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April 2024
Resistance on the Rise
With each passing year, we are seeing changes in the parasite distribution and incidence across the United States and around the world. While some researchers have seen a decrease in the number of cases of heartworm resistance to preventives, cases of hookworm multi-anthelmintic drug resistance are more concerning.
Trends in Heartworm and Hookworm Resistance
With each passing year, we are seeing changes in the parasite distribution and incidence across the United States and around the world. Cassan N. Pulaski, DVM, MPH, PhD, clinical assistant professor and director of the Diagnostic Parasitology Lab at the University of Georgia College of Veterinary Medicine, has been studying trends in parasite prevalence and response to treatment and also continues to practice as a small animal relief veterinarian.
As part of her work, Pulaski has followed trends in resistance of parasites to commonly used preventives and anthelmintics. While she has seen a decrease in the number of cases of heartworm resistance to preventives, cases of hookworm multianthelmintic drug resistance are more concerning. Here, we review the known contributing factors to each of these types of resistance and how to best prevent and treat these conditions in dogs.
Heartworm Resistance
In 2020, the American Heartworm Society reported that all the macrocyclic lactones on the market had been shown in at least one study to be “less than perfect,” meaning that some dogs taking these drugs regularly still developed heartworm disease. Pulaski reports that many contributing factors added to reported resistance. These involve a combination of natural genetic variation that resulted in drug resistant worms and human activity that has helped to select for these mutations.
The Asian tiger mosquito, Aides albopictus, originally entered the country on tire barges. This mosquito is very aggressive and feeds all day long, unlike other mosquito species that mainly feed at dusk and dawn. Particularly in rural areas and areas where dogs spend more time outside, there was a greater chance of microfilaria transmission from one dog to another due to the increased potential feeding time.
Other factors include the movement of animals throughout the country. For example, after Hurricane Katrina, many dogs were displaced from their homes in Louisiana and other areas. Many of these dogs ended up being transported to shelters in surrounding states or in other parts of the country. This population included some heartworm positive dogs, some of whom carried worms that were resistant to one or more macrocyclic lactones.
The movement of dogs has not been limited to catastrophic weather events. As people travel and move around more, they are bringing their pets with them. Colorado, a state that previously had very low heartworm prevalence, has been experiencing an increase in heartworm cases since 2013, and the only significant causative factor was determined to be the import of over 100,000 dogs into the state.
The Current State of Heartworm Resistance
Pulaski reports that heartworm resistance is not considered to be as big of a problem now as it was in previous years. She attributes this to a few important factors:
First, melarsomine works. There have been no documented cases of heartworm resistance to melarsomine.
Second, the widespread use of doxycyline has “kept this problem from erupting,” according to Pulaski. Killing the Wolbachia organism that lives in symbiosis with the heartworms weakens the worms and results in less pathology for the dog. Doxycyline also helps to block the transmission cycle of heartworms, Pulaski adds, because without Wolbachia, L3 are no longer infective.
There have been no documented cases of heartworm resistance to melarsomine.
To help reduce the risk of a resurgence of resistant heartworm infections, Pulaski recommends abandoning any thinking that some areas are “heartworm areas” and others are “nonheartworm areas.” While this may have been true in the past, it is no longer the case. Another important recommendation is to avoid using large animal parasiticides off-label for heartworm prevention in dogs. Of course, all efforts to improve compliance with heartworm prevention are extremely important.
Hookworm Resistance
Pulaski reports that hookworm resistance scares her a lot more than heartworm resistance ever has. Twenty years ago, she shares, hookworms that were resistant to pyrantel pamoate were being reported in racing greyhound populations. These dogs were being treated as a herd: they were routinely dewormed every two weeks without being weighed, meaning some dogs likely received suboptimal doses of dewormer. They were housed in kennels with sand bedding, what Pulaski describes as “paradise for hookworms.”
They were being transported around the country for races, where they mingled with or were housed in close proximity to other dogs. All of these practices helped to select for mutations coding for resistance against multiple commonly used parasiticides and to propagate these resistant worms around the country.
While resistance to parasiticides in hookworms is no longer just a greyhound problem, the breed is still overrepresented in Pulaski’s consulting work. Pulaski reports that when she sees outbreaks or hot spots of hookworm infestations in other breeds of dog, they are most often tied to a dog park, daycare, kennel, or breeding facility.
Diagnosing Resistance
Going Further
Clinicians who are treating cases of MADR hookworms don’t have to struggle alone. Pulaski recommends some strategies that can help provide support to both the pet owner and the veterinary team:
For dogs who have been receiving regular anthelmintic treatment and are suspected to have hookworm resistance, reach out to the manufacturer of the drug(s) they have been taking. The manufacturer will want to have this information, and they may be willing to assist with the cost of future treatment.
Veterinarians can also reach out to their local university parasitologist for assistance and guidance. Reference laboratories can be another source of expert advice.
Pulaski also recommends the “Getting Rid of Parasites in Retired Racing Greyhounds” Facebook group. This group is moderated by a veterinarian and has a lot of good information.
When Pulaski sees a hookworm positive dog where resistance is suspected, these are the questions she asks:
- Was the correct dose of dewormer used to treat the patient? If the patient was underdosed or not treated at an appropriate frequency, they may not have been able to clear their infection.
- Is this a case of reinfection? In this case, the treatment may have cleared the infection, only for the dog to be reinfected by hookworm exposure either in their own yard or another site such as a dog park or boarding facility.
- Is this a case of larval leak syndrome? In this syndrome, worms are not resistant, but rather encysted in tissue outside the intestinal tract and therefore not affected by oral anthelmintic treatment.
- What is the dog’s fecal egg count per gram of feces? Counts can reach as high as 800–1,200 hookworm eggs per gram.
Answering all these questions can help determine if resistance is likely or if another cause for the persistent infection is to blame. Both history and diagnostic testing results are necessary to rule out these other differentials. Determining whether a dog has been reinfected, for example, requires knowing not only the exposure history and whether the owner is adequately preventing hookworm egg shedding in the dog’s home environment, but also whether a fecal sample was at some point negative after treatment.
Pulaski stresses that we must always recheck a fecal sample after treating for intestinal parasites. Performing a fecal egg count reduction test (FECRT), which is different from a standard fecal flotation test, allows for measuring of any reduction in fecal egg counts. In cases where it appears that dogs are continually infested after appropriate anthelmintic treatment, it is ideal to perform a FECRT before treatment and 10–14 days after treatment, depending on the drug used for treatment.
To help identify cases that are not truly multianthelmintic drug resistant (MADR), Pulaski will use certain anthelmintics, either alone or in combination, and then monitor fecal egg counts posttreatment. Advantage Multi has a high enough dose of moxidectin to be effective against most cases of larval leak syndrome, she explains. For cases that do not respond to Advantage Multi alone, she will use a combination treatment such as Advantage Multi with Drontal Plus or Advantage Multi with three days of Panacur. This is a strategy that is used a lot in large animal medicine that Pulaski advocates for more use in small animal medicine—combination of medications not so much to improve their spectrum, but rather their efficacy.
Some of these dogs may respond to repeated monthly combination therapy if their fecal egg counts were somewhat reduced after the first round of combination treatment. For these dogs, it is important to look for continued response while also ensuring that the dog is not contaminating their own environment to prevent reinfection.
For dogs with no reduction in their fecal egg count, they are likely infested with MADR hookworms. “Drug-resistant worms tend to produce very high numbers of eggs, and that doesn’t change” even after treatment, Pulaski explains. Dogs with MADR hookworms are unlikely to respond to any of the anthelmintics typically recommended for treating intestinal parasites in dogs.
An Extralabel Treatment Option
A 2020 paper by Pablo Jimenez Castro, DVM, PhD, and others describes the extralabel use of emodepside in the treatment of MADR hookworm infestations. Emodepside is the active ingredient in Profender, a topical parasiticide for cats. The authors clarify that they do not recommend this course of treatment due to limited data on safety but provide the information for clinicians to decide for themselves. While it is labeled for topical use in cats, emodepside must be used orally to kill drug-resistant hookworms in dogs. The dose that has been suggested is 1 mg/kg.
There are multiple safety concerns with the extralabel use of emodepside in dogs. Pulaski reports that the drug is very effective at killing heartworms. In fact, it kills them so quickly that a heartworm-positive dog who takes this drug orally would be at increased risk for anaphylaxis secondary to rapid, widespread worm kill-off. Additionally, the authors of the study reported that dogs with the MDR1 gene for multidrug sensitivity may be at higher risk for “severe adverse effects,” especially if they are dosed incorrectly.
Extralabel use of emodepside in dogs reportedly kills heartworms so quickly that a heartworm-positive dog who takes this drug orally would be at increased risk for anaphylaxis secondary to rapid, widespread worm kill-off.
Despite the risks with emodepside, Pulaski reports that it is sometimes the only drug that works. Before deciding to use it to treat suspected MADR hookworms, she recommends running a fecal polymerase chain reaction test to look for the mutation that codes for benzimidazole resistance. In the paper, Jimenez Castro also recommends treating patients with triple-drug combination therapy (febantel/pyrantel pamoate/praziquantel and moxidectin or fenbenazole, pyrantel pamoate, and moxidectin) and documenting failure of this treatment via FECRT first.
When considering extralabel emodepside use, it is also important to choose patients carefully, screening for heartworm disease and the MDR1 mutation if appropriate. Pet owners must be adequately warned about the risks and the extralabel nature of the treatment, and treatment must be administered in the hospital where patients can be monitored closely, Pulaski said.
When considering extralabel emodepside use, it is also important to choose patients carefully, screening for heartworm disease and the MDR1 mutation if appropriate.
If emodepside treatment is elected, some dogs may need up to three doses of the drug to be totally cleared of their hookworms but should not continue with this treatment long term. Even if they reach “no parasite” status with emodepside, Pulaski cautions, these dogs should still have their fecal samples checked at least three to four times per year. Their owners should continue to take precautionary measures to avoid reinfection and environmental contamination, which involves picking up feces immediately. She even describes how some dog owners will place a paper plate on the ground before their dog defecates so that their stool never touches the grass.
With multiple factors influencing the prevalence and drug resistance of heartworm and hookworm infestations, it is more important than ever to convey to clients the importance of prevention and to be aware of the myriad risk factors involved.
Emily Singler, VMD, is AAHA’s veterinary content specialist, a mom of four, and an advocate for working parents in veterinary medicine. Her book, Pregnancy and Postpartum Considerations for the Veterinary Team, is available at emilysinglervmd.com |
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