterinarian alternated the two medications with a third. All of them failed to knock out the hookworms. In mid-March, the pup developed bloody diarrhea.
Feeman was witnessing a development that veterinary parasitologists have been warning about since 2019.
That’s the year researchers reported for the first time that some isolates of Ancylostoma caninum, the most common species of canine hookworm in the country, appear to be resistant to all three classes of dewormers, called anthelmintics, that are approved by the U.S. Food and Drug Administration for use in dogs.
Hookworms are parasites that attach with sharp teeth to the intestines of their animal host, feeding on its blood. Dogs pick them up in the soil or from an infected mother during nursing. Signs of hookworm infection include coughing, weakness, anemia, loss of appetite, weight loss, difficulty breathing and bloody diarrhea. Untreated puppies can die from anemia. In otherwise healthy adult dogs, hookworms usually don't pose serious problems, but if they harbor resistant hookworms, they may spread the parasites in their stool.
(A. caninum can infect all canids. People whose skin is exposed to the larvae of this species of hookworm can develop itchy inflammations called cutaneous larva migrans, a minor if irritating condition.)
Seeking advice from a parasitologist, Feeman described the border collie case on a message board of the Veterinary Information Network, an online community for veterinarians and parent of the VIN News Service. Feeman told VIN News that during 21 years of practice, he'd never seen a case in a puppy not resolve with a single deworming treatment. He'd only ever seen such persistent hookworms in adult greyhounds, a breed he takes a special interest in.
It turns out that greyhounds retired from the racetrack and adopted as rescues may be the original source of multidrug-resistant hookworms spreading around the country. Several of the researchers on the 2019 study — including Drs. Ray Kaplan and Pablo David Jimenez Castro — have produced follow-up research, including a 2021 study that found most racing greyhounds in the U.S. are infected with multidrug-resistant hookworms. Today, according to parasitologists, the spread is more common among dogs other than greyhounds.
It's an overlooked emerging threat, says Kaplan, a professor of pathobiology at St. George's University School of Veterinary Medicine in Grenada who began researching hookworms while on the faculty at the University of Georgia College of Veterinary Medicine. In order for the prevalence of resistance to get as high as it is now, he said, resistant hookworms must have been spreading through the dog population for many years.
"The fact that there were no reports of resistance until I started doing my research just a few years ago suggests that there was a severe lack of surveillance within the veterinary community regarding drug efficacy," Kaplan said. "Which means, essentially, that the veterinarians were just assuming that drug treatments worked without doing any follow-up and checking."
Along with others in the field and under the auspices of the Hookworm Task Force created by the American Association of Veterinary Parasitologists (AAVP) in 2021, Kaplan and Jimenez Castro — the task force vice chair — are working to increase awareness among clinicians about the emergence and spread of resistant hookworms and to provide direction to veterinarians on how to modify their approach to screening and testing.
The AAVP task force is also calling on clinicians to share what they are seeing in their practices. Dr. Jeba Jesudoss Chelladurai, an assistant professor of parasitology at Kansas State University College of Veterinary Medicine and chair of the task force, is collecting data on what has worked and not worked in clinics. (See details on submitting cases below.)
Test after treatment
The three classes of anthelmintic drugs approved in the U.S. to treat hookworm infection in dogs are benzimidazoles (such as febantel and fenbendazole), macrocyclic lactones (such as moxidectin and milbemycin oxime) and tetrahydropyrimidines (such as pyrantel).
Until recently, veterinarians who encountered persistent infections could rely on a combination of these drugs to kill off the hookworms.
"Drug resistance is not absolute," Kaplan explained. "Each drug will still maintain some level of efficacy. By using multiple drugs, you get an additive effect."
In the case of the border collie puppy, Feeman was ultimately able to clear the infection with a combination of fenbendazole and a high extra-label dose of pyrantel pamoate.
Determining whether a case of persistent hookworms is multidrug-resistant can take a few steps.
Dr. Antoinette Marsh, an associate professor of veterinary parasitology at The Ohio State University College of Veterinary Medicine and a past president of AAVP, recommends using a process of testing and treating and testing again. (Marsh co-authored a recently published paper on hookworm resistance that calls it "a critical issue we neglected to forecast.")
One way to measure resistance is to check the patient's stool for hookworm eggs 12 to 14 days after administering any anthelmintic drug, Marsh said. This method, known as a fecal egg count reduction test, can be done in the clinic or sent out to a diagnostic lab. Unlike a fecal flotation test, which identifies only the presence of hookworm eggs, the egg count test measures the number of eggs.
Here's how it might work in practice: A fecal egg count test finds that a dog is shedding 500 eggs per gram of feces. Drug No. 1 is administered. If, 12 days after treatment, the feces still contain 450 eggs per gram, drug No. 1 didn't work. Drug No. 2 is administered. The follow-up fecal count shows five eggs per gram.
A drop of that magnitude means the second drug worked, judging from a 2020 article in Clinician's Brief by Kaplan and Jimenez Castro, who say that an egg-count reduction greater than 95% indicates an effective treatment strategy. If the reduction ranges between 75% and 95%, the treatment needs to be repeated. A reduction of less than 75% indicates the hookworm is resistant to the drug used.
Chelladurai, the AAVP Hookworm Task Force chair who is asking practices to share information, said she is accepting only cases where fecal egg count reduction tests, or FECRTs, were performed within 10 to 14 days after treatment. "Without FECRT, the evidence of drugs working or not working will not be acceptable in the scientific community since FECRT is our current gold standard," she said in an email to VIN News. Qualifying treatment and diagnosis information can be sent to Chelludurai at email@example.com.
Another thing to consider: The hookworm life cycle can throw a wrench in determining whether a persistent infection is, in fact, a case of drug-resistant hookworms. That's because as hookworm larvae migrate to the intestines, some are waylaid in muscles and other organs, where they go dormant. These larvae may become reactivated and can migrate back to the intestine and develop into adults, re-establishing the infection. This is known as larval leak.
"Owners don't always understand," Marsh said. "I describe it as a sponge filled with larvae. You squeeze it, and larvae come out. You continue to squeeze, and the larvae keep coming out from the tissues to repopulate the gastrointestinal tract."
Kaplan and Jimenez Castro say that in addressing persistent cases of A. caninum infection, it's important that clinicians differentiate between larval leak with drug-susceptible hookworms and infection with multiple-anthelmintic-drug-resistant hookworms.
Antech Diagnostics, a commercial diagnostic laboratory, offers molecular tests that detect hookworms that are resistant to benzimidazoles, one of three classes of anthelmintic drugs. But such tests are not available for the other two classes, Marsh said, so it's important that veterinarians quantify the number of eggs in a fecal sample after treatment to assess efficacy.
"Veterinarians should try to educate the clients; to say, 'We're not wasting your money, but rather, we're providing a really important service to ensure that this drug has been efficacious,' " Marsh added. "Years ago, we never tested; we gave the dewormer and trusted it would work. Now, with drug-resistant hookworm, we can't do that."
Feeman recognizes that the testing is important but said the price tag can be an obstacle. "Cost-wise, some people are not going to do that," he said. "Not every owner has hundreds of dollars to spend on fecal samples. Some will decline the number of fecal samples needed to prove multidrug resistance."
Extra-label drug promising with caveats
Researchers have found efficacy with another anthelmintic, emodepside, which is approved in Europe but not in the U.S. for use in dogs.
In a 2020 study using a canine tablet approved in Europe containing a combination of emodepside and praziquantel, Kaplan, Jimenez Castro and others found it effective in treating laboratory beagles infected with a hookworm isolate resistant to all drugs labeled for use in dogs to treat hookworms, including pyrantel pamoate, milbemycin oxime and fenbendazole.
More recently, Jimenez Castro co-authored a study that looked at multiple anthelmintic drug resistance in 22 dogs, mostly Labrador retrievers, in a Georgia kennel. The researchers found emodepside effective against the resistant hookworms. (Jimenez Castro, who recently became director of parasitology at Antech, was a graduate student in Kaplan's University of Georgia lab.)
The U.S. does have one FDA-approved product containing emodepside, Profender. It's a topical solution that also contains praziquantel and is labeled for use in cats. Some veterinarians are using the feline drug extra-label (a legal use also known as off-label) to treat multidrug-resistant hookworms in dogs. But the promise of emodepside comes with a few caveats.
It can be dangerous if a dog is coinfected with heartworm, Marsh said. Because heartworm larvae, known as microfilariae, are extremely vulnerable to emodepside, they can die rapidly after treatment and provoke a severe, even fatal, reaction in a dog, according to an article in the Journal of the American Veterinary Medical Association.
Therefore, administering the emodepside-praziquantel combo should be preceded by a blood test for heartworm microfilariae.
In addition, dogs with a gene mutation that makes them sensitive to certain drugs may not be able to tolerate emodepside, according to case reports published in 2014 and 2019. Neurological symptoms such as tremors and seizures were observed in those cases.
There are several breeds, such as collies, that are much more likely to have the relevant mutation, Kaplan said. "I would not test all dogs, but if treating one of the breeds known to have the mutation at moderate to high levels, I would have the test done."
Marsh said whether to do a DNA test comes down to a veterinarian-pet owner risk assessment, which includes determining whether there is any known gene risk in the dog's family history. The test adds time and cost to the treatment, she said. "An alternative is to treat the dog in the clinic and monitor it for adverse signs for four hours."
The adverse effects are not fatal and can be treated, according to Kaplan.
There is also concern about resistance developing to emodepside if it is overused. While resistance is unlikely to develop in the case of individual dogs treated with the drug, Kaplan said, the major concern is "breeding/training kennels where many infected dogs are treated with emodepside, creating a situation similar to the situation where resistance developed in the first place."
Chelladurai, the AAVP Hookworm Task Force chair, urges caution. She said, "Emodepside should never be used except as a last resort — when nothing else works."
Summarizing best practices, she said the first line of attack is to use the labeled drugs singly, and the second line is to use the labeled products in combination. Only after all those approaches have failed should emodepside be used.
Screen for hookworms more frequently
Chelladurai said it's important that veterinarians be aware of the prevalence of hookworms in their area so that they can advise their clients accordingly. The Companion Animal Parasite Council, a nonprofit organization that works to raise awareness about parasites that affect pets, provides a parasite prevalence map that includes hookworms by U.S. county.
Kaplan offers one caution when thinking about prevalence: Even if hookworms aren't prevalent in an area, the hookworms that are there may have a high prevalence of resistance. "So, one cannot discount the risk just because the prevalence is low in their area," he said.
He and Jimenez Castro recommend that for optimal precaution, quarterly fecal flotation screenings for internal parasites become routine for all dogs. He added that even twice-yearly fecal screening would be beneficial compared with an annual test.
Screening can help identify infected dogs that may be asymptomatic and get them treated early, Kaplan said. Otherwise, he said, a dog can pick up hookworms, excrete eggs in its stool that could develop into infective larvae, and thereby reinfect the dog with more resistant worms, as well as spread the parasites to other dogs for months before it's recognized that the asymptomatic dog is infected.
This is especially likely at dog parks. "Given the prevalence, probably every dog park is contaminated with drug-resistant hookworm larvae at some level," Kaplan said.
Does that mean pet owners should avoid taking their dogs to dog parks? Not necessarily, Kaplan said: "[S]ocial, physical and psychological benefits of visiting the dog park often should outweigh the risks of drug-resistant hookworm." He encourages owners who take their dogs to off-leash parks be vigilant about doing regular fecal screenings and keeping their dog on a heartworm preventive product that includes protection against hookworms.
AAVP also urges veterinarians to report suspected treatment failure to the product manufacturer or to the FDA by calling 1-888-FDA-VETS or online.
Lisa Wogan contributed to this report.