The current monthly oral and topical heartworm preventives, as well as ProHeart6, the injectable six-month formulation for dogs, are all members of the same pharmaceutical class: the macrocyclic lactones. These are compounds or chemical derivatives of compounds produced by various soil-dwelling species of actinomycete bacteria within the genus Streptomyces. Ever since the introduction to small animal veterinary medicine of the first member of the class, ivermectin (as Heartgard), these compounds have become the mainstay of heartworm prevention in the United States and around the world. These are amazing compounds with efficacy at remarkably low doses against internal and external parasites. With the exception of the well-known blood-brain barrier problem in certain collie breeds, this drug class poses almost no significant safety concerns. These compounds have moved heartworm prevention from the world of the daily into the monthly (or semi-annual with ProHeart6) and, either on their own or in formulations with other products, also provide concurrent protection against internal parasite infections. All in all, from the point of view of the dog and cat, health care now is similar to that of people after World War II when penicillin and related antibiotics jumped onto the scene and provided a remarkable method of combating bacteria. Life is good! The safety of the molecules and their great efficacy are unfortunately lulling people into a sense of complacency. All practicing veterinarians know of a colleague who treats heartworm-infected dogs with the simple administration of a monthly preventive. All veterinarians have argued with clients or themselves about the need to annually test animals that are on year-round (or even soundly prescribed seasonal) prevention. Veterinarians who treat heartworm cases with Immiticide are aware of the recommendation to treat dogs first with a monthly preventive (usually ivermectin), and thus are aware that the medications can be safely administered to microfilaremic dogs. And if you read the labels for the canine products Heartgard Plus, Interceptor, Sentinel, Revolution, Iverhart Max and Advantage Multi, you will see that they all say they are safe for dogs with circulating microfilariae. Thus, there are those who argue that there is no reason to check a dog before beginning a preventive program, because it is not dangerous for the dog, it will “slowly kill” the adult heartworms over a number of months, and any microfilaremia will eventually resolve after the adult worms are removed. If the above arguments are true, if you can treat existing infections with a monthly product, if you do not have to check heartworm status before you start preventive and if annual checks are pointless because the worms will ultimately be killed by the product anyway--then, why not just sell heartworm preventives over the counter? Make the products available in Target and Wal-Mart. There are people out there who firmly believe that this is what should be done and that veterinarians are positioning themselves between the products and consumers simply to make money. I would argue, however, that the products should not be used off-label as described above and that it is critical for veterinarians to remain directly involved in heartworm prevention and verification of product efficacy. In 1992, I presented at the meeting of the American Heartworm Society marketing work that had been done on the use of milbemycin oxime versus ivermectin in a study supported by Ciba Geigy, now Novartis. The reason for the work was that, in the field, it was being stated that ivermectin was not microfilaricidal, therefore Knott’s tests could be used for the annual heartworm check in dogs on Heartgard while antigen tests were required for dogs on Interceptor. By giving the two different products to a number of dogs with naturally acquired heartworm infections that were both antigen- and microfilaria-positive, it was shown that both products were microfilaricidal. This basically meant that for verification of efficacy of either heartworm preventive, it was necessary to run an antigen test. The results have been verified by other researchers utilizing the exact same experimental design. However, the aspect of the work that was always of greater interest to me was that, in all the studies done with these products, 10 to 20 percent or more of the dogs remained microfilaremic for a year or more after the product was first administered. I found this horribly worrisome, because it seemed to me that this would be a perfect means of selecting for anthelmintic-resistant microfilariae. Ever since I did the work, this idea has been a maggot burrowing about in my brain, surfacing now and again to bother me anew. For a long time, others said that heartworms would never develop resistance because the life cycle is too long, there is a significant amount of refugia in the environment that would produce genetic backcrosses to dilute any resistance genes, and there is no direct proof of resistant microfilariae occurring in dogs. However, I have continued to worry and to express my concern. Now I have met practitioners who tell me that they are treating every heartworm-positive dog in shelters where they work in Florida by just starting them on a monthly preventive before adoption. So, if 10 to 20 percent of these dogs on monthlies still have circulating microfilariae–microfilariae which are produced by female worms exposed to ivermectin monthly or living in its presence in the bloodstream–are we not in a position where a lot of worms are in constant contact with these products? If you wanted to create a strain of bacteria resistant to an antibiotic, you would grow it in the presence of the antibiotic, and transfer the colonies that grew onto a new plate. My argument is that this is exactly what we are doing with heartworms in dogs. We are using these dogs as giant petri dishes to select for microfilariae that thrive in the presence of macrocyclic lactones. Then, we are using mosquitoes as our bacterial loops to pick up those potentially resistant microfilariae for the purpose of transferring them to a new plate. Here the counter-argument is always raised that with backcrossing from worms in the surrounding “refugia” that are not seeing product (dogs not on treatment, coyotes, etc.), we will see a dilution of any brewing resistance. However, this does not always happen with nematodes; we have some pretty convincing evidence from horse strongyles and sheep trichostrongyles that backcrossing does not significantly reduce fitness for survival (or else we have selected for other fitness genes as well as the resistance genes). Once the resistance switch is flipped, the worms stay resistant even after the pressure of regular chemotherapy with the compound of interest is removed. My argument is simply this: There is no reason to play the game. We have an excellent adulticide in Immiticide. There is no good reason to use a monthly as an adulticidal treatment. It is only after Immiticide therapy that we should give dogs the preventive or elevated doses of macrocyclic lactones to clear microfilariae. This potential resistance scenario should have remained a simple academic exercise that I played out in my head, not something that is happening in the real world. Unfortunately, it is happening in the real world. So, my recommendation is this: Veterinarians should take full ownership, stewardship and responsibility for heartworm preventives. These products should be used for prophylaxis as intended, not for treatment of existing infections. We need to make certain that product being sold over the Internet is ONLY being given to dogs that have already tested negative for infection. Dogs should be checked annually to verify that we have not already foolishly created a genie that is trying to get out of the bottle. (In some countries in the world, veterinarians are often not as involved in the administration of these products.) Veterinarians need to stay fully involved and make sure these molecules are functioning just like they should be. This isn’t asking too much. Simply, veterinarians should take charge and uphold good medicine and stewardship to protect against product failures caused by our own improper use of these compounds. <HOME> Dwight Bowman, M.S., PhD., is a professor of parasitology at Cornell University’s College of Veterinary Medicine.
