Clarke E. Atkins, DVM, DACVIM (Internal Medicine & Cardiology)
The introduction of the macrolide agents ivermectin (Heartgard®), milbemycin oxime (Interceptor®), moxidectin (ProHeart® and ProHeart® 6) and selamectin (RevolutionTM) has provided the veterinary profession with effective heartworm (HW) preventatives in a variety of formulations. Such 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. These agents are superior to diethylcarbamazine (DEC) in: convenience; producing less severe reactions when inadvertently given to microfilaremic dogs; allowing a grace period for inadvertent lapses in administration; efficacy with treatment lapses of up to 2-3 months when used continuously for the next 12 months1; and lastly, having a dual role as microfilaricides.2-4
Ivermectin, a chemical derivative of avermectin B1 which is obtained from Streptomyces sp. 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. Ivermectin is effective as a prophylactic with lapses of up to 2 months occur. This is extended with continuous 12 month administration post-exposure to 3 months with 98% efficacy and to 4 months with 95% efficacy.1 As stated above, ivermectin is microfilaricidal at preventative doses (6-12 mcg/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.5,5a Collies have been identified as a breed in which certain individuals are at increased risk of central nervous system signs and even death due to increased concentrations of ivermectin in the central nervous system. It is important to note that such adverse reactions have not been identified at preventative or even microfilaricidal doses of ivermectin. 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.6
Milbemycin oxime is a member of a family of milbemycin macrolide antibiotics derived from a species of Streptomyces. At 500-999 ug/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 "reach back effect" of 2 months when doses are inadvertently delayed. With 12 months' continuous treatment post-exposure, this "safety net" can be extended to 3 months with 97% efficacy, falling to 41% with lapses of 4 months.1 At the preventative dosage, 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, as it is a potent microfilaricide at preventative doses.7 Adverse reactions, similar to those observed with ivermectin at microfilaricidal doses may be observed in microfilaremic dogs receiving milbemycin at preventative doses.7 As with microfilaricidal dosages (50 ug/kg) of ivermectin, Benadryl (2 mg/kg IM) and dexamethasone (0.25 mg/kg IV) may be administered prior to milbemycin to prevent adverse reactions, particularly in dogs with high microfilarial counts. Milbemycin is also safe for use in collies at the preventative dose. With appropriate use, milbemycin is virtually 100% efficacious as a HW prophylactic.
The macrolide preventative, moxidectin, has been recently marketed and has been shown to be safe and virtually 100% effective at 3 mcg/kg given monthly or bimonthly up to 2 months post-infection.8 Moxidectin, at this dosage, is gradually microfilaricidal and did not produce adverse reactions in a small number of microfilaremic dogs treated with the prophylactic dose.9 At 15 mcg/kg, 98% reduction in microfilarial numbers was documented 2 months post-treatment.9 Lastly, moxidectin appears to be safe in collies.10 A new liposomal formulation of moxidectin gives 6 months' protection with one subcutaneous injection.11 With 12 months' (2 injections) continuous treatment, injectable moxidectin is 97% effective at preventing infection after a 4 month lapse in preventative therapy.12
Most recently, a semi-synthetic macrolide, selamectin, has been developed and marketed. It is unique in its spectrum and in the fact that is applied topically once monthly. Its efficacy is similar to that of other macrolides (virtually 100%, when used as directed).13,14 At 6-12 mg/kg topically, this preventative is effective at preventing heartworms infection and kills fleas and flea eggs, sarcoptic mange mites, ticks and ear mites.13 Bathing and swimming, as soon as 2 hours after application, did not affect efficacy. Safety has been shown at 10-fold topical doses, with oral consumption of single doses, and, in ivermectin-sensitive collies, at recommended dosages and five-fold overdoses for 3 months.15 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.13,16 Selamectin has microfilaricidal activity similar to other macrolides.16
In summary, the macrolides offer a convenient, effective and safe method of HW prophylaxis with varying spectra and methods of administration. Prophylaxis should be commenced at 6-8 weeks of age in endemic areas, or as soon thereafter as climatic conditions dictate.5,5a Although safer than DEC 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 positive). Although protective for at least 8 weeks post-exposure, macrolides should be administered precisely as indicated by the manufacturer. If accidental lapses occur, the preventative should be reinstituted at recommended doses and maintained for a continuous 12 months. Macrolides can also be used to "rescue" dogs which have lapsed in their DEC daily therapy for up to 60-90 days.5,5a If a lapse in preventative is prolonged (>2 months) and the risk for HWI deemed moderate or high, macrolides should be continued for a year without interruption. In addition, an antigen test should be performed approximately 6 months after the last chance for exposure to detect infection.
An important breakthrough in the management of heartworm infection (HWI) is the adulticide melarsomine, an organoarsenical superior in safety and efficacy to thiacetarsemide.17 This product, which is administered twice, at 2.5 mg/kg q24h, has a mean retention time 5 times longer than thiacetarsemide and its metabolites are free in the plasma, on which HW feed.18 In a study of 382 dogs with HWI receiving melarsomine, none required cessation of therapy due to hepato-renal toxicity, as compared to 15-30% with thiacetarsemide.18 With 2 doses, the efficacy is over 96% with the useful flexibility of a 50% worm kill with 1 dose. A "split-dose" protocol can be utilized in severely afflicted individuals or in those in which pulmonary thromboembolism (PTE). This method allows destruction of only one-half the worms initially (1 IM injection of 2.5 mg/kg), thereby lessening the chance for embolic complications. This single dosage is followed by a 2 dose regimen in 1-3 months, if clinical conditions permit. While the manufacturer recommends this protocol (Figure 1) for severely affected dogs, the author employs it all cases unless there is financial constraint or underlying concern for arsenical toxicity (for example, preexistent severe renal or hepatic disease). One disadvantage to the "split-dose" method, in addition to the expense, is the need for 2 months' exercise restriction.
In 55 dogs, with severe heartworm disease (HWD) and treated in this 3-dose manner, 96% had a good or very good outcome with >98% negative for antigenemia 90 days post-therapy.18 Although symptomatic and even fatal PTE can result from treatment with melarsomine, no case of severe PTE was seen in the 382 dogs of this series.19 Of the 55 severely affected dogs, 31% had "mild or moderate PTE"; no fatalities resulted. The most common sign was fever, cough, and anorexia 5-7 days post-treatment. This was associated with mild perivascular caudal lobar pulmonary radiographic densities and subsided spontaneously or after corticosteroid therapy.
The most common complication to melarsomine therapy is the local inflammatory reaction at the injection site. This can be minimized by following the manufacturer's directions explicitly (change needles before injecting, choose deep IM site with care, put pressure on site after injection, and alternate sites). In addition, corticosteroids (e.g., dexamethasone) can be given at the time melarsomine is administered to lessen the reaction.
It is now known that certain macrolides have adulticidal properties.6,16,20 Ivermectin, when administered for 31 months continuously has nearly 100% efficacy in young heartworm infections.20 It has been shown, however, that lung and pulmonary vascular manifestations of HWD still result when ivermectin "prophylaxis" is begun 5.5 and 6.5 months postinfection and continued for 1 year.21 Selamectin, when administered continuously for 18 months killed approximately 40% of transplanted worms.16 Sustained release moxidectin appears to have only modest adulticidal efficacy.12 While there may be a role for this therapeutic strategy in cases in which financial constraints or concurrent medical problems prohibit melarsomine therapy, the current recommendations are that macrolides not be adapted as the primary adulticidal approach.
Surgical removal of HW can minimize PTE, as compared to pharmacologic adulticides, such as melarsomine.22,23 This procedure, however, requires specialized training and instrumentation, including fluoroscopic imaging capabilities. Nevertheless, it remains a useful alternative for the management of high risk patients.
Corticosteroids are indicated in HWD only in the face of pulmonary parenchymal complications (including PTE), to treat or prevent adverse reactions to microfilaricides, and possibly to minimize tissue reaction to melarsomine. Early studies demonstrated that corticosteroid therapy reduced pulmonary blood flow and worsened intimal disease in a model of HWI after adulticide.24 For allergic pneumonitis, prednisolone (1 mg/kg/day) is administered for 3-5 days and discontinued or tapered, as indicated.25 The response is generally favorable. Prednisolone has also been advocated for the management of PTE. Because of the potential for fluid retention, steroids should be used cautiously in the face of heart failure.
Cage rest is an important aspect of the management of HWD after adulticidal therapy, after PTE, or during therapy of heart failure. This can often be best, or only, accomplished in the veterinary clinic. If financial constraints preclude this, crating at home and/or tranquilization are useful alternatives.
Despite the fact that no agent is FDA-approved for the elimination of microfilaria, microfilaricidal therapy is traditionally instituted 4-6 weeks after adulticide administration. The macrolides offer a new and effective alternative to levamisole and dithiazanine.5,5a Microfilariae are efficiently and rapidly cleared with ivermectin at 50 ug/kg (approximately 8 times preventative dose) or milbemycin at 500 mg/kg (preventative dose), although this represents an extra-label use of the drugs.5,5a Ivermectin can be diluted 1:9 in propylene glycol (Ivomec®, MSD Agvet, Rahway, NJ) or in water (Eqvalan®, MSD Agvet, Rahway, NJ) and administered orally at 1 ml/20 kg25, although is practice is now discouraged.5a Adverse reactions, the severity of which is likely related to microfilarial numbers, were observed in 6% of 126 dogs receiving ivermectin at the microfilaricidal dose.30 Signs included shock, depression, hypothermia, and vomiting. With fluid and corticosteroid (dexamethasone at 2-4 mg/kg IV) therapy, all dogs recovered within 12 hours. One fatality was observed 4 days after microfilaricidal therapy. Similar findings and frequency have been reported with milbemycin at the preventative dosage.31 Dogs so treated should be hospitalized and carefully observed for the day. Dogs <16 kg, harboring >10,000 microfilaria per ml blood are more apt to suffer adverse reactions.32 Benadryl (2 mg/kg IM) and dexamethasone (0.25 mg/kg IV) can be administered prophylactically to prevent adverse reactions to microfilaricidal doses of macrolides.
A 90% microfilaricidal success rate can be expected with ivermectin25, while milbemycin at 500 ug/kg cleared 6/8 (75%) dogs which had received adulticide therapy and did not harbor male and female adults; microfilarial numbers were reduced by 99% on the day after treatment.31 A slower microfilarial kill rate can also be achieved with ivermectin, moxidectin, and selamectin at preventative doses.1-4
The American Heartworm Society recommends that macrolide therapy (50 mcg/kg for ivermectin or 500 mcg/kg milbemycin) for microfilaria be instituted 3-6 weeks after adulticide.5,5a In 2-3 weeks, a second microfilaria concentration test should be performed and, if negative, preventative started. If still positive, the treatment is repeated or alternatively, chemoprophylaxis begun (assuming that no adverse reaction occurred on the initial treatment).5,5a Persistent antigenemia indicates continued patent infection.
This author chooses an alternative approach, beginning the administration of a macrolide preventative at the time of diagnosis, often days to weeks prior to adulticidal therapy. With the "slow micro-filaricides" (ivermectin, moxidectin, or selamectin), there is little chance of an adverse reaction, but the owner is warned and advised to administer the medication on a day when he/she will be at home. If milbemycin is used, it is administered in the hospital and/or preceded by administration of dexamethasone and Benadryl, as described above.