Presumptive fenbendazole toxicosis in North American porcupines

Martha A. Weber Disney's Animal Kingdom, PO Box 10000, Lake Buena Vista, FL 32830.

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Michele A. Miller Disney's Animal Kingdom, PO Box 10000, Lake Buena Vista, FL 32830.

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Donald L. Neiffer Disney's Animal Kingdom, PO Box 10000, Lake Buena Vista, FL 32830.

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Scott P. Terrell Disney's Animal Kingdom, PO Box 10000, Lake Buena Vista, FL 32830.

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Abstract

Case Description—4 North American porcupines were evaluated because of diarrhea or neutropenia (or both) that developed after treatment with fenbendazole for intestinal parasites.

Clinical Findings—Complete blood cell count abnormalities included severe neutropenia in all affected porcupines and mild anemia in some of them. In 2 porcupines, postmortem findings included bone marrow hypoplasia and intestinal crypt cell necrosis.

Treatment and Outcome—Affected porcupines received supportive care including fluid supplementation and broad-spectrum antimicrobials. The 2 surviving animals recovered after 9 to 33 days of treatment.

Conclusions and Clinical Relevance—Fenbendazole is an anthelminthic that may be used in an extralabel manner for the treatment of intestinal parasitism in wildlife species. The drug inhibits mitosis and can affect rapidly dividing cell lines, such as those in the bone marrow and intestinal crypt mucosa. Fenbendazole may not be an appropriate anthelminthic choice in North American porcupines.

Abstract

Case Description—4 North American porcupines were evaluated because of diarrhea or neutropenia (or both) that developed after treatment with fenbendazole for intestinal parasites.

Clinical Findings—Complete blood cell count abnormalities included severe neutropenia in all affected porcupines and mild anemia in some of them. In 2 porcupines, postmortem findings included bone marrow hypoplasia and intestinal crypt cell necrosis.

Treatment and Outcome—Affected porcupines received supportive care including fluid supplementation and broad-spectrum antimicrobials. The 2 surviving animals recovered after 9 to 33 days of treatment.

Conclusions and Clinical Relevance—Fenbendazole is an anthelminthic that may be used in an extralabel manner for the treatment of intestinal parasitism in wildlife species. The drug inhibits mitosis and can affect rapidly dividing cell lines, such as those in the bone marrow and intestinal crypt mucosa. Fenbendazole may not be an appropriate anthelminthic choice in North American porcupines.

A2-year-old male North American porcupine (Erethizon dorsatum; porcupine 1) was evaluated because of decreased appetite and weight loss of 3 days' duration. It was maintained in an individual enclosure; skunks, raccoons, and 2 other porcupines were housed nearby. This porcupine was anesthetized with ketamine (5.5 mg/kg [2.5 mg/lb], IM), and anesthesia was maintained with isoflurane administered via face mask. An initial physical examination (performed on day 1) revealed moderate dehydration but no other obvious abnormalities. A CBC was performed; abnormalities included hemoconcentration (PCV, 51%; reference range, 31% to 41%) and severe leukopenia (1,800 WBCs/μL; reference range 5,100 to 10,600 WBCs/μL) characterized by an absence of neutrophils (reference range, 1,600 to 6,000 neutrophils/μL). Lymphocytes and eosinophils were also counted (lymphocytes, 1,782 cells/μL [reference range, 1,800 to 5,000 lymphocytes/μL]; eosinophils, 18 cells/μL [reference range, 0 to 500 eosinophils/μL]). Platelet numbers were subjectively considered to be adequate.

Differential diagnoses at this time included bacterial septicemia, viral infection, and bone marrow injury. The porcupine was treated with ceftiofur (11 mg/kg [5 mg/lb], IM, q 24 h) and enrofloxacin (10 mg/kg [4.5 mg/lb], IM, q 24 h), and lactated Ringer's solution (22 mL/kg [10 mL/lb]) supplemented with potassium chloride (16 mEq/mL) and mixed with hyaluronidase (150 U/L) was administered SC every 24 hours. Oncedaily administration of medications was chosen because the temperament of the animal was such that anesthesia was required for handling and treatment.

The following day, the porcupine had signs of depression and continued to be anorectic. The results of a CBC were similar to the previous day's findings, except the differential WBC count revealed no cell types other than lymphocytes. Treatment with ceftiofur, enrofloxacin, and supplemented lactated Ringer's solution (44 mL/kg [20 mL/lb], SC) was continued. Flunixin meglumine (0.25 mg/kg [0.11 mg/lb], IM, q 24 h) was also administered because of its antiendotoxic properties.

A blood sample and a rectal swab specimen, both collected at the initial examination, were submitted for aerobic bacterial culture, and Escherichia coli was isolated from the latter; no organisms were cultured from the blood sample. Six days after initiation of treatment, the porcupine developed pitting edema on dependent regions of the body. It was anesthetized and a catheter was placed in the right jugular vein via a cut-down procedure. At this time, the porcupine was hypoproteinemic (4.4 g/dL; reference range, 5.2 to 7.6 g/dL) and it was suspected that the edema was secondary to hypoalbuminemia and possible fluid overload. Equine hyperimmune plasma (5.4 mL/kg [2.5 mL/lb], IV) was administered to the porcupine in an attempt to improve intravascular colloidal pressure. The animal was then treated IV with lactated Ringer's solution supplemented with potassium chloride as previously, enrofloxacin, and ceftriaxone (20 mg/kg [9.1 mg/lb], IV) every 12 hours. Ranitidine (0.18 mg/kg [0.08 mg/lb], IV, q 12 h), metoclopramide (0.18 mg/kg, PO, IM, q 12 h), and sucralfate (90 mg/kg [41 mg/lb], PO, q 24 h) were added to the treatment regimen because of concerns about gastric stasis and ulceration.

Two days after the IV catheter was placed, it was no longer patent and was removed. Intramuscular administration of all injectable medications was reinstated. At this time, the porcupine was beginning to sample food items and was passing small quantities of feces. Serum IgG titers against feline panleukopenia virus and canine parvovirus were both reported as negative (titers < 1:10). A CBC was performed; the PCV was 36%, and the WBC count was high (16,900 WBCs/μL; lymphocytes, 10,647 cells/μL) with a left shift (neutrophils, 3,887 cells/μL; band neutrophils, 676 cells/μL [reference range, 0 to 586 cells/μL]). Myelocytes (507 cells/μL) and metamyelocytes (1,014 cells/μL) were detected. Thirteen days after initial evaluation, the porcupine was eating well. All medications administered IM were discontinued, and treatment with trimethoprim-sulfamethoxazole (30 mg/kg [13.6 mg/lb], PO, q 12 h) was initiated.

Twenty-three days after the beginning of treatment, the porcupine had a PCV of 32% and a WBC count of 27,500 cells/μL (lymphocytes, 5,225 cells/μL; neutrophils, 20,350 cells/μL; and monocytes, 1,925 cells/μL [reference range, 0 to 800 monocytes/μL]). This leukocytosis and neutrophilia were believed to reflect rebound release of WBCs from the bone marrow. The porcupine was released from the hospital on day 33.

Four other North American porcupines were evaluated during the first week of treatment of porcupine 1. An adult male (porcupine 2) that had signs of depression and diarrhea for 2 days was found recumbent; it was dehydrated (PCV, 50%) and leukopenic (3,600 WBC/μL) with severe neutropenia (72 neutrophils/μL); the lymphocyte and monocyte counts were 3,456 and 72 cells/μL, respectively. A jugular catheter was placed via a cut-down procedure, and treatment with unsupplemented lactated Ringer's solution and 3% hypertonic saline (NaCl) solution (3.4 mL/kg [1.55 mL/lb], IV) and IM administrations of flunixin meglumine, enrofloxacin, and ceftriaxone were started. This porcupine died 1 hour after treatment was started.

Another adult male porcupine (porcupine 3) also had poor appetite, lethargy, and weight loss of 3 days' duration. This porcupine developed diarrhea on the fourth day of illness. On day 4, PCV was within reference limits (35%), but it was leukopenic (1,200 WBCs/μL) and neutropenic (12 neutrophils/μL); the lymphocyte and monocyte counts were 1,104 and 84 cells/μL, respectively. A rectal swab specimen was submitted for aerobic bacterial culture, and E coli was isolated. This porcupine was treated with supplemented lactated Ringer's solution, enrofloxacin, ceftiofur, and flunixin meglumine. Four days after the initial examination, the porcupine began to appear more alert and had interest in food. On day 7 of treatment, the porcupine's condition deteriorated and it had marked leukocytosis (33,200 WBCS/μL); although lymphocytes and neutrophils were within reference limits (2,656 and 3,984 cells/μL, respectively), high concentrations of band neutrophils (7,304 cells/μL), myelocytes (4,980 cells/μL), metamyelocytes (12,948 cells/μL), and monocytes (1,328 cells/μL) were detected. Amikacin (4.5 mg/kg [2.0 mg/lb], IM, q 12 h) was added to the treatment regimen. Nine days after the initial examination, the porcupine died.

A healthy-appearing adult female porcupine (porcupine 4) that was housed in a separate area of the holding facility was anesthetized for examination and blood sample collection. A CBC was performed; abnormalities included mild anemia (PCV, 30%), leukopenia (5,000 WBCs/μL), and neutropenia (200 neutrophils/μL) with a left shift (band neutrophils, 300 cells/μL); other cell counts were within reference limits (lymphocytes, 4,000 cells/μL; eosinophils, 100 cells/μL; and monocytes, 100 cells/μL), but metamyelocytes were present (300 cells/μL). Although the porcupine did not have signs of disease, it was treated prophylactically with trimethoprim-sulfamethoxazole and metronidazole (15 mg/kg [6.8 mg/lb], PO, q 12 h). Nine days later, results of a CBC were within reference limits.

Porcupine 5 was a juvenile female and was not housed near any of the other animals. This porcupine also appeared healthy. A CBC revealed PCV of 37% with a slightly high WBC count; results of a differential WBC count were within reference limits.

On review of husbandry practices, there had been no recent changes in the porcupines' diet and no known opportunity for accidental ingestion of toxic materials. Ten days prior to the onset of clinical signs in porcupine 1, infections with a Syphacia spp nematode had been diagnosed via fecal flotation in porcupines 1 through 4; these porcupines were treated orally with fenbendazole (50 mg/kg [22.7 mg/lb]) once daily for 3 days.

Complete postmortem examinations were performed on porcupines 2 and 3. Grossly, both animals had evidence of hemorrhagic enteritis and fetid redbrown intestinal contents. The cecum and colon were discolored brown-green and dilated with gas, and the mucosae were variably thickened with multifocal ulceration, necrosis, and hemorrhage. Bacterial culture of a blood sample collected from porcupine 2 at necropsy yielded Pseudomonas aeruginosa. Cultures of liver samples from both porcupines did not yield bacterial growth; P aeruginosa (porcupine 2) and E coli (both porcupines) were isolated from samples of cecum and colon. Results of anaerobic bacterial cultures of intestinal tissues were negative. Contents of the jejunum from porcupine 3 were submitted for parvoviral immunofluorescent staining, and feces were submitted for viral screening via electron microscopy; results were negative.

Histologically, severe necrotizing enteritis and typhlocolitis were identified in porcupines 2 and 3. Both porcupines had villus atrophy with necrosis and dysplasia of crypt epithelial cells that were most notable in the jejunum. Necrosis and dysplasia of colonic gland epithelial cells were observed in the cecum and colon as well. The small intestinal, cecal, and colonic mucosae were colonized by a mixed population of bacteria in porcupine 2, and the microflora included a mixed population of bacteria and fungi in porcupine 3. Porcupine 2 had severe bone marrow hypoplasia consistent with the WBC changes detected in blood. Porcupine 3 had survived the disease process longer and had evidence of myeloid hyperplasia in the bone marrow consistent with hematologic findings prior to death.

Discussion

Differential diagnoses for severe neutropenia and enteritis with crypt cell degeneration and necrosis in mammals include viral infections, sepsis, damage induced by ionizing radiation, and toxin or drug exposure.1,2 Necrotizing enteritis with crypt dilation and villus blunting has been reported3 in North American porcupines and was postulated to be associated with parvovirus infection, although the diagnosis was not definitively determined. The skunks and raccoons housed near porcupines 1, 2, and 3 had been vaccinated against canine and feline parvoviruses. Results of serologic testing for antibodies against canine parvovirus and feline panleukopenia virus were negative in the 1 porcupine that was evaluated. Histologic or electron microscopic examination of tissues from porcupines 2 and 3 did not reveal evidence of viral infection.

Histologically, there was evidence of a systemic bacterial infection in porcupine 2, but this was believed to be secondary to compromised integrity of the intestinal mucosa and neutrophil depletion. Similarly, bacterial and fungal colonization of compromised intestinal mucosa was identified in porcupine 3.

Benzimidazole anthelmintics have been associated with bone marrow hypoplasia and intestinal crypt cell damage in several species; adverse effects have been less commonly reported in mammals than in avian species.4,5 Benzimidazoles bind to tubulin, thereby compromising microtubule formation and cellular division.6,7 The most severe effects are evident in organs with rapidly dividing cell lines, including intestinal crypt cell epithelium and bone marrow.1

Fenbendazole is widely used in veterinary medicine, and there have been few reports8,9 of adverse reactions in mammals. In the past, all the porcupines of this report had been treated orally with fenbendazole at dosages ranging from 25 to 50 mg/kg (11.4 to 22.7 mg/lb) once daily for 3 treatments. There were no reported adverse effects associated with the earlier treatments, and it is unknown whether the previous treatments did not affect rapidly dividing cell lines or whether the porcupines had a subclinical form of disease similar to that identified in porcupine 4. The dosages and frequencies of fenbendazole administration were based on published recommendations.10 Since the events described in the present report, there has been another case of bone marrow hypoplasia and enteritis associated with fenbendazole use in a North American porcupine.a That porcupine had received oral treatment with fenbendazole (50 mg/kg) for 5 days. Its appetite decreased on day 4 of treatment, and signs of depression and anorexia developed 8 days after fenbendazole treatment was started.

Presently, fenbendazole is labeled for use in dogs, cattle, and horses. It has been used in many other species, generally without associated complications. Porcupines are hindgut-fermenting herbivores with relatively prolonged retention of food particles.11 It is possible that slower movement of ingested material may allow more absorption of an administered dose of fenbendazole, leading to development of toxicosis. Administration of alternative deworming agents or lower dosages of fenbendazole may be appropriate in this species and other hindgut-fermenting rodents.

a.

Ketz C, Topeka Zoological Park, Topeka, Kan: Personal communication, 2004.

References

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  • 2

    Liu C, Crawford JM. The gastrointestinal tract. In: Kumar V, Abbas AK, Fausto N, eds. Pathologic basis of disease.. 7th ed. Philadelphia: Elsevier Inc, 2005;797875.

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  • 3

    Frelier PF, Leininger RW, Armstrong LD, et al. Suspected parvovirus infection in porcupines. J Am Vet Med Assoc 1984;185:12911294.

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    Stokol T, Randolph JF, Nachbar S, et al. Development of bone marrow toxicosis after albendazole administration in a dog and cat. J Am Vet Med Assoc 1997;210:17531756.

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  • 5

    Weber MA, Terrell SP, Neiffer DL, et al. Bone marrow hypoplasia and intestinal cell necrosis associated with fenbendazole administration in five painted storks. J Am Vet Med Assoc 2002;221:417419.

    • Search Google Scholar
    • Export Citation
  • 6

    Lacey E. Mode of action of benzimidazoles. Parasitol Today 1990;6:112115.

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    Gull K, Dawson PJ, Davis C, et al. Microtubules as target organs for benzimidazole anthelmintic chemotherapy. Biochem Soc Trans 1987;15:5960.

    • Search Google Scholar
    • Export Citation
  • 8

    US Food and Drug Administration, Center for Veterinary Medicine web site. Adverse drug experience reporting. Available at: www.fda.gov/cvm/adetoc.htm. Accessed Feb 13, 2006.

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    • Export Citation
  • 9

    Hayes RH, Oehme FW, Leipold H. Toxicity investigation of fenbendazole, an anthelmintic of swine. Am J Vet Res 1983;44:11081111.

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    Carpenter JW, Mashima TY, Rupiper DJ. Rodents. In: Carpenter JW, Mashima TY, Rupiper DJ, eds. Exotic animal formulary.. 2nd ed. Philadelphia: WB Saunders Co, 2001;273.

    • Search Google Scholar
    • Export Citation
  • 11

    Felicetti LA, Shipley LA, Witmer GW, et al. Digestibility, nitrogen excretion, and mean retention time by North American porcupines (Erethizon dorsatum) consuming natural forages. Physiol Biochem Zool 2000;73:772780.

    • Search Google Scholar
    • Export Citation
  • 1

    Kane AB, Kumar V. Environmental and nutritional pathology. In: Kumar V, Abbas AK, Fausto N, eds. Pathologic basis of disease.. 7th ed. Philadelphia: Elsevier Inc, 2005;415468.

    • Search Google Scholar
    • Export Citation
  • 2

    Liu C, Crawford JM. The gastrointestinal tract. In: Kumar V, Abbas AK, Fausto N, eds. Pathologic basis of disease.. 7th ed. Philadelphia: Elsevier Inc, 2005;797875.

    • Search Google Scholar
    • Export Citation
  • 3

    Frelier PF, Leininger RW, Armstrong LD, et al. Suspected parvovirus infection in porcupines. J Am Vet Med Assoc 1984;185:12911294.

  • 4

    Stokol T, Randolph JF, Nachbar S, et al. Development of bone marrow toxicosis after albendazole administration in a dog and cat. J Am Vet Med Assoc 1997;210:17531756.

    • Search Google Scholar
    • Export Citation
  • 5

    Weber MA, Terrell SP, Neiffer DL, et al. Bone marrow hypoplasia and intestinal cell necrosis associated with fenbendazole administration in five painted storks. J Am Vet Med Assoc 2002;221:417419.

    • Search Google Scholar
    • Export Citation
  • 6

    Lacey E. Mode of action of benzimidazoles. Parasitol Today 1990;6:112115.

  • 7

    Gull K, Dawson PJ, Davis C, et al. Microtubules as target organs for benzimidazole anthelmintic chemotherapy. Biochem Soc Trans 1987;15:5960.

    • Search Google Scholar
    • Export Citation
  • 8

    US Food and Drug Administration, Center for Veterinary Medicine web site. Adverse drug experience reporting. Available at: www.fda.gov/cvm/adetoc.htm. Accessed Feb 13, 2006.

    • Search Google Scholar
    • Export Citation
  • 9

    Hayes RH, Oehme FW, Leipold H. Toxicity investigation of fenbendazole, an anthelmintic of swine. Am J Vet Res 1983;44:11081111.

  • 10

    Carpenter JW, Mashima TY, Rupiper DJ. Rodents. In: Carpenter JW, Mashima TY, Rupiper DJ, eds. Exotic animal formulary.. 2nd ed. Philadelphia: WB Saunders Co, 2001;273.

    • Search Google Scholar
    • Export Citation
  • 11

    Felicetti LA, Shipley LA, Witmer GW, et al. Digestibility, nitrogen excretion, and mean retention time by North American porcupines (Erethizon dorsatum) consuming natural forages. Physiol Biochem Zool 2000;73:772780.

    • Search Google Scholar
    • Export Citation

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