Safety and effectiveness of therapies are essential to eliminate microfilariae
Each clinic has a model or photo of a heart, teeming with adult heartworms to help educate clients about heartworm disease. It is therefore not surprising that adult heartworms receive the most attention. After all, adult female heartworms can grow up to 12 inches in length.1 Worms can live 5-7 years,1 obstruct the heart and pulmonary arteries and potentially contribute to pulmonary hypertension, right enlarged heart, liver or kidney disease, and in some cases vena cava syndrome.
What attracts less attention, perhaps because they are less visible, are the tiny, mobile microfilariae, many more numerous than adults, that circulate in the dog’s body.
Because domestic dogs are the definitive hosts of Dirofilaria immitis, a heartworm positive dog can harbor a large number of microfilariae, up to 60,000 or more in a single milliliter of blood.2 When microfilariae circulate in tissues, they can cause structural damage to organs, such as the lungs and kidneys.3
Removing these microfilariae is essential for a dog’s health and reducing reservoirs of infection that pose a risk to other pets and wildlife, including other dogs, cats, coyotes, and wolves. But a way to safely and effectively kill microfilariae has not always been available.
A life cycle review
After mating, adult heartworms release microfilariae into the bloodstream. Microfilariae must be ingested during a blood meal by an intermediate host, a mosquito, to become infectious. When investigators collected mosquitoes from the kennel of a single heartworm positive dog, they found that 74% (84/114) of those mosquitoes were infected with Microfilariae immitis.4
Inside the mosquito, the microfilariae moult several times, eventually becoming infectious larvae in the third instar (L3). The next time the mosquito vector takes a blood meal, it deposits L3 larvae on the skin surface which enter the dog through the puncture wound. Within days, the larvae molt into fourth instar larvae (L4), which move between muscle and subcutaneous tissue.
With another molt, the larvae become immature adults and enter the bloodstream and eventually reach the pulmonary arteries, where they become adults and the life cycle begins again. If left untreated, microfilariae can continue to circulate in a dog for up to 2.5 years.5
The problem with microfilaricides
Over the years, a number of compounds have been used as microfilaricides, including stibophene, diethylcarbamazine citrate (DEC), fenthion, and levamisole. While some are effective, they are often accompanied by serious adverse effects and toxicities.
Veterinary professionals eventually switched to macrocyclic lactones, an effective and safer class of drugs, for off-label use as microfilaricides.6 Current compounds of this class include ivermectin, selamectin, milbemycin oxime, and moxidectin.
However, most heartworm products containing these compounds, when given in preventative doses, are not designed to be completely microfilaricidal.5 Since microfilariae are generally less sensitive than L3 and L4 larvae to macrocyclic lactones, higher doses may be required.7 For example, to effectively remove microfilariae, ivermectin should be given up to 8 times the preventive dose.5
Nevertheless, the American Heartworm Society recommends caution when administering macrocyclic lactones to dogs with high microfilariae counts because of the potential for anaphylactic reactions associated with rapid mortality. As more people travel with their dogs and homeless dogs are increasingly transported to other places for adoption, safe and effective macrocyclic lactones are crucial to help reduce the spread of D. immitis of microfilariae dogs.
Transdermal moxidectin is labeled as a microfilaricide
Tansdermal Advantage Multi® (imidacloprid + moxidectin) for dogs is a heartworm prevention approved by the United States Food and Drug Administration (FDA) to kill circulating microfilariae in dogs with heartworms. This approval was based on studies in dogs infected experimentally and naturally with heartworm, which focused not only on effectiveness, but also on safety.
In a controlled laboratory study, adult heartworms were surgically implanted in 20 dogs 82 days before application of the product.6 Participating dogs had to have at least 300 microfilariae per milliliter of blood. On study days 0 and 28, Advantage Multi was applied to 10 dogs and an equivalent volume of mineral oil was administered to 10 control dogs. Blood samples were taken for the microfilaria count on the first 3 days, then weekly through day 28, and again on day 42. The average microfilaria count for the treated dogs was reduced by more than 99.7% from days 14 to 42. No treatment-related adverse events were noted.
Another study evaluated the effects of Advantage Multi on dogs naturally infected with D immitis.8 To be eligible, the 22 dogs carrying the heartworm had to have at least 300 microfilariae per milliliter of blood. As in the previous study, half of the dogs were treated with Advantage Multi on Study Days 0 and 28, and the control dogs were treated with mineral oil. Blood samples for the microfilaria count were performed on a similar schedule. In this case, the results were similar to those in the previous study: on days 14 to 42, the number of microfilariae was reduced by more than 99.9% in the treated dogs. No treatment-related adverse events were observed.
Finally, a multicenter field study evaluated 181 client-owned dogs with heartworms and circulating microfilariae.9 The dogs were divided into 2 groups. All dogs were treated with Advantage Multi on Study Days 0 and 28; however, half of the dogs were also treated with melarsomine on days -14, 14 and 15. After the microfilaria counts were performed on days 28 and 42, the group that received Advantage Multi and melarsomine experienced a 99.6% and 99.7% microfilaria reduction. respectively. The group treated with Advantage Multi demonstrated similar success with reductions in reductions of 98.8% and 99.2%, respectively. Advantage Multi was well tolerated when given to heartworm positive dogs, alone or in combination with melarsomine.
Treat microfilaria early
Currently, the American Heartworm Society recommends treating dogs with heartworms with a macrocyclic lactone and doxycycline at the time of diagnosis.
As a product with an FDA approved indication to treat circulating microfilariae in heartworm positive dogs, Advantage Multi may be a useful part of any clinical arsenal, especially in heartworm endemic areas of the country.
The transdermal formulation is designed to safely deliver the highest approved dose of moxidectin (2.5 mg / kg) on the market. When applied, moxidectin is rapidly absorbed through the skin and enters the bloodstream. It is concentrated in fat and tissue and remains active throughout the month. Advantage Multi kills adult fleas, treats flea infestations, treats and controls sarcoptic mange and parasitic intestinal infections, and of course prevents heartworm disease and treats circulating microfilariae.
- Heartworm disease in dogs. American Heartworm Society. Available at: www.heartwormsociety.org/images/pdf/AHS_dog_brochure-Final1.pdf.
- Nguyen C, Koh WL, Casteriano A, et al. Heartworm transmitted by mosquitoes Dirofilaria immitis in Australian dogs. Parasite vectors. 2016; 9 (1): 535. doi: 10.1186 / s13071-016-1821-x
- Ames, little Marisa. A selective summary of the 2019 Triennial Heartworm Symposium. Accessed February 1, 2021. https: // todaysveterinarypractice.com/a-selective-summary-of-the-2019-triennial-heartworm-symposium/.
- McKay T, Bianco T, Rhodes L, Barnett S. Prevalence of Dirofilaria immitis (Nematoda: Filarioidea) in mosquitoes from northeast Arkansas, USA. J Med Entomol. 2013; 50 (4): 871-878. doi: 10.1603 / me12197
- Bowman DD, Atkins CE. Biology, treatment and control of heartworm. Vet Clin North Am Small Anim Pract. 2009; 39 (6): 1127-1158. doi: 10.1016 / j.cvsm.2009.06.003.
- McCall JW, Arther R, Davis W, Seetje T. Safety and efficacy of 10% imidacloprid + 2.5% moxidectin for the treatment of circulating microfilariae of Dirofilaria immitis in experimentally infected dogs. Veterinary parasitol. 2014; 206 (1-2): 86-92. doi: 10.1016 / j.vetpar.2014.09.011
- Bowman D, Mannella C (2011). Macrocyclic lactones and Dirofilaria immitis microfilariae. Best Anim Med Companion. 2011; 26 (4): 160-172.
- Bowman DD, Charles SD, Arther RG, Settje T. Laboratory evaluation of the efficacy of 10% imidacloprid + 2.5% moxidectin topical solution (Advantage® Multi, Advocate®) for the treatment of circulating microfilariae of Dirofilaria immitis in dogs. Parasitol Res. 2015 ; 114 (Suppl 1): S165-174. doi: 10.1007 / s00436-015-4522-z
- Elanco. Data on file. Summary Supplement on Access to Information, NADA: 141-251.