In the world of canine heartworm disease research, reluctance to use the R word has evaporated. Leading authorities in pet parasites now concur that resistance to the class of drugs used in heartworm preventive drugs is real.  
 
“We now have proof there is resistance to the macrocyclic lactone (ML) class,” said Dr. Byron Blagburn, an Auburn University parasitologist who did much of the research on strains of heartworm found in the Mississippi Delta, where loss of efficacy to preventive drugs was first suspected. “It’s accepted by the entire industry now,” Blagburn said.

This recognition has placed the industry in uncertain territory. While the entire ML class is implicated in the resistance data, variations in product formulation and ingredient combinations may mean some products work better than others.

In an interview with the VIN News Service, Blagburn was careful to distinguish between drug class and drug product. “All preventives contain at least one macrocyclic lactone and at least one product (containing each ingredient in the class) failed. It does seem to involve all major drugs in that category,” he said, “but not all products are equal.”

The question of whether drug-resistant strains of heartworm are emerging in the United States has been scrutinized for years. Until now, however, experts have been careful to avoid using the so-called R word, “resistant,” to describe the strains that appear not to respond as expected to macrocyclic lactones.

Blagburn credits the evolution in understanding of heartworm susceptibility and identification of the resistant strains to “an inter-collegiate, inter-laboratory, collaborative process.”

The consensus is embodied in a recent update by the Companion Animal Parasite Council (CAPC) of its heartworm prevention guidelines. The new text on the CAPC website states: “Recent work has shown that there are isolates of heartworms that are capable of developing to adults in dogs receiving routine prophylaxis with any of the available macrocyclic lactones.”

In short, a dog faithfully given heartworm-prevention medication may still become infested with the parasitic worm Dirofilaria immitis, which inhabits the arteries of the lungs and sometimes a portion of the heart, causing serious and potentially fatal disease.

Convincing evidence of resistance was presented by multiple researchers at a meeting of the American Association of Veterinary Parasitologists in Chicago last month, according to CAPC President-elect Dr. Susan Little, a veterinary parasitologist at Oklahoma State University. Although research has focused on heartworm isolates from the South and Southeast, the CAPC notes that "At this time, the geographic extent of these resistant heartworms is not known."

The macrocyclic lactone class of drugs in question comprises avermectin drugs (ivermectin and selamectin) and milbemycins (milbemycin oxime and moxidectin). These drugs are found in all commercial heartworm preventives, including: Heartgard (ivermectin), Tri-Heart Plus (ivermectin), Sentinel (milbemycin oxime), Revolution (selamectin), Advantage Multi (moxidectin), ProHeart6 (moxidectin), and Trifexis (milbemycin oxime).

The resistance finding begs the question: Is there any point to using the products?

Absolutely, say Blagburn and Little. Both state that the preventive products still work very well. There may be breaks in prevention with certain products in certain areas, but to the expert mind, this state of affairs only increases the need for year-round preventive action and annual testing for heartworm disease.

“To make a presumption that because resistance exists, the products should be discontinued is absolutely ludicrous,” Blagburn said.

While increased use of a drug usually is implicated in speeding the development of resistance in target parasites or pathogens, the canine heartworm may be different. With the heartworm, a number of factors work against the propagation of resistant genetics, according to Blagburn. The factors include:

• Refugia. The population of heartworms not exposed to the drugs — heartworms living in wild canids such as wolves, foxes and coyotes, and in untreated domestic dogs — helps to dilute the heartworm gene pool, keeping the resistant genes from predominating.
• Life cycle. Heartworms go through multiple larval stages, taking a relatively long time to reach reproductive maturity. The longer it takes a species to reach reproductive age, the slower the genetic change in its population.
• Involvement of an insect vector. Heartworms are transmitted from host to host via the bites of infected mosquitoes, a fact that acts as a speed bump to genetic turnover.

   
While the spread of resistant genes is inevitable, Blagburn said, drug resistance is likely to spread geographically more slowly than has been the case with related worms, such as gastrointestinal parasites.

The recent heartworm research is notable not only for the multi-institute approach, but because the investigation into reports of product failure was spearheaded by the manufacturer of one of the products in question. In communication with the VIN News Service, Dr. Jason Drake of Novartis Animal Health explained the genesis of the studies:

“In recent years, the U.S. Food and Drug Administration (FDA) has seen an increase in reports of lack of efficacy in all approved heartworm preventive therapies – reports that were from manufacturers and veterinarians," Drake said. "After listening to the concerns of veterinarians in the Mississippi River Valley, Novartis Animal Health decided to invest in understanding this problem and, if resistance was confirmed, to work with veterinarians to help contain the spread of resistance.”  

He highlighted data demonstrating that the entire drug class is affected. “Regardless of which product was used, whether it was oral, topical or injected, protection against some Dirofilaria immitis isolates from the Mississippi River Valley was less than 100 percent for all active ingredients included in the ML class,” he said.

While the entire class of drugs appears vulnerable to resistance, not every product has shown reduced efficacy.

Bayer Animal Health, maker of Advantage Multi, a topical drug that contains moxidectin, said by email to the VIN News Service that while research has shown a failure of injectable moxidectin to protect all dogs in a challenge study, the company is unaware of any published data showing a similar failure of moxidectin product applied to the skin.

Little, the parasitologist and CAPC president-elect, confirmed this. She explained: “The CAPC statement refers to all active ingredients because of the injectable moxidectin data, which have been presented in detail. Topical moxidectin is thought to result in higher plasma levels than injectable moxidectin, so there are likely differences in performance. But right now, we don’t fully understand what those differences may be.”   

Another pharmaceutical company, Merial, maker of Heartgard Plus, expressed support for the updated CAPC guidelines but downplayed resistance concerns. “Presently, there is no evidence that reduced susceptibility to macrocyclic lactones is a widespread phenomenon in the D. immitis population or will ever become one,” the company stated by email to the VIN News Service. “Further work will be needed to determine the extent to which the existence of resistant isolates will be a concern.”

In the meantime, how concerned should dog owners be about whether their dog’s heartworm preventive is effective?

Little advises that dog owners should not panic, but make sure they pay attention to maintaining a good heartworm prevention program, working in conjunction with their veterinarian. “Compliance is more important than ever before," she said.

“What worries me,” Little continued, “is when I hear people say, “Oh, heartworm preventives — I hear those don’t work anymore.” She stressed that preventive products still work quite well for their intended function – preventing heartworm disease.

“Not every third-stage larva is resistant,” she said, referring to the infective stage in the heartworm life cycle. “It’s not uniform throughout the population, and the number of worms is correlated with the severity of disease.”

Little went on to say that because “disease severity is linked, in part, to the number of worms present in a dog,” if one or two worms escape a preventive rather than the 25 to 30 worms that may infest an un-medicated dog, “that may be a success in terms of disease prevention.”

Little pointed out that the heartworm preventive products have always been marketed as heartworm disease preventives. “And they still are. They’re just not, in some areas, complete heartworm infection preventives.”

The CAPC guidelines emphasize the need for year-round use of heartworm preventives in uninfected dogs and annual antigen testing.   

One method of treating heartworm disease, using preventive products over a long period to kill adult worms, has been fingered as a suspect in the development of resistant heartworms.

A passage in the CAPC guidelines written in capital letters practically shouts the importance of using approved "adulticide" products to treat heartworm infected dogs rather than the “slow-kill” method of using macrocyclic lactone preventives to gradually treat an adult heartworm infection.

According to the American Heartworm Society, this method can take up to two years of continuous administration to clear an infection entirely.

The need to abandon the slow-kill approach was reiterated in no uncertain terms by Blagburn. He said: “We have good data to convey to veterinarians that using anything other than the available adulticide to eliminate heartworm infections can be risky. We need to avoid slow-kill in every situation if at all possible.”

The problem with using the slow-kill technique to kill adult heartworms, experts say, is this: If there are microfilariae in the infected dog that are resistant to the macrocyclic lactone drug used, those parasites will be transmitted to mosquitoes, potentially finding their way to a new dog in which to reproduce, increasing the risk to all dogs in the area.

Little repeated the prohibition against the slow-kill technique even more strongly, calling the method irresponsible given what we now know. “If we select for resistance, even in an individual dog, we put every animal in the area at risk. We just can’t do slow-kill anymore," she said.

That's not to blame those who used the technique previously, she added. “We didn’t know. We thought it was OK. We were trying to do in some situations what we thought was best for the dog. But it's no longer a viable option.”

Little and Blagburn stressed that if a veterinarian believes that the slow-kill approach truly is medically indicated, the dog first must be free of circulating microfilariae. Only dogs without microfilariae should be maintained on preventives long-term, they said.

Given the preponderance of evidence of resistance presented at the veterinary parasitology meeting last month, Little said the CAPC board had no difficulty concluding that resistance is an issue.

"When we saw the data, it was confirmation," she said. "It was very compelling because it was multiple laboratories finding the same evidence. We have very strong evidence that there has been a shift in preventive efficacy in laboratory studies that corresponds with what veterinarians have been telling us from the field.

"There are some veterinarians who are now rightfully saying, 'I told you so,' " she commented with a smile, but added, "We needed the lab confirmation."