Resisting heartworm prevention

A small number of heartworms resistant to prophylaxis
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Dr. Ray M. Kaplan said nearly all dogs given heartworm prophylaxis are protected, but he has seen compelling evidence that some heartworms are resistant to prophylaxis.

Animal heart with heartworms
©Merial Limited, Duluth, Ga. Used with permission.

Those resistant parasites were found in small numbers of dogs in the Mississippi Delta, including areas of Louisiana, Arkansas, Mississippi, and western Tennessee.

Dr. Kaplan, a professor at the University of Georgia College of Veterinary Medicine in the Department of Infectious Diseases, and Dr. Byron L. Blagburn, a professor and director of clinical parasitology diagnostics at the Auburn University College of Veterinary Medicine, discussed evidence of resistance among heartworms and answered questions from attendees July 22 during a session at the AVMA Annual Convention.

Dr. Blagburn said dogs should continue receiving the same products for heartworm prophylaxis, and now is not the time to panic. His interest in resistance began when he received reports five to six years ago about product failures in animals that veterinarians believed had received proper doses from owners who complied with dosage instructions.

Heartworms obtained from animals following product failures had decreased susceptibility to preventives, Dr. Blagburn said.

“Our interpretation was, yes, some of these isolates were less susceptible, and, at that point, we were convinced that these failures were indeed true failures,” he said.

His research team then intentionally infected research dogs with the resistant isolates while treating these dogs with preventive products.

“The products failed, so, in our opinion, that was confirmation,” he said. He noted that the tests involved limited samples of heartworms from a small geographic region.

Dr. Kaplan said members of the veterinarian and parasitologist communities have disagreed whether any heartworms were resistant to commercial products, but, he said, “The evidence is very compelling that there are indeed drug-resistant isolates of heartworm that are circulating.”

“So the question, then, is how big of a problem is this, and should it change how we view parasite control, heartworm control, in dogs?” he asked.

He said all available heartworm preventives are in the macrocyclic lactone drug class and, thus, have the same basic mechanism of action. As a result, rotating products would accomplish nothing except to confuse clients.

“Resistance is going to be across all products in the class,” he said.

Dr. Blagburn said he agrees with Dr. Kaplan, although further studies may show differences in products under certain conditions.

FDA raised concerns in 2005

In an October 2005 issue of Veterinary Parasitology, Dr. Victoria A. Hampshire of the Food and Drug Administration’s Center for Veterinary Medicine wrote that her agency first received complaints about ineffective macrocyclic lactone heartworm preventive products in 1998. The volume of complaints exceeded 1,000 annually in 2002.

The FDA was not able to detect a distribution pattern for product ineffectiveness by breed, sex, or age. But reports were concentrated in regions with heavy endemic heartworm infection, including southern Texas, Florida, North Carolina, the areas around the Mississippi and Ohio rivers, and in Great Lakes states.

FDA spokeswoman Siobhan DeLancey said in August that the agency would develop a strategy to respond if it determined that a drug were no longer safe or effective, and she noted that the agency has not implemented such a strategy for resistance associated with heartworm preventives.

Earlier in 2005, the CVM’s surveillance division asked that companies marketing heartworm preventives refrain from claiming their products are 100 percent effective. The request followed reports of lack of effectiveness among all marketed preventives, according to the November/December 2005 edition of the FDA Veterinarian Newsletter.

DeLancey said the FDA has not changed its position that promotional claims of 100 percent effectiveness among heartworm preventives are not supported by either preapproval information or postapproval adverse drug experience reports.

In the 2005 newsletter, Dr. Martine L. Hartogensis wrote that the CVM had been receiving an increasing number of reports of lack of effectiveness in products designed to prevent heartworm disease in dogs and cats. When her article was published, the CVM database of adverse drug experience reports included about 5,800 reports of lack of effectiveness of heartworm prevention drugs, although many of those failures could have occurred when owners improperly administered preventives or when dogs did not swallow or regurgitated oral doses, the newsletter states. But CVM specialists determined that 1,300 of those reports were related to product failures.

“These cases were well-documented concerning administration of the product according to the label, proper purchase history, and negative heartworm antigen tests prior to initiation of the drug and at least seven months after beginning prevention followed by a positive antigen test,” it states.

The increased number of reports could be connected with increased awareness among veterinarians and pet owners about heartworm prevention effectiveness or could be problems with products, the newsletter stated. Updated report figures were not immediately available.

The American Heartworm Society’s document “Heartworm Preventive Resistance: Is it possible?” states that anecdotal evidence and preliminary studies suggest some heartworms react differently when exposed to macrocyclic lactones. Researchers have been studying and working to potentially identify resistant strains of heartworms.

However, the document states that inconsistent heartworm preventive administration and inappropriate testing intervals are common factors when preventives lack efficacy.

More than 50 percent of dogs seen by veterinarians in the southern U.S. “never receive a single dose of preventive,” the document states, and inconsistent heartworm testing can account for many cases involving lack of efficacy.

Preventive use still needed

Dr. Kaplan similarly said during the 2013 AVMA convention that the failure of pet owners to comply with directions for heartworm preventive administration or failure to administer heartworm medication remain the biggest threats to heartworm control.

“We need to be very, very careful that we don’t hear that there is resistance and then take the next step and say, ‘Well, the drugs don’t work; there’s no sense in using them,’ because that’s not true, and that’s not the story we need to be communicating,” he said.

Dr. Blagburn said that, without further research, it remains unclear how resistance could spread. He said veterinarians can help prevent the spread of resistance as well as determine how widely it has spread.

He noted that at least one dog that was moved from the Mississippi Delta region to Ontario following Hurricane Katrina was infected with heartworms with microfilariae that were not killed by aggressive treatments. Dr. Kaplan said empirical epidemiologic evidence suggests resistant heartworms may have decreased ability for transmission, and no further reports of resistance have emerged from Ontario.

Dr. Kaplan also said he has seen patterns of heartworm resistance that differ from expectations based on drug resistance in livestock parasites, and more research is needed.

When Dr. Blagburn asked the few dozen veterinarians in attendance whether any had detected heartworms in the pets of compliant clients, at least seven raised their hands. They said they practice in Arkansas, Louisiana, Michigan, New Jersey, and Texas.

Dr. Blagburn suggested that veterinarians encourage clients to walk dogs at times when mosquitoes are less active as well as implement screening for kennels. Dr. Kaplan said clients need to know that mosquitoes are vectors and threats to their dogs.

Dr. Blagburn encouraged testing, particularly among pets in high-challenge areas and patients with histories of client noncompliance with preventive treatment schedules. While he thinks some animals should be tested every six months, he said yearly tests are otherwise acceptable.