The macrocyclic lactones (avermectins and milbemycins) are products or chemical derivatives of soil microorganisms belonging to the genus Streptomyces. The avermectins in commercial use are ivermectin, abamectin, doramectin, eprinomectin, and selamectin. Commercially available milbemycins are milbemycin oxime and moxidectin. The macrocyclic lactones have a potent, broad antiparasitic spectrum at low dose levels. They are active against many immature nematodes (including hypobiotic larvae) and arthropods. The published literature contains reports of use to treat infections of >300 species of endo- and ectoparasites in a wide range of hosts. Moreover, a single therapeutic dose can persist in concentrations sufficient to be effective against new nematode infections for prolonged periods after treatment.
The macrocyclic lactones are well absorbed when administered PO or parenterally; the pour-on formulations exhibit greater variability. Regardless of the route of administration, macrocyclic lactones are extensively distributed throughout the body and concentrate particularly in adipose tissue. However, the route of administration and formulation may affect the drug pharmacokinetics. The residence time of macrocyclic lactones administered SC may also be influenced by the body condition of the animal.
Effective levels are reached in the GI system, lungs, and skin regardless of the route of administration. There is, however, a very complex interaction between pharmacokinetic compartments and the quantitative and qualitative availability of drug/metabolite in one compartment. For example, the association of macrocyclic lactones with digesta affects absorption; systemic availability and elimination of ivermectin given PO may differ significantly with feed quantity or composition in sheep. Also, the practice of feed withdrawal before PO treatment broadens the pharmacokinetic profile, significantly increasing anthelmintic efficacy.
Although there has long been concern over the use of chemical additives in livestock feed (eg, potential consequences of insect-free manure), the effects on nontarget dung insects and dung dispersal primarily became a concern with the macrocyclic lactones. The commercially available macrocyclic lactones are primarily excreted in the feces, and a broad range of insecticidal activities has been observed against dung-inhabiting insect species.
Extensive fate and effects studies have been conducted with the macrocyclic lactones, with most data reported for ivermectin. Ivermectin in feces or soil degrades at a slow but significant rate. In a northern hemisphere winter environment, decomposition is slow (half-life of 91–217 days); when exposed to an outdoor summer environment, ivermectin in soil has a half-life of 7–14 days.
Although macrocyclic lactones are highly toxic to some species of aquatic organisms, their tight soil-binding mitigates against aquatic exposure via run-off or leaching. Macrocyclic lactones have little adverse effect on freshwater algae and virtually none on germination or growth of plants; however, residues in animal feces have the potential to affect arthropod development in a variety of ways. The larvae of cyclorrhaphous Diptera are generally more sensitive to ivermectin and other macrocyclic lactones than are Coleopteran larvae. Mature adult Coleoptera are usually unaffected by macrocyclic lactone residues found in dung, probably because they are exposed to less macrocyclic lactone residue than their bulk-feeding larvae. Overall, the commercially available milbemycins appear to be less harmful to fly and beetle larvae tested than the avermectins. There is no evidence that ivermectin residues exert any direct effect on the development or survival of earthworms; however, effects on other dung-feeding organisms, in particular fly and beetle larvae, may disturb the processes of succession.
Although macrocyclic lactones have the potential to disrupt the ecology of dung fauna if given in persistent formulations or sustained-release devices, there is no evidence for longterm adverse effects of macrocyclic lactone residues on the degradation of dung pats or on the accumulation of dung on pasture. In most husbandry systems, a large proportion of the feces will not contain residues of macrocyclic lactones, thus providing a large reservoir of safe habitat for dung insects. Therefore, it is unlikely that use of macrocyclic lactones will have a significant ecotoxicologic impact on a global or regional scale.
A single therapeutic dose of an avermectin can persist in concentrations sufficient to be effective against susceptible nematode infections for prolonged periods. The clinical significance of prolonged efficacy is important. Sustained availability protects animals from reinfection by some nematode (and arthropod) species for several weeks, which helps control pests that intermittently or constantly challenge livestock. Large variations in the persistent efficacy of a particular macrocyclic lactone against a particular worm species have been reported. Potential reasons for these variable results include study design and host- and parasite-related factors. Persistent efficacy has been investigated mainly against the three major cattle nematodes Ostertagia ostertagi, Cooperia oncophora, and Dictyocaulus viviparus, and the sheep nematodes Haemonchus contortus and Teladorsagia circumcincta. The duration of persistent efficacy varies according to the macrocyclic lactone and formulation used and may be (excluding specific long-acting formulations) 14–45 days for Ostertagia, 0–35 days for Cooperia, and 21–42 days for Dictyocaulus. The persistent efficacy of oral moxidectin (2–5 wk) gives it a special role in control of haemonchosis and T circumcincta in sheep and in resistance development.
Ivermectin, eprinomectin, abamectin, doramectin, and moxidectin are variously available as PO, SC, and pour-on formulations for use in cattle. The SC and PO formulations are given at 0.2 mg/kg, whereas the pour-on formulation is used at 0.5 mg/kg. Topical administration (ie, pour-on formulations) is more convenient but results are more variable between animals than when administration is SC or PO. Grooming behavior of cattle has a major influence on the plasma disposition of topical macrocyclic lactones. Undesirable subtherapeutic concentrations in both treated and untreated cattle may contribute to development of drug resistance.
An oil-based, long-acting formulation of ivermectin (3.15% w/v ivermectin) is available in Brazil and most Latin American and African countries. One low-volume SC dose (1 mL/50 kg, equivalent to ivermectin at 630 mcg/kg) effectively treats and prophylactically controls many internal and external parasites of cattle for up to 77 days. A long-acting parenteral formulation for moxidectin has also been developed. The injectable solution (1 mg/kg, SC, behind the ear) is an oil-based formulation containing 10% moxidectin; it is registered in Latin America, Australasia, and some European countries. In controlled studies, the periods of protection against some nematode infections using this long-acting moxidectin formulation were 90–150 days according to the species. Recently, a long-acting injectable formulation of eprinomectin (1 mg/kg, SC, in front of the shoulder) was registered for use in cattle. Treatment provides persistent parasite control for 100–150 days, depending on parasite species.
The macrocyclic lactones have a very high (>98%) efficacy against all stages (including inhibited forms) of the common cattle nematodes. The least susceptible nematodes are Cooperia and Nematodirus spp. Because of their high potency and elimination through milk, the macrocyclic lactones are not recommended for use in animals that produce milk for human consumption. Eprinomectin and moxidectin pour-ons are exceptions and have no milk withdrawal time in many countries.
A wide range of effective chemoprophylactic systems has been developed to prevent outbreaks of parasitic gastroenteritis and control infections in first-season grazing calves. Strategic anthelmintic medication during the first half of the grazing season, using carefully timed administration of macrocyclic lactones, has proved to be highly effective in western Europe for the control of GI nematodes of grazing calves during their first year. Because of differences in management, pasture infectivity, and climate, it is difficult to identify which program is most effective. Any chemoprophylactic program should be beneficial, as long as it is adapted to the epidemiologic situation and farm management.
Ivermectin, doramectin, and moxidectin are variously available as PO, SC, and IM formulations for use in small ruminants. As for cattle, the macrocyclic lactones have a very high (>98%) efficacy against all stages, including inactive forms, of the common sheep and goat nematodes. However, because of management practices leading to selection for resistance to macrocyclic lactones among nematodes of small ruminants, mainly in the southern hemisphere, their use is more problematic (see Resistance to Anthelmintics). Although moxidectin, at its recommended dose rate, can initially be effective against some parasite strains resistant to ivermectin, there is side-resistance between the avermectins and the milbemycins, so this efficacy is temporary. Oral moxidectin has a persistent efficacy of up to 5 wk for Haemonchus contortus and Teladorsagia circumcincta. Ivermectin controlled-release capsules have been used by sheep producers. The delivery rate, maintained for 100 days, is 0.8 mg ivermectin/day for sheep 20–40 kg in weight and 1.6 mg/day for sheep weighing 41–80 kg.
In pigs, ivermectin and doramectin are given at 0.3 mg/kg body wt, SC, or ivermectin is given in feed for 7 days at 0.1 mg/kg body wt/day for the treatment of all adult and larval stages of the common swine parasites, including the kidney worm Stephanurus. The exception is Trichuris suis, in which efficacy is ~80%.
Ivermectin and moxidectin are the two most common macrocyclic lactones available for use in horses. In certain regions, abamectin is also available. Ivermectin and abamectin are used in horses at a dosage of 200 mcg/kg, whereas moxidectin is used at 400 mcg/kg. Ivermectin, abamectin, and moxidectin are effective against a broad range of adult and migrating larval stages of nematode (including large and small strongyles) and arthropod (Gasterophilus spp) parasites. The only reported difference in efficacy of the two products is that at therapeutic dosages, ivermectin has not shown significant efficacy against the arrested stages and intramucosal developing stages of the cyathostomes, and moxidectin appears less potent against stomach bots (Gasterophilus spp). The persistence of moxidectin in circulation can provide horses with 2–3 wk of protection from infective cyathostome larvae. Moxidectin and ivermectin may not be the drugs of choice to treat infections with Parascaris equorum because of emerging resistance.
Ivermectin, selamectin, moxidectin, and milbemycin oxime may be used in dogs for the prevention of heartworm disease and control of GI roundworms. Many canine parasites are susceptible to ivermectin at the dosages used in other animals; however, because some dogs are adversely affected at these levels, ivermectin is used in dogs at 6 mcg/kg body wt, PO, given at 1-mo intervals, to prevent development of Dirofilaria immitis, the cause of heartworm disease. At higher dosages (>100 mcg/kg), some Collies and individual dogs of other breeds are adversely affected by ivermectin. At a dosage of 0.5 mg/kg, PO, milbemycin oxime is used for prevention of heartworm infection and for treatment of hookworms, ascarids, and whipworms in dogs. Moxidectin is also effective for prevention of heartworm infection at a dose rate of 3 mcg/kg, PO. The safety of milbemycin and moxidectin in dogs, including those sensitive to macrocyclic lactones, appears to be similar to that of ivermectin.
Selamectin, an avermectin monosaccharide, and moxidectin are available in topical formulations. Selamectin and moxidectin are also true endectocides at their recommended dosages, because their activity encompasses common intestinal nematodes (eg, Toxocara), heartworms, and external parasites (fleas, biting lice, and mites).
Ivermectin and other avermectin/milbemycin compounds have been used extensively as antiparasitic agents in a wide variety of exotic pets, including ferrets, rabbits, rodents, birds, and reptiles. Although the activity of these compounds was first established in laboratory animal parasite systems, their use in rodents and other exotic pets is extra-label, and treatment protocols are often established through empirical clinical experience rather than controlled studies.