Treatment of Cryptococcal Meningoencephalitis and Presumed Pulmonary Cryptococcoma in a King Cheetah (Acinonyx jubatus) with Fluconazole and Amphotericin B
A 6-yr-old, 44-kg, captive male king cheetah (Acinonyx jubatus) was evaluated for intermittent lethargy and depression of 1.5 wk duration. Initial workup, consisting of radiographs, bloodwork, and urinalysis, revealed a focal nodule in the left lung. Bloodwork results, including common feline disease serology, were within normal limits or negative. Results of the physical examination were unremarkable other than slightly decreased skin turgor. Over the next several days, central neurologic signs became more evident, with mental dullness progressing to stupor, ataxia, protrusion of the third eyelids, dilated but responsive pupils, protrusion of the tongue, occasional slow head tremors, and anorexia. Physical examination under anesthesia was again unremarkable. Further workup included CT scan, cerebrospinal fluid (CSF) tap, repeat bloodwork, and abdominal ultrasound. Cytology of the CSF showed elevated protein (300–400 mg/dl; feline normal reference range, <25 mg/dl), leukocytosis (7,000 cells/μl, mostly neutrophils; feline reference range, 0–3 cells/μl), and yeast organisms consistent with Cryptococcus sp. Serum and CSF Cryptococcus antigen titers by latex agglutination (Texas Veterinary Medical Diagnostic Laboratory [TVMDL], College Station, TX, USA, and Cornell Diagnostic Laboratory, College of Veterinary Medicine, Ithaca, NY, USA, respectively) were both positive at 1:32. Complete blood cell count and serum chemistries were again within normal limits. Fluconazole (compounded by Pet Health Pharmacy, Youngstown, AZ, USA) (4.5 mg/kg PO BID) and lactated Ringer's solution (1 L SC BID) was started. Fluconazole was chosen for its superior penetration into the central nervous system.2
Cultures of the CSF were negative for bacteria, and positive for Cryptococcus neoformans, the variant undetermined. Sensitivity results revealed intermediate sensitivity to fluconazole, and complete sensitivity to amphotericin B and the other azoles.
The cheetah became more alert and responsive over the next several days, but still had a poor appetite and necessitated hand-feeding. Clinical signs varied in severity from day to day, but greatly deteriorated 5 days later, at which point the dose of fluconazole was increased to 13.5 mg/kg divided BID (400 mg in a.m., 200 mg in p.m.). Six days later, amphotericin B therapy was initiated in hopes of achieving a synergistic effect, using an established veterinary protocol.1 Initial treatment was amphotericin B (X-Gen Pharmaceuticals, Big Flats, NY, USA) 0.5 mg/kg diluted in 1 L of warmed 0.45% NaCl + 2.5% dextrose fluids, administered SC three times per wk. An additional 700–1000 ml of unmedicated fluids was also given SC for supportive care as needed. This protocol was chosen for its reported decreased nephrotoxicity1 and ease of administration in this patient. As clinical signs continued to fluctuate, and included one episode of vomiting, treatment for gastritis was again started with amoxicillin (22 mg/kg PO BID; STADA Pharmaceuticals, Inc., Cranbury, NJ, USA) and esomeprazole (1 mg/kg PO SID; Nexium, AstraZeneca, Wilmington, DE, USA). Amoxicillin was discontinued after 10 days, but esomeprazole continued for prophylaxis, especially due to the potential nephrotoxicity of the antifungal agents.
Venipuncture via the medial saphenous vein was performed every 7 days as long as the cheetah allowed. Urinalyses were run opportunistically. Samples did not necessarily reflect fasting, and water was always available. The first urine sample collected 3 wk after initiating amphotericin B was isosthenuric (specific gravity 1.010). Although the blood urea nitrogen fluctuated but remained in normal range, creatinine increased to 5.5 mg/dl (ISIS reference values, 2.4±0.9 mg/dl) 4 wk after initiating amphotericin B therapy. This azotemia also correlated with a sudden aversion to food. Amphotericin B was thus temporarily discontinued, but normal subcutaneous fluids were administered BID for diuresis. Creatinine decreased to 4.2 mg/dl 3 days later, 3.6 mg/dl 1 wk later, and remained under 3.0 mg/dl for the next 5 wk. Thereafter, two urinalyses showed concentrated urine (specific gravity >1.040).
Amphotericin B therapy was reinstituted just 4 days after the discontinuation, because of relapsing neurologic signs but a restored appetite. The protocol, however, was modified to 10 mg of amphotericin B diluted in 1 L of 0.45% NaCl + 2.5% dextrose SC three times per wk.
Neurologic signs continued to fluctuate, with the cheetah appearing to have relapses of several days' duration approximately every 2 wk. No further relapses were evident after 10 wk of combined therapy, and the cheetah's "personality" finally returned to normal. Esomeprazole was tapered to every other day, and amphotericin B therapy was further tapered to twice-weekly dosing.
Four months into treatment, the cheetah was immobilized for re-evaluation. Cerebrospinal fluid was sterile on fungal culture, and cytology showed mild protein elevation (30 mg/dl), and few leukocytes (10 cells/μl, with 70% lymphocytes and 30% neutrophils). Cryptococcus antigen titers (TVMDL) were undetectable in the CSF, and positive at 1:2 in the serum. The pulmonary nodule was still present on radiographs but subjectively appeared less radiodense. Physical examination was unremarkable.
Amphotericin B therapy was continued until a cumulative dose of 20 mg/kg was achieved, almost 8 mo after initial treatment. The cheetah was then re-evaluated under anesthesia. Cerebrospinal fluid was again sterile and analysis showed protein of 30 mg/dl, and a leukocyte count of 1.6 cells/μl was within the reference range. Cryptococcus antigen titers (TVMDL) were undetectable in the CSF and serum. Radiographs showed the pulmonary nodule significantly reduced in size. The cheetah is considered in remission, but is being maintained on oral fluconazole.
This is the first reported case of a successful treatment of central nervous system cryptococcosis in a captive cheetah. The administration of amphotericin-B SC is reportedly less nephrotoxic; however, this cheetah did become significantly azotemic. The goal of achieving a cumulative dose of this medication allowed flexibility in the dosing schedule, enabling adjustment and continuation of therapy. The overall combination of fluconazole and amphotericin-B has proven safe and effective for this cheetah.
The authors thank Dr. Richard Malik for his advice, Dr. James Cook and Dr. Ron Burk for their assistance in diagnostics, Dr. Michael Garner for cytology interpretation, and the entire Wildlife Show staff, Miami Metrozoo, for their excellent care of this cheetah.
1. Malik, R., A. J. Craig, D. I. Wigney, P. Martin, and D.N. Love. 1996. Combination chemotherapy of canine and feline cryptococcosis using subcutaneously administered amphotericin B. Aust. Vet. J. 73:124–128.
2. Plumb, D.C. 2002. Veterinary Drug Handbook. 4th ed. Iowa State Press, Ames, IA. Pp. 360–361.