Toxicosis Associated with Topical Administration of Ivermectin in Dog-Faced Fruit Bats (Cynopterus brachyotis)
Eleven of 40 dog-faced fruit bats administered one drop of 1% ivermectin topically developed generalized paresis. Six of the bats recovered within 24 to 48 hours. The remaining five died or were euthanatized within 3–5 days of the development of clinical signs. Histologic evaluation revealed renal tubular necrosis in three of the five bats.
Ivermectin, an endo- and ectoparasiticide, potentiates the action of gamma aminobutyric acid (GABA) by increasing its release and binding at postsynaptic receptors.3,12 Since GABA is an inhibitory neurotransmitter its potentiation by ivermectin further decreases nerve conduction. In mammals, GABA receptors are restricted to the central nervous system, which is not easily penetrated by the large avermectin compounds. In contrast, in many invertebrates these receptors regulate peripheral muscle activity,3,12,13 making ivermectin an effective and safe parasiticide for use in mammals.
In dogs, safe and effective ivermectin dosages range from 0.006 mg/kg orally for heartworm prevention to 0.2 mg/kg by subcutaneous or intramuscular administration for the treatment of mites and nematodes.15 An exception is in collie breeds, which may show toxic effects at dosages as low as 0.1 mg/kg.15 This susceptibility appears to be associated with a more permeable blood-brain barrier.14,15 In cattle, horses, sheep, and birds the recommended dosage is 0.2 mg/kg orally or by subcutaneous or intramuscular administration for susceptible parasites.15
Ivermectin toxicosis is well recognized but its pathogenesis is not well understood. High dosages (e.g., >2 mg/kg orally) in dogs cause mydriasis, ataxia, tremors, depression, emesis and stupor.12,16 In some dogs paralysis, weakness, coma and death may occur.12 Clinical signs of toxicosis have been reported in cattle, horses and swine at oral dosages of 4, 2 and 30 mg/kg respectively.3,16 The oral LD50 in mice, rats, dogs and rhesus monkeys is 25, 50, 80 and 24 mg/kg respectively.2,3 Topical LD50 for rats and rabbits is >400 mg/kg.3 Therapeutic doses of ivermectin are well below these LD50 values. The following case report describes toxicosis in a captive collection of dog-faced fruit bats associated with topical administration of ivermectin.
Five adult male dog-faced fruit bats (Cynopterus brachyotis), weighing 30–40 g, were evaluated at the Veterinary Medical Teaching Hospital (VMTH), University of Florida, because of sudden onset of generalized paralysis. These animals were housed indoors with other fruit bats in free-flight enclosures at a private facility and maintained on a diet of fresh fruit, vitamins, and protein supplements.
The day before admission these and 35 other bats were administered a 1% ivermectin solution (Ivercide® 10 mg/ml, Phoenix Pharmaceutical, Inc., St. Joseph, MO) as part of an annual physical examination and preventive care program. Each bat was administered one drop from a 0.5 ml insulin syringe (Terumo Medical Corporation, Elkton, MD) on the skin of the chest or the patagium (membranous wing). The following morning, 11 of the 40 treated bats had fallen from their perches and were lying either on the ground or in their food bowl, unable to move. Two days later another animal was found in a food bowl.
Six bats recovered within 24–48 hours. The first four bats admitted will be identified as bats A, B, C, D and the final one, E. Physical examination of bats A–D revealed spontaneous respiration, but they could not eat or perch and had minimal movements in all parts of the body. They were placed in an incubator at 25°C and tube fed every 2 hours with 0.4 ml of a carbohydrate liquid supplement (Carbo-Fuel®, Twin Laboratories, Inc., Ronkonkoma, NY). One bat could lap up fluid on its own. Bat A was given 0.02 mg of flumazenil (Romazicon®, Hoffman-LaRoche, Basel, Switzerland) by subcutaneous administration. The following day three bats died spontaneously, and one was euthanatized. Bat E, evaluated 5 days after the ivermectin treatment because of weakness, died spontaneously 2 days after admission. All bats were submitted for necropsy evaluation.
Histopathologic examination of representative tissues from bats A, B, and C revealed mild to moderate acute tubular necrosis with evidence of tubular epithelial regeneration. A proliferative glomerulonephritis, with marked cortical tubular distension and tubular proteinosis was present in bat C. In addition, bat C also had a severe hemorrhagic gastroenteritis with intralesional fungal organisms. A suppurative bronchopneumonia was present within bat E.
The paralysis/paresis observed in these bats was most likely due to ivermectin. This diagnosis is based on the clinical signs, and the recent history of ivermectin administration. Other differential diagnoses for acute paralysis include spinal cord injury, polyneuropathy, polymyopathy, metabolic abnormalities and other toxicants.11 These were ruled out because of the acute onset of the clinical signs in combination with multiple animal involvement and the history of recent topical ivermectin therapy.
Ivermectin is used percutaneously in canaries, finches and budgerigars.18 Reported topical dosages for psittacines and pigeons are 200 µg/kg of 1% ivermectin and one drop of 0.8% ivermectin, respectively.18 One drop of the bovine formulation of ivermectin on the skin of small birds is common practice.4
The volume of one drop of 1% ivermectin from an insulin syringe was determined to be approximately 0.0054 ml. Based on this volume, the dose of ivermectin applied topically to these bats was calculated to be 1.8–2.1 mg/kg. Topical application of ivermectin and abamectin (a compound that differs from ivermectin by a single double bond in chemical structure3 in rats, rabbits and monkeys has shown poor dermal absorption of these compounds because of their large size. Absorption is thought to be less than 1% of the dermally applied dose.3 In goats the peak plasma level of ivermectin after topical application was considerably lower compared to oral administration but was detectable in the plasma longer (192 days topical dosing versus 144 days in oral dosing).19 If 0.5% of the drug was absorbed3 the calculated absorbed dosage for each bat was approximately 0.009–0.012 mg/kg. This is comparable to safe therapeutic dosages in other mammal and bat species.8
Given the estimated dose appears within safe limits for use in other mammals, there are few possible reasons why these animals showed clinical signs of toxicity: 1) more than one drop was administered per bat, 2) increased drug absorption through the patagium, 3) oral ingestion of the drug through auto- and allo-grooming, and 4) this species is more sensitive to ivermectin.
Some of the animals received the topical dose on the skin of the ventral thorax whereas others received it on the patagium. The patagium is a thin membrane-like wing containing a generous blood supply,10 and it is possible that absorption is increased because of the thin barrier between the drug and underlying vasculature. Unfortunately, it was not possible to relate topical application site to toxicosis because the site of administration was not recorded.
The use of flumazenil on one bat was to reverse benzodiazepine-mediated CNS depression. It is reported that avermectins potentiate benzodiazepine receptor binding.3 No change was seen in the animal after administration.
The acute tubular necrosis observed in three of the five bats is consistent with a toxic or ischemic insult.9 Possible causes for ischemic insult include hypotension (associated with hemorrhage, dehydration, or vasodilation), vasoconstriction or thromboembolism. Known nephrotoxic substances include aminoglycosides, some heavy metals, ethylene glycol and many plants.9 Although it was difficult to assess hypotension at presentation, there was no evidence of hemorrhage and hydration was assumed to be maintained with the fluid diet. However, gastroenteritis of bat C may have led to dehydration in this animal. There was no history of either drug therapy or access to toxic plants or chemicals in this group of animals.
Renal damage attributable to ivermectin toxicity has not previously been reported. The exception is in humans with onchocerciasis in which glomerular and tubular kidney dysfunction was noted following ivermectin treatment and likely related to microfilarial load.1,7 In teleost fish, ivermectin is readily taken up by the tubular epithelial cells and transported in the kidney proximal tubules by a p-glycoprotein transporter.6 Teleost tubules are functionally identical to mammalian renal proximal tubules.6 Additionally in a study in which pig kidney cells were bathed in ivermectin solutions of various concentrations, cell death occurred within 24 hours at 40 µg/ml.17
It is not completely clear why these bats showed ivermectin toxicity and why three of the animals suffered renal tubular necrosis. It is possible that this species represents a group particularly sensitive to the ivermectin compound and that the renal damage may have been related to administration of ivermectin. It is, therefore, recommended that 1% ivermectin solution not be topically administered to dog-faced fruit bats.
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