Abstract

Sulfonamide antimicrobials such as sulfadiazine (SDZ) and sulfamethoxazole (SMX) are used in human and veterinary medicine, to include treatment of infections in cetaceans. However, some physicians and small animal veterinarians are reluctant to use these antibiotics because of the occurrence of hypersensitivity reactions (HS) in some humans and dogs. The clinical syndrome presents a similar pattern in both species: a delayed onset (5-14 days); symptoms including fever, cutaneous eruption, hepatitis, and blood dyscrasias (thrombocytopenia, neutropenia); recovery after drug withdrawal; and faster onset and more severe symptoms with re-exposure.

We report the first confirmed case of HS in a killer whale (Orcinus orca) leading to serious neutropenia and thrombocytopenia. Approximately 10 days after successfully treating a 22-year-old killer whale for a severe respiratory illness, with 21 days of Amikacin (11 mg/kg IM SID, Ambifuse, Vetus Pharmaceuticals) followed by 68 days of trimethoprim-sulfadiazine (TMP-SDZ, Uniprim, 7 mg/kg PO SID, Macleod Pharmaceuticals) and folic acid (0.06 mg/kg PO TID, West-ward Pharmaceuticals Inc.) the whale presented with profound leukopenia and neutropenia and but no clinical signs of illness. TMP-SDZ was immediately withdrawn, however nine days later the WBC and neutrophil counts had further dropped and the platelet count was also diminished. Granulocyte colony stimulating factor, G-CSF (Neupogen, Amgen) was administered at 0.001 mg/kg IM for three days. Within 10 days the WBC count was back to normal while the platelet count continued to drop, finally returning to normal by day 32.

Long term or high dose therapy with potentiated sulfonamide antibiotics, such as TMP-SDZ, may inhibit the activity of folic acid reductase, which is necessary to activate folic acid to folinic acid. This dose-dependent and pharmacological adverse effect (type A adverse drug reaction) can be associated with thrombocytopenia and neutropenia because folinic acid is required for DNA synthesis and therefore cell multiplication. This reaction can be prevented or treated by supplementation with high doses of folic acid or directly folinic acid. However, potentiated sulfonamides are also known to trigger non dose-dependent non-pharmacological reactions (type B adverse drug reactions, idiosyncratic reactions) in some humans and dogs. These delayed hypersensitivity reactions are thought to be immune-mediated, and several immunological markers have been found in humans and dogs with sulfonamide HS: anti-drug antibodies in both tolerant and HS patients (but at a higher frequency in HS patients); anti-platelet antibodies; and anti-neutrophil antibodies in dogs.

Thus, following complete recovery of the killer whale, serum samples were sent to the Laboratory of Clinical Pharmacology at the University of Wisconsin-Madison to determine whether this killer whale presented similar immune markers to those reported in humans and dogs with sulfonamide-associated blood dyscrasias. We looked for anti- SDZ antibodies (by ELISA); anti-platelet antibodies (by flow cytometry); and anti-myeloperoxidase antibodies (by ELISA). Sera from the affected killer whale before its exposure to SDZ, sera from 2 SDZ-"tolerant" whales before and during exposure to SDZ, and serum from a SDZ-naïve whale were used as negative controls. Anti-SDZ antibodies were detected in both tolerant and HS whales, but with a higher titer in the HS animal. Only the HS whale displayed anti-platelet antibodies and no anti-myeloperoxidase antibodies were detected.

In conclusion, this case report shows that clinical findings and immunological markers similar to those reported in sulfonamide HS humans and dogs can be detected in a killer whale. This study also suggests that clinical signs observed in this killer whale could have been those of a delayed HS reaction to sulfonamides rather than those of a drug-induced deficiency in folinic acid.