Ivermectin: Macrolide Antiparasitic Agents

Chapter 51 Ivermectin: Macrolide Antiparasitic Agents





Ivermectin, selamectin, moxidectin, and milbemycin are macrolides (or macrocyclic lactones) that are used to treat a variety of parasitic diseases in dogs and cats.1 In the United States, each of these agents is licensed for use as a heartworm preventive in dogs. In cats, macrolide antiparasitic agents are licensed for use as heartworm preventives, and some are licensed for the treatment of otodectes and hookworms, Ancylostoma braziliense and Ancylostoma tubaeforme. In an extralabel manner, and at doses greatly exceeding the recommended label dose, macrolide antiparasitic agents are also used to treat scabies, lice, cheyletiella, demodecosis, gastrointestinal nematodes, and the microfilaria of Dirofilaria immitis.1 Macrolide antiparasitic agents are generally considered to have a wide margin of safety.2 However, a percentage of collies and other herding breeds harbor a mutation in the MDR1 (ABCB1) gene that renders them exceptionally susceptible to toxicity from most, if not all, of these agents.3 It is important to note that at the labeled doses for heartworm prevention, the macrolide antiparasitic agents are safe for use in herding breeds, even those dogs with the mutant MDR1 genotype. While toxicosis in nonherding dog breeds and cats generally results from an extreme overdose (i.e., when a product marketed for livestock is used off-label in small animals), the author is aware of reports of suspected toxicosis in a dog (moxidectin) and cat (topical ivermectin) receiving the approved label dose of the particular macrolide.


Doramectin and eprinomectin are macrolides approved for use in cattle only.4 The manufacturers of these agents do not recommend their use in other species.


Clinical signs associated with macrolide toxicity reflect the actions of these drugs on the central nervous system.1 A specific antidote is not available, but most animals experiencing toxicosis from exposure to these drugs will have a complete recovery if appropriate supportive care is provided.



SOURCES


Ivermectin (Heartguard, others) is a mixture of 22,23-dihydroavermectin B1a (>80%) and B1b (<20%), formulated to control a number of internal and external parasites in animals.1 It is produced from the fungus Streptomyces avermitilis and is marketed for dogs and cats (tablets, chewables, and an otic solution [cats]), with some formulations also containing pyrantel pamoate, cattle (injectable, pour-on, bolus), swine (injectable, premix), horses (liquids and pastes), and sheep (drench).


Moxidectin (Proheart) is approved for use in dogs (tablet, injectable), cattle (pour-on), and horses (oral gel). Proheart 6, an injectable, sustained-release heartworm prevention product for dogs, has recently (September, 2004) been removed from the U.S. market after the Food and Drug Administration cited concerns regarding its safety. Moxidectin products are still available in Australia, Canada, and Europe. Like ivermectin, moxidectin is used to control many types of internal and external parasites. Moxidectin is a chemically altered product of Streptomyces aureolacrimosus noncyanogenus.1


Selamectin (Revolution) is marketed as a topical solution for use in dogs and cats for the control of both internal and external parasites. Selamectin, a macrolide antibiotic, is a fermentation product of Streptomyces avermitilis.1


Milbemycin (Interceptor) oral tablets are approved for use in dogs and cats for the prevention of Dirofilaria, and for treatment of some internal parasites. Milbemycin is a fermentation product of Streptomyces hygroscopicus aureolacrimosus.1


Doramectin (Dectomax) is marketed as an injectable or pour-on formulation for the control of endoparasites and ectoparasites in cattle. Doramectin is a fermentation product of Streptomyces avermitilis.5


Eprinomectin (Eprinex) is marketed as a pour-on formulation for the control of endoparasites and ectoparasites in cattle.5


Abamectin (Avert cockroach bait; Kraft TM; others) is an environmental insecticide/pesticide that is frequently used for insect control. It is licensed for use on crops, yards, and within buildings (including homes, offices, and restaurants).


Relatively high concentrations of macrolide antibiotics can be excreted in the feces in their active form. Toxicosis has occurred in dogs that have ingested the feces of sheep and/or horses that were treated with some macrolides.



TOXIC DOSE


Ivermectin is approved for use in dogs and cats for the prevention of dirofilariasis at oral doses of 0.006 and 0.024 mg/kg, respectively, once a month. Most dogs tolerate oral ivermectin dosages up to 2.5 mg/kg before clinical signs of toxicity occur.6 The LD50 for beagle dogs is 80 mg/kg.7 Some dogs, especially collies and other herding breeds, are more sensitive to ivermectin and can only tolerate doses up to 0.1 mg/kg, which is sixteenfold higher than the label dose.3,8,9 There are numerous reports of ivermectin toxicity in collies and other herding breeds receiving “antiparasitic” doses of ivermectin (0.2 to 0.6 mg/kg).6,1013 Two Australian shepherd dogs receiving ivermectin at oral dosages of 0.17 mg/kg and 0.34 mg/kg, respectively, developed clinical signs of toxicosis,12 as did an old English sheepdog mix that received 0.15 mg/kg ivermectin orally (PO).13 However, at the recommended dosage for heartworm prevention (0.006 mg/kg), ivermectin is safe for all dog breeds.


Cats generally tolerate dosages of 0.2 to 1.3 mg/kg ivermectin given orally or subcutaneously (SQ).1,14 The apparent no-effect level for oral ivermectin in cats is approximately 0.5 to 0.75 mg/kg of body weight. Toxicosis has been reported in a limited number of cats and kittens exposed to lower doses (0.30 to 0.40 mg/kg SQ).15


Moxidectin is available in tablet form for monthly oral administration at a dose of 0.003 mg/kg, and as a sustained release injectable formulation at a dose of 0.17 mg/kg administered every 6 months.5 The manufacturer’s package insert states that moxidectin was administered orally to dogs at doses 300-fold greater than the label dose without producing signs of toxicity. However, at 0.09 mg/kg (30×label dose), clinical signs of moxidectin toxicosis were observed in a collie.1 Furthermore, moxidectin toxicosis has been reported in a collie that consumed the equine product16 and a sheltie that received an injection of the sustained release product labeled for use in dogs.


Milbemycin is available in tablet form for monthly administration at a dose of 2 mg/kg (cats) and 0.5 mg/kg (dogs).5 Beagles have received doses 200 times greater than the label dose, with no apparent signs of toxicity.1 In a study involving collies, hypersalivation, ataxia, mydriasis, and central nervous system depression were observed in 2 of 5 collies treated with 5 mg/kg (10× label dose), and 5 of 5 collies treated with 10 mg/kg (20× label dose).17 According to some dermatologists, milbemycin can be used at a dose of 0.5 to 1.6 mg/kg daily to treat canine demodecosis.18 However, toxicosis has been reported in collies when milbemycin has been used according to this protocol.


According to the manufacturers, selamectin was proven safe when given at 10 times its recommended dose to puppies and kittens, and 5 times its recommended dose when administered to collies (a 10× topical dose in collies caused ataxia).5,19 Oral administration of selamectin at the recommended topical dose in young beagle dogs did not cause any noticeable adverse reactions.1,5 When selamectin was administered orally at dosages of 2.5, 10, or 15 mg/kg to ivermectin-sensitive collies, only one animal showed ataxia at the 15 mg/kg exposure dosage (oral dose of 2.5 times the label dose for topical administration). Oral administration of selamectin to cats at the recommended topical dose (6 mg/kg) caused salivation and vomiting.1,5 There is one report of a kitten (0.3 kg) that died 8 hours after receiving a single topical dose of selamectin. However, this young kitten was malnourished and underweight for its age.


Doramectin has been used safely for treating spirocercosis in dogs at a dose of 0.4 mg/kg injected subcutaneously at 2-week intervals for 6 treatments. Beagles treated with this protocol demonstrated no signs of toxicity.20 However, doramectin toxicosis has been reported in a collie.21


Limited information exists in the literature on the toxic dose of eprinomectin for dogs and cats. It is likely that eprinomectin has a safety profile similar to those of other macrolides.

Sep 11, 2016 | Posted by in SMALL ANIMAL | Comments Off on Ivermectin: Macrolide Antiparasitic Agents
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