Lack of efficacy and resistance to heartworm preventives
Q. What do we know about heartworm resistance – and what don’t we know?
Clarke Atkins: Since the first peer-reviewed article on the potential emergence of resistant heartworm isolates to macrocyclic lactone (ML) preventives was published more than ten years ago, scientists have been working to better understand why cases of heartworm infections have developed in dogs purported to have been treated appropriately with heartworm preventives, as well as increased difficulty in clearing heartworm microfilariae with ML medications. What we do know is that heartworm resistance violates the classical rules of resistance. These “rules” include:
- “Resistance is much less likely to occur in a region with large refugia.” Suspect ML lack of efficacy (LOE) cases have been reported predominantly in the lower Mississippi Delta region; however, the Delta has the largest refugia for heartworm in the U.S.
- “Resistance is characterized as rapidly spreading.” LOE reports have not occurred in numbers greater than expected outside of the Mississippi Delta.
- “Resistance is forever.” The incidence of LOEs peaked in 2009 and by 2011 had dropped by nearly half. Meanwhile, the vast majority of LOE reports have been invalidated with careful scrutiny of medical records and product purchase history.
So we know that resistance is real, and that it has been demonstrated with all four ML molecules in veterinary use. However, we don’t know the geographical extent of heartworm resistance or how much resistance plays a role in treatment failure (LOEs).
Q. What studies are needed to better address heartworm resistance?
Ray Kaplan: It’s important to study the genetics of drug resistance in heartworm. We want to try to identify which genes are involved, as well as markers that can be used for diagnosis. Currently we don’t know which genes might be involved or what the inheritance patterns of resistance are. All of these things are going to be very important for developing a diagnostic test and then developing models that will enable us to predict the likelihood of spread. We hope that if we can develop some good diagnostic molecular markers, we can then perform molecular epidemiological studies, taking samples from around the country and looking for the specific alleles that are involved with resistance. That is the goal. There’s a lot of work before we get there.
For more on this topic, see the papers by Dr Elena Carretón and colleagues on cardiopulmonary and inflammatory biomarkers and acute phase proteins and markers of oxidative stress as well as the paper from Dr Changbaig Hyun and colleagues in the Symposium Proceedings.
Q. Not every case of heartworm preventive “failure” is a resistant case. When should veterinarians suspect resistance?
Ray Kaplan: Many things can cause failure of prevention other than resistance (e.g. poor owner compliance). The problem is that reports are just reports, and there’s no way to prove if they are associated with true resistance or not. The FDA has received more than 45,000 reports from around the country since 2005 and, as yet, most are not validated. Veterinarians need to look at the medical history, the testing history and the purchase history and decide if product failure is likely. If there are gaps in the purchase history, the veterinarian should question the conclusion that it’s resistant.
For more on this topic, see the paper by Dr Ray M Kaplan and colleagues in the Symposium Proceedings.
Q. You and your colleague, Dr Andy Moorhead, recently developed an algorithm that may help veterinarians know whether to suspect they have a resistant heartworm isolate. Can you explain?
Ray Kaplan: Currently we have no diagnostic test for resistance, so when a case comes in that looks like it might be resistant, a veterinarian is unable to easily confirm or refute whether resistance is there. To address this problem, Dr Moorhead and I created a decision tree to help practitioners make the distinction of whether they might have a resistant case.
We recommend performing a microfilarial (MF) suppression test by taking a blood sample and determining the number of microfilariae present using a Knott’s test, then treating the dog with a microfilaricidal dose of ivermectin or milbemycin oxime. A week later, we recommend performing another MF count. In most studies, a very rapid and profound reduction in MF numbers was seen. Thus one should expect to see a reduction of greater than 75 percent, and typically 90 percent or higher. So if a practitioner sees less than a 75 percent reduction in MF, the case can be considered highly suspicious for resistance.
For more on this topic, see the paper by Dr Andrew R Moorhead and colleagues in the Symposium Proceedings.
Q. What additional advice do you have for veterinarians?
Clarke Atkins: In the vast majority of reported LOE cases, compliance actually is the culprit. Fortunately, we have the ability to affect this. Veterinarians also need to know that MLs should be used year-round, as the American Heartworm Society advocates. I also believe that in areas where exposure potential is massive – where there are lots of mosquitoes and a very high mosquito infectivity rate – it is even more important to make sure that compliance is exact.
Heartworm treatment protocols
Q. You feel strongly about the importance of Wolbachia elimination as part of heartworm treatment. Can you explain?
Laura Kramer: I think that the discovery of Wolbachia within the heartworm was one of the most important discoveries made within the last 20 years in parasitology, and it has important repercussions in human filarial infections as well.
What researchers have seen after years of intensive research is that these bacteria are essential for heartworm survival, reproduction and development. We know that they are very strongly pro-inflammatory and that they’re one of the most important components in post-adulticide pathology. When a heartworm dies, both the heartworm and the Wolbachia release somatic antigens, with the latter being an important contributor to the negative effects of worm death on the host. If we eliminate Wolbachia through doxycycline therapy prior to treatment with melarsomine, or simply administer it with macrocyclic lactones in an adulticidal protocol, we know that lung pathology and clinical manifestations of adulticidal therapy, are much, much lower than if we weren’t using doxycycline. It’s fundamental to maintaining cardiovascular health during and after adulticidal therapy for heartworm disease.
Q. You and others have been studying adulticide protocols for dirofilarial infections. What is the value of exploring alternative protocols for heartworm treatment?
Laura Kramer: First of all, it’s important to make clear that looking for alternative protocols does not meant that melarsomine isn’t the drug of choice for heartworm treatment; it’s an excellent drug. At the same time, we know that mild to serious side effects can result with melarsomine, that problems can arise with owner compliance during treatment and, in many parts of the world, there are issues with melarsomine availability and affordability. Identifying alternative adulticidal protocols will help to guarantee that each pet and owner’s needs are met.
My group in Parma has conducted field studies that use macrocyclic lactones and antibiotics, particular doxycycline, to eliminate adult parasites. These combinations have been found to be very effective in eliminating adult parasites, although they require time – up to a year or more (hence, heartworm elimination is slower than with melarsomine). Our most recent studies were with combinations of moxidectin and doxycycline, which were found to have superior efficacy to an ivermectin/doxycycline combination. Our findings can be applied in two ways: (1) we can use a combination of macrocyclic lactones and doxycycline to prep dogs for Immiticide therapy, thereby reducing lung pathology, or (2) if melarsomine therapy is not possible, we can use the combination as an alternative adulticidal treatment.