The medical management of heartworm infection is complex because of the complicated parasite life cycle, the marked variability in clinical manifestations and severity of HWD, prophylactic considerations, adulticidal and microfilaricidal considerations, and the relative toxicity and complications associated with adulticidal therapy. For these reasons, the diagnosis, prevention, and treatment of heartworm infection remains a challenge
Prevention of heartworm infection is an obvious and attainable goal for the veterinary profession. Prevention failure results from ignorance on the part of owners as to the presence or potential severity of HWI, lack of owner compliance, or from inadequate instruction on preventative measures by the attending veterinarian. Studies of owner compliance have revealed that approximately 55% of dog owners that use veterinary care purchase heartworm preventative, and enough medication is dispensed only to meet the needs of approximately 56% of those dogs. Hence the proportion of “cared for” dogs in the population that receive adequate heartworm prophylaxis is less than one third. If one takes into consideration doses purchased but not administered and dogs that are never taken to a veterinarian, the percentage of protected dogs falls drastically. This was emphasized in North Carolina in 1999, when Hurricane Floyd caused extensive flooding and disruption in the poorest part of the state. Of dogs rescued from the floodwaters, 67% were infected with heartworms (personal communication, Dr. Kelli Ferris, North Carolina State University, 2003). In addition, evidence suggests that the veterinary profession is failing in its education of clients. New and colleagues, upon questioning veterinary clients purchasing macrolide preventatives, found that 38% did not realize that their prescribed drug’s spectrum was broader than solely preventing HWI.
Diethylcarbamazine (DEC), which long enjoyed popularity as the preventative of choice, has now been largely replaced by the safer and more convenient macrolide preventatives. This product is safe (only in amicrofilaremic dogs) and effective; however, it must be given daily, making owner compliance problematic. Diethylcarbamazine is thought to kill L3 and early L4 tissue migrating larvae but only has a small temporal window of therapeutic efficacy, thus explaining the need for frequent administration. Preventative should be administered daily from the onset of mosquito season, continuously until 1 to 2 months after a killing frost. In some geographic regions, the persistence of mosquitoes dictates yearlong prophylaxis, although this is controversial for much of the United States (see discussion of controversies, following).
Diethylcarbamazine must only be administered to dogs free of microfilariae, thus dictating a yearly heartworm test prior to reinstitution of preventative therapy. Inadvertent administration of diethylcarbamazine to microfilaremic dogs produces an adverse, possibly immune-mediated reaction in approximately 30%. Signs associated with this adverse drug reaction usually occur within 1 hour of medication and include depression, ptyalism, vomiting, diarrhea, weak pulse, pale mucous membranes with poor capillary refill time, and bradycardia. Subsequently some dogs may become recumbent, dyspneic, and tachycardic, and 18% of reactors succumb. Restated, 6% of microfilaremic dogs to which diethylcarbamazine is administered will die due an adverse reaction.
Not infrequently, owners inadvertently miss one or more doses of Diethylcarbamazine preventative. If 1 day of therapy is omitted, no problem exists and drug administration should continue. In the event of a more prolonged lapse in diethylcarbamazine treatment, reinstitution of medication should be advised, with the realization that infection may have occurred during the prophylactic hiatus.
These dogs should be reevaluated in 6 to 7 months to determine if infection has resulted. If a dog is found to be microfilaremic when receiving diethylcarbamazine, prophylaxis should be continued; however, if inadvertently stopped, reinstitution may result in the aforementioned adverse reaction.
The introduction of the macrolide agents (macrocyclic lactones) ivermectin (Heartgard ®), milbemycin oxime (Interceptor ®), moxidectin (ProHeart ® and ProHeart ® 6), and selamectin (Revolution ™) has provided the veterinary profession with effective heartworm preventatives in a variety of formulations. These agents, because they interrupt larval development during the first 2 months after infection, have a large window of efficacy and are administered monthly or less frequently. Macrolide agents are superior to Diethylcarbamazine in convenience. They produce less severe reactions when inadvertently given to microfilaremic dogs, allow a grace period for inadvertent lapses in administration, are more effective with treatment lapses of up to 2 to 3 months when used continuously for the next 12 months, and have a dual role as microfilaricides. Recently it has been shown that some macrolides have adulticidal activity, if used continuously for prolonged periods. (NOTE: ProHeart ® 6 is no longer oh the market.)
Ivermectin, a chemical derivative of avermectin B1 that is obtained from Streptomyces spp., is effective against a range of endo- and ectoparasites and is marketed as a once-monthly heartworm preventative. It is also marketed in a form with pyrantel pamoate to improve efficacy against intestinal parasites (). Macrolides provide a wide window of efficacy and provide some protection when lapses in therapy occur. Ivermectin is effective as a prophylactic with lapses of up to 2 months. Protection is extended, with continuous 12-month administration postexposure, with lapses of 3 months (98% efficacy) and of 4 months (95% efficacy). As stated previously, ivermectin is microfilaricidal at preventative doses (6 to 12 µg/kg/month), resulting in a gradual decline in microfilarial numbers. Despite this gradual microfilarial destruction, generally mild, adverse reactions (transient diarrhea) can occur if administered to microfilaremic dogs. Some breeds (collies and Shedand sheep dogs) are susceptible to ivermectin (and other macrolide) toxicosis at high doses, suffering neurologic signs. This has typically resulted with the use of concentrated livestock preparations, with clinical signs recognized with doses greater than 16 times the recommended dose. For this reason, only preparations designed for pet use should be administered to dogs. When used appropriately, ivermectin is virtually 100% effective in preventing HWI. Additionally, recent studies have shown ivermectin to have partial adulticidal properties when used continuously for 16 months and virtually 100% effective with continuous administration for 30 months. (See discussion of controversies, following.)
Milbemycin oxime is a member of a family of milbemycin macrolide antibiotics derived from a species of Streptomyces. At 500 to 999 Hg/kg, it has efficacy against developing filarial larvae, arresting development in the first 6 weeks. It can therefore be given at monthly intervals with a reachback effect of 2 months when doses are inadvertently delayed. With 12 months’ continuous treatment postexposure, this “safety net” can be extended to 3 months (97% efficacy), falling to 41% with lapses of 4 months. At the preventative dose, milbemycin is a broad-spectrum parasiticide, being also effective against certain hookworms, roundworms, and whipworms (). In microfilaremic dogs, milbemycin has greater potential for adverse reactions than do other macrolides, because it is a potent microfilaricide at preventative doses. Adverse reactions, similar to those observed with ivermectin at microfilaricidal doses, may be observed in microfilaremic dogs receiving milbemycin at preventative doses. As with microfilaricidal doses (50 ug/kg) of ivermectin, Benadryl (2 mg/kg intramuscularly) and dexamethasone (0.25 mg/kg intravenously) may be administered prior to milbemycin to prevent adverse reactions, particularly in dogs with high micro-filarial counts. Milbemycin is also safe for use in collies at the preventative dose. With appropriate use, milbemycin is virtually 100% efficacious as a heartworm prophylactic.
The macrolide preventative, moxidectin, has been more recently marketed as a narrow-spectrum heartworm preventative () and shown to be safe and virtually 100% effective at 3 ug/kg orally, given monthly or bimonthly up to 2 months postinfection. Moxidectin, at this dose, is gradually microfilaricidal and did not produce adverse reactions in a small number of microfilaremic dogs treated with the prophylactic dose. At 15 ug/kg, 98% reduction in micro-filarial numbers was documented 2 months post-treatment. Lastly, moxidectin appears to be safe in collies. A new liposomal formulation of moxidectin, which provides the potential to improve owner compliance, gives 6 months’ protection with one subcutaneous injection. With 12 months’ (two injections) continuous treatment, injectable moxidectin is 97% effective at preventing infection after a 4-month lapse in preventative therapy. (This product was removed from the market in late 2004 pending further study.)
Selamectin is a semisynthetic macrolide. It is unique in its broad spectrum and in the fact that it is applied topically once monthly (). Its efficacy is similar to that of other macrolides (virtually 100%, when used as directed). At 6 to 12 mg/kg topically, this preventative is effective at preventing heartworms infection and kills fleas and flea eggs, sarcoptic mange mites, ticks, and ear mites. Bathing and swimming, as soon as 2 hours after application, does not alter efficacy. Safety has been shown at tenfold topical doses, with oral consumption of single doses and, in ivermectin-sensitive collies, at recommended doses and fivefold overdoses for 3 months. Like other macrolides, selamectin has at least a 2-month reach-back effect and with 12 months’ continuous administration is 99% protective after 3-month lapses in prophylaxis. Selamectin has microfilaricidal activity similar to other macrolides. Chronic, continuous selamectin administration has adulticidal efficacy, although no published data indicate it is as effective in this role as ivermectin.
In summary, the macrolides offer a convenient, effective, and safe method of heartworm prophylaxis with varying spectra and methods of administration (). They each have microfilaricidal efficacy and render female heartworms sterile. Hence microfilarial tests for heartworm infection cannot be reliably used in dogs receiving these products. Prophylaxis should be commenced at 6 to 8 weeks of age in endemic areas or as soon thereafter as climatic conditions dictate. Although safer than Diethylcarbamazine in microfilaremic dogs, before first-time administration any dog over 6 months of age and at risk of infection should be tested (antigen test, followed by a microfilaria test, if antigen positive). Additionally, even though protective for at least 8 weeks postexposure, macrolides should be administered precisely as indicated by the manufacturer. If accidental lapses of more than 10 weeks occur, the preventative should be reinstituted at recommended doses and maintained for 12 consecutive months. Macrolides can also be used to “rescue” dogs that have lapsed in their Diethylcarbamazine daily therapy for up to 60 to 90 days. In the event of a lapse in preventative administration during a time of known exposure risk, an antigen heartworm test should be performed 7 months after the last possible exposure to determine if infection has occurred.
The necessary duration of protection is controversial. The American Heartworm Society indicates that in colder climates, yearlong prevention is not necessary, advocating beginning macrolides within 1 month of the anticipation of transmission season and continuing 1 month beyond the transmission season. On the other hand, some experts believe that yearlong prevention should be embraced, regardless of geographic location. This author advocates yearlong prevention, at least below the Mason-Dixon line in North America.