Aplastic Anemia in Two Kittens Following a Prescription Error
A medication error resulted in two kittens being treated with azathioprine (12 and 12.5 mg/kg) instead of azithromycin for 2 weeks. On clinical examination, the kittens were febrile, weak, and had oronasal hemorrhage. Complete blood cell counts indicated severe bone marrow suppression. Treatment consisted of multiple transfusions, antibiotics, and granulocyte colony-stimulating factor. One of the kittens responded to therapy and had a complete recovery. The other kitten was treated for 40 days with no clinical response before dying. Both kittens also contracted Mycoplasma hemofelis infection from a contaminated blood transfusion.
Introduction
Azathioprine is a thiopurine used for the treatment of immune-mediated diseases. Azathioprine interferes with de novo synthesis of purine nucleotides that are important for lymphocyte proliferation.1 It is metabolized in the liver to the active metabolite 6-mercaptopurine (6-MP), which inhibits T-cell lymphocyte function and helper-cell effects on antibody synthesis.1,2 After azathioprine is converted to 6-MP, it is further converted to thiopurine nucleotide analogues. These analogues are subsequently incorporated into deoxyribonucleic acid (DNA), which is believed to be the mechanism for the drug’s cytotoxic action.2–4 Inactivation of azathioprine via methylation by thiopurine methyltransferase (TPMT) is responsible for conversion to nontoxic 6-MP nucleotides.
In people, there is a genetic polymorphism that determines high or low levels of TPMT. In people, low levels of TPMT are associated with an increased risk of myelosuppression.4–6 One study found dogs had variable TPMT activity, which may make some dogs more susceptible to azathioprine toxicity.7 However, another study found that six dogs with azathioprine-associated myelotoxicity had intermediate or high TPMT enzyme activity, suggesting that TPMT activity may not solely be responsible as the cause of severe azathioprine-associated myelosuppression in this species.8 Cats may also have low TPMT levels that could predispose them to bone marrow suppression.9,10
Azithromycin is a macrolide antibiotic that inhibits protein synthesis by penetrating the cell wall and binding to the 50S ribosomal subunits in susceptible bacteria.11 It has a broad spectrum of activity and is useful for a variety of infections in cats.12 The medication is generally well tolerated in cats, with the most common side effect being vomiting.12
Blood transfusions are used to treat a variety of different diseases in cats. Although blood transfusions may be life saving, they do have potential complications. In addition to immune-mediated reactions caused by infusion of allogeneic cells or proteins, blood-borne infectious organisms can be transmitted and potentially cause disease in the transfused recipient.13 Current guidelines instituted by the American College of Veterinary Internal Medicine recommends testing for Mycoplasma spp., Bartonella spp., feline leukemia virus, and feline immunodeficiency virus in cats that are used as blood donors.14 Failure to prevent blood contamination with these agents can lead to infection of the transfused recipient.
The purpose of this paper is to describe two cats that received an overdose of azathioprine, resulting in severe myelosuppression secondary to a prescription error, and blood transfusions contaminated with Mycoplasma spp.
Case Reports
Case No. 1
An approximately 7-month-old, spayed female, domestic shorthair kitten was presented to the Foster Hospital for SmallAnimals at the Tufts University Cumming’s School of Veterinary Medicine (TCSVM) for lethargy and anorexia. Coughing, sneezing, and infection with Bartonella spp., based on polymerase chain reaction (PCR) assay, had occurred 3 weeks earlier. The referring veterinarian prescribed azithromycina at a dosage of 12 mg/kg per os (PO) q 24 hours. After 17 days of therapy, the kitten became lethargic, anorexic, and pyrexic (41.1°C). The kitten was given subcutaneous (SC) fluids (100 mL lactated Ringer’s solution) and was started on amoxicillinb (22 mg/kg PO q 12 hours). A complete blood count (CBC) performed 24 hours later showed neutropenia (0.384 × 103/μL; reference range 2.5 to 8.5 × 103/μL) and thrombocytopenia (90 × 103/μL; reference range 200 to 500 × 103/μL). The kitten was referred for further diagnostic testing and treatment.
At the initial presentation at TCSVM, a bottle of compounded medication provided by the client was labeled as azathioprine rather than azithromycin as intended. The referral medical record documented that azithromycin was intended; however, in retrospect, an error was made when the prescription was called into the compounding pharmacy (as was noted in a subsequent medical record entry in the referral medical record), and azathioprine was prescribed instead.
On initial examination (day 1), the kitten weighed 2.5 kg, was febrile (40.5°C), tachycardic (heart rate of 228 beats per minute [bpm]), and tachypneic (respiratory rate of 64 breaths per minute). A CBC showed leukopenia (white blood cell count [WBC] 2.700 × 103/μL; reference range 4.5 to 15.7 × 103/μL), thrombocytopenia (estimate <15,000 × 103/μL; reference range 183 to 643 × 103/μL), absolute neutropenia (0 × 103/μL; reference range 2.1 to 10.1 × 103/μL), and anemia (hematocrit 18%; reference range 31% to 46%). The kitten was admitted and treated with cefazolinc (22 mg/kg intravenously [IV] q 8 hours) and a typespecific (A) transfusion of packed red blood cells (RBCs) (30 mL IV). The following day, ticarcillin-clavulanic acidd was also started (50 mg/kg IV q 6 hours) for a persistent fever (40.2°C).
Because the neutrophil count remained 0 [Table 1], filgrastime (granulocyte colony-stimulating factor [G-CSF]) (5 units/kg SC q 24 hours for 10 days) was started on day 4. Three fresh whole blood transfusions (30 mL) were also given on days 4, 6, and 12. Body temperature remained elevated [see Figure] until day 13. By day 15, the WBC and neutrophil counts began to improve. The kitten was discharged on day 17 on amoxicillin-clavulanic acidf (13.75 mg/kg PO q 12 hours).
At a recheck examination 2 days later (day 19), a CBC identified persistent leukopenia [Table 1], mild thrombocytopenia, neutropenia, anemia, and increased nucleated red blood cells (nRBC). The kitten was doing well at home and was continued on the previous medication prescribed. On day 27, another CBC revealed persistent anemia but a normal neutrophil count [Table 1].
Eighteen days after the kitten was discharged from the hospital (day 35), she was returned for lethargy and anorexia. On physical examination, her temperature was mildly elevated (39.7°C), the heart rate was 228 bpm, and respiratory rate was 72 breaths per minute. The mucous membranes and sclera were icteric, and splenomegaly was present. A CBC performed at admission showed mild neutropenia, thrombocytopenia, anemia, reticulocytosis (uncorrected 4.9%; reference range 0), and 151 nRBC/100 WBC [Table 1]. The kitten was readmitted to the hospital, and 50 mL of packed RBCs were administered IV. Doxycyclineg (5 mg/kg PO q 12 hours) was started for a suspected infection with Mycoplasma (M.) hemofelis. Although this parasite was not found in the kitten’s blood samples, other recipients of transfusions from the same donor (including case no. 2) became infected with M. hemofelis. After 3 days in the hospital, the kitten had improved and was discharged with a hematocrit of 26% on day 38. No further clinical problems occurred, and the kitten was clinically normal at the last recheck examination.
Case No. 2
An approximately 6-month-old, spayed female, domestic shorthair kitten was presented to TCSVM for anemia and oronasal hemorrhage. The kitten was from the same household and was adopted at the same shelter, but it was not a sibling to case no. 1. This kitten had the same previous medical problems and was treated the same as case no. 1 by the referring veterinarian. A CBC performed by the referring veterinarian showed leukopenia (0.9 × 103/μL; reference range 3.5 to 16.0 × 103/μL), thrombocytopenia (78 × 103/μL), and anemia (hematocrit 24.1%; reference range 29% to 48%). On physical examination, the kitten weighed 2 kg, was febrile (37.9°C), tachycardic (heart rate of 196 bpm), and tachypneic (respiratory rate of 76 breaths per minute). This kitten had also received azathioprine (12.5 mg/kg PO q 24 hours) for 17 days. The kitten was very weak, pale, and was hemorrhaging from the mouth and nose.
The kitten was admitted to the hospital, started on oxygen therapy, and given 50 mL of lactated Ringer’s solution IV rapidly. Cefazolin (22 mg/kg IV q 8 hours) was started, and packed RBCs (30 mL) were transfused IV. The hematocrit was 7% pretransfusion and 12% posttransfusion. The initial CBC showed leukopenia, absolute neutropenia, thrombocytopenia, and anemia [Table 2]. A biochemical profile documented hyperglycemia (164 mg/dL; reference range 70 to 120 mg/dL) and elevations in blood urea nitrogen (39 mg/dL; reference range 15 to 32 mg/dL), alanine transferase (1907 U/L; reference range 29 to 145 U/L), aspartate transferase (2930 U/L; reference range 12 to 42 U/L), and creatine kinase (817 U/L; reference range 41 to 493 U/L). Decreases in total protein (4.1 g/dL; reference range 6.0 to 8.4 g/dL), albumin (1.7 g/dL; reference range 2.4 to 3.9 g/dL), and potassium (3.0 mEq/L; reference range 3.6 to 5.4 mEq/L) were also noted.
On the following day, another 30 mL of packed RBCs were transfused IV, bringing the posttransfusion hematocrit to 13%. Ticarcillin-clavulanic acid (50 mg/kg IV q 8 hours) was added because of persistent fever. Fresh whole blood (30 mL) was given on days 3 and 5, because the hematocrit remained low and the oronasal hemorrhaging continued.
The neutrophil count remained 0, so the kitten was started on filgrastim (5 units/kg SC q 24 hours) on day 4. Amikacinh (15 mg/kg IV q 24 hours) was also begun when the temperature rose to 41°C [see Figure], and it was continued until day 8. On day 16, the ticarcillin-clavulanic acid was discontinued, and amikacin (15 mg/kg IV q 24 hours) was reinstituted when the body temperature again rose to 41.8°C. Lactated Ringer’s solution (IV) was also started. On day 18, the amikacin and cefazolin were discontinued, and imipenem-cilastatini (5 mg/kg IV q 8 hours) was begun because of persistent fever [see Figure]. This antibiotic was continued until day 40. Another fresh whole blood transfusion (30 mL) was given on day 23 because of continued oronasal bleeding, probably secondary to profound thrombocytopenia [Table 2].
On day 26, a CBC revealed a moderate number of RBCs infected with M. haemofelis, and therapy with doxycycline (5 mg/kg PO q 12 hours) was initiated. On day 35, another course of treatment with filgrastim (5 units/kg SC q 24 hours) was instituted, because the neutrophil count was again 0. On day 40, the kitten experienced cardiopulmonary arrest and could not be revived. Over the course of her hospitalization, 17 blood transfusions (4 units packed RBCs, 13 units fresh whole blood) had been administered. A bone marrow core biopsy was considered as a diagnostic option, but it was not performed. Histopathological evaluation of the bone marrow in case no. 2 would have been potentially useful in prognosticating the likelihood of marrow recovery, but it was not performed.
Discussion
Medication errors are rarely reported in veterinary medicine. Amedication error is defined as any preventable event that may cause or lead to inappropriate medication use or to harm of the patient, while the medication is in the control of the healthcare professional, patient, or consumer.15 Medication errors can occur because of similar-sounding brand and generic names. Prescription drug errors have been identified as one of the most prominent safety issues in human medicine.16 The estimated cost for drug errors in people is 7% of the total expenditure for national health care.16 Adverse drug events are estimated to injure or kill more than 770,000 people in hospitals annually, with prescribing errors being the most frequent event.17
In the cases reported here, the medication prescription was written correctly in the chart by the referring veterinarian; however, when the prescription was called into a local compounding pharmacy, it was called in incorrectly.Although the compounding pharmacy specialized in veterinary products, the apparent error was not noticed, and the prescription was filled as dictated. The solutions to medication errors are multifactorial and include careful attention and knowledge by the veterinarian, the pharmacist, and the technician.
Azathioprine is rarely recommended as a therapeutic agent in cats because of its high potential for bone marrow toxicity.18 If used, the recommended dosage is 1.1 mg/kg PO q 48 hours.11 In one study, five cats treated with an azathioprine suspension (2.2 mg/kg PO q 48 hours) developed a profound neutropenia after a mean of 14.8 doses (30 days).18 In four of the cats, neutropenia and thrombocytopenia resolved after azathioprine was discontinued.18 Another report described the use of azathioprine in eight cats (1.1 mg/kg PO q 48 hours) for the treatment of pemphigus foliaceus.2 Four of the cats became leukopenic after a mean of 8.25 doses (18 days).2 In humans, the severity of the myelosuppression is related to the dose and duration of the azathioprine therapy.4
The surviving cat (case no. 1) of this report had increased neutrophil and platelet counts 19 days following discontinuation of azathioprine. In the nonsurviving cat, even 39 days after discontinuation of azathioprine, no evidence of bone marrow recovery was seen.
In the kittens of this report, azathioprine-induced bone marrow suppression was considered the underlying cause of the aplastic anemia. Treatment of aplastic anemia in cats is very challenging and often includes blood transfusions. Multiple blood transfusions were given to the kittens to provide time for bone marrow recovery. Following bone marrow recovery of case no. 1, hope was that case no. 2 would also recover. Drug-associated aplastic anemias in dogs have a variable prognosis depending upon the drug that caused the bone marrow toxicity and the severity of the insult.19 It was unclear why one kitten recovered and the other did not. The surviving kitten received a slightly lower dosage (12 mg/kg versus 12.5 mg/kg) of azathioprine, and this may have been a significant difference.While both kittens were from the same household, they were not siblings, so inherent differences in the metabolism (e.g., TPMT activity) of azathioprine may have played a role.
The kittens in this report received a combined total of 21 transfusions. Although transfusions are often life saving, the cats in this report developed a serious complication associated with the transfusions: specifically, confirmed or presumed infection with M. hemofelis. The development of M. hemofelis in both recipients was unfortunate and was ultimately traced back to a single donor who retrospectively tested positive via a PCR for M. hemofelis.At the time the kittens were hospitalized at TCSVM, routine testing of feline blood donors did not include testing for M. hemofelis. Since the transmission of this infectious agent occurred, testing for M. hemofelis is required of all feline blood donors.
The role of immune-mediated hemolysis in perpetuating the anemia in these kittens was unclear. Since the kittens did not exhibit any clinical signs of hemolysis such as icterus, splenomegaly, or hemolysis on blood smears, the role of transfusion incompatibility seemed unlikely. Traditional feline transfusion medicine has supported only the transfusion of type-specific rather than cross-matched blood; however, with multiple transfusions, cross-matching would be ideal to prevent any transfusion incompatibility that could result in premature hemolysis of some of the transfused cells. Because of a scarcity of available feline blood donors during the 6 weeks these kittens were treated, cross-matching was not performed.
Conclusion
Two kittens developed aplastic anemia secondary to an inadvertent overdose of azathioprine from a prescription error. One kitten survived despite severe myelosuppression following intensive medical therapy with blood transfusions and G-CSF. In addition, M. hemofelis was apparently transmitted to both kittens through blood transfusions.
Zithromax; Pfizer Labs, New York, NY 10017
Amoxi-drop; Pfizer Labs, New York, NY 10017
Cefazolin; CURA Pharmaceutical Co., Eatontown, NJ 07724
Timentin; GlaxoSmithKline, Research Triangle Park, NC 27709
Neupogen; Amgen Inc., Thousand Oaks, CA 91320
Clavamox; GlaxoSmithKline, Research Triangle Park, NC 27709
Vibramycin; Pfizer Labs, New York, NY 10017
Amikacin; The Butler Company, Columbus, OH 43228
Primaxin; Merck & Co., Inc., Whitehouse Station, NJ 08889
Acknowledgments
The authors acknowledge the assistance of Drs. Armelle deLaforcade and Danna Torre in case management; the support of Diane Welsh, AS, CVT, and manager of the Tufts University Cummings School of Veterinary Medicine blood bank; and Dr. Liz Rozanski for editorial assistance.
Citation: Journal of the American Animal Hospital Association 44, 1; 10.5326/0440025
Daily body temperature fluctuations showed persistently high fevers in two kittens with bone marrow suppression from an overdosage of azathioprine. Temperatures were not measured in case no. 1 during the time period that the cat was at home.
