• Open Access

Adverse Neurologic Events Associated with Voriconazole Use in 3 Cats

Authors


Corresponding author: Jessica M. Quimby, DVM, DACVIM, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 300 West Drake Road, Fort Collins, CO 80523; e-mail: jquimby@colostate.edu.

Abstract

Background: Voriconazole has a broader spectrum of activity in comparison to fluconazole, itraconazole, and amphotericin B. Little documentation regarding appropriate dosing, efficacy, or adverse effects exists for cats. Neurologic adverse effects have been reported as a result of administration in other species.

Hypothesis: Voriconazole administration resulted in neurologic abnormalities in 3 cats.

Animals: Three cats that received voriconazole.

Methods: Observational study of adverse effects associated with voriconazole administration.

Results: All 3 cats had ataxia, which in 2 cats progressed to paraplegia of the rear limbs. Two of the cats had visual abnormalities including mydriasis, decreased to absent pupillary light responses, and decreased menace response. Arrhythmia and hypokalemia were noted in 2 separate cats.

Conclusions and Clinical Importance: Voriconazole has potential neurologic adverse effects in cats. Additional information regarding pharmacokinetics of the drug in this species must be gathered to help determine how it can be dosed most effectively with minimal adverse effects.

Abbreviations:
CLDC

cationic liposome DNA complexes

CP

conscious proprioception

CT

computed tomography

FeLV/FIV

feline leukemia virus/feline immunodeficiency virus

PLRs

pupillary light responses

A 3-year-old female spayed domestic longhaired cat was examined for swelling, depigmentation, and ulceration of the nasal planum of 1 week's duration and sneezing of several years' duration. Cytologic examination of the nasal discharge did not identify infectious organisms, but a Cryptococcus latex agglutination antigen assaya was positive at 1 : 128. The nasal ulceration responded to fluconazoleb and a novel injectable immunotherapeutic agent (cationic liposome DNA complexes [CLDC]c), but could not be controlled despite a negative follow-up Cryptococcus titer. Rhinoscopy and biopsy did not indicate another underlying cause, and additional antifungal therapy was recommended because of the previous response. The cat was treated with voriconazoled 25 mg PO every 24 hours (10 mg/kg/d).

Four days after initiating voriconazole therapy, the owners reported the cat was “staring off into space” and was inappetent and lethargic. On physical examination, mydriasis was noted with normal pupillary light responses (PLRs) and a retinal examination performed by a veterinary ophthalmologist was normal. Ataxia was not observed and it was unknown whether the clinical abnormalities resulted from voriconazole therapy or from spread of the presumed fungal disease to the nervous system. Six days after initiating the voriconazole, the cat developed anorexia and was described as “wobbly” by the owners. On physical examination, the cat was unkempt, dehydrated, thin (body condition score 2/9; weight, 2.1 kg), and still exhibiting mydriasis with weak PLRs. The cat preferred to crouch in the examination room, and slunk when induced to walk. In addition, the cat was unsuccessful jumping onto a chair. The ataxia appeared to be because of weakness in the rear legs. Spinal reflexes were within normal limits. Conscious proprioceptive (CP) and postural reaction deficits were noted in the pelvic limbs but were difficult to assess in the front limbs because of the cat's unwillingness to cooperate. Spontaneous nystagmus and a subtle bobbling head tremor also were noted. The tremor was similar to an intention tremor, but did not increase in severity when the cat attempted activities. The nystagmus resolved before it could be fully evaluated. The cat had an abnormal menace response and appeared to be blind, but retinal examination by a veterinary ophthalmologist again was within normal limits. With the exception of the abnormal menace response, cranial nerve tests were normal. The neurologic abnormalities were felt to be consistent with a central lesion, possibly in the vestibular or cerebellar area. A previously unrecognized arrhythmia was auscultated. The nasal ulceration was improved. CBC and serum biochemistry results were within normal limits. The voriconazole was discontinued and the cat admitted for IV fluid therapy. By the time ECG leads were placed, the arrhythmia could no longer be identified. Within the first 24 hours of hospitalization, the cat began to eat, ataxia improved, and the head tremor resolved. After discharge, the ataxia continued to improve over the next week, but lethargy and inappetence persisted. The owners elected euthanasia 10 days later. A necropsy was performed and no ocular or neurologic abnormalities were noted. Severe chronic eosinophilic granulomatous rhinitis and perichondritis were documented in the nasal tissues. The nasal ulceration was not present at the time of necropsy and was not evaluated histopathologically.

A 6-year-old female spayed domestic shorthaired cat was examined for bilateral nasal discharge of 1 month's duration. Aspergillus sp. was grown from a nasal flush sample and itraconazolee was prescribed at 25 mg PO every 12 hours for 60 days for treatment of presumptive aspergillosis. At reevaluation 2 months later, little improvement was noted. At this time, the owner declined referral to a specialist and the cat was treated with voriconazole 50 mg PO every 24 hours (13 mg/kg/d).

Five days after beginning treatment, the cat presented for inability to use the hind limbs. On physical examination, the major abnormality noted was paraparesis. Motor function appeared intact, but delayed CP was detected in both hind legs. Both hind paw pads were pink and pulses were strong and synchronous. The cat appeared nonpainful and was able to move its tail normally. The pupils were dilated with slowly responsive PLRs and the cat had a decreased menace response. A complete neurologic examination was not performed and neurolocalization was not determined. A CBC and serum biochemistry results were within normal limits except for mild hypokalemia (3.2 mEq/L; reference range, 3.6–5.6 mEq/L) and increased CK activity (2,110 IU/L; reference range, 0–368 IU/L). A generalized, moderately severe bronchial pattern was seen on thoracic radiographs, and abdominal radiographs were interpreted as normal. Voriconazole was discontinued and the cat was hospitalized and given fluids IV and 2 mEq of potassium gluconatef PO every 12 hours. Continued gradual improvement in hind limb function and appetite were noted, and the cat was discharged 5 days later. The cat later was seen by a veterinary internist, and rhinoscopy, biopsy, and culture were performed. No lesions were noted on rhinoscopy. Biopsy revealed mucinous rhinitis mixed with hemorrhage, stromal edema, and mild submucosal gland hyperplasia. No evidence of cellular atypia, neoplasia, or Aspergillus spp. was noted. Azithromycin (compounded by unknown person) was prescribed at 40 mg PO every 24 hours (10 mg/kg/d) for 10 days. Fungal culture of a nasal flush was positive for Aspergillus sp., but the organism was considered to be a contaminant. Two weeks later nasal signs were resolved but the owner reported the cat was still walking slightly abnormally. One year later, the cat was considered clinically normal.

A 10-year-old domestic shorthaired cat was presented for periorbital swelling and conjunctivitis in the left eye. A presumptive diagnosis of retrobulbar aspergillosis was made based on CT-guided biopsy of a retrobulbar mass that disclosed marked mixed cell deep conjunctivitis with fungal hyphae that were confirmed to be morphologically consistent with Aspergillus sp. based on special stains. The cat was treated with voriconazole 54 mg PO every 24 hours (10 mg/kg/d). On reevaluation 2 weeks later, the cat was described by the owner as lethargic, “wobbly,” and inappetent. Weight loss of 0.5 kg was recorded. CBC and serum biochemistry results were within normal limits. Two days later, the cat presented again for difficulty in walking. Physical examination indicated that the cat would only walk in a crouched position and had a plantigrade stance. A split heart sound was heard on auscultation, and femoral pulses were normal. Blindness was not detected and cranial nerve evaluation was normal. A complete neurologic examination was not performed and neurolocalization was not determined. Voriconazole was discontinued and the cat was hospitalized and given IV fluids and meloxicam (0.1 mg/kg) for pain for 2 days. Over the course of a week, the gait became more normal. Four days after discharge, the cat became inappetent and started vomiting. Supportive therapy including metoclopramide (1.5 mg PO q12h for an unspecified period) and SC fluids was instituted, which resulted in resolution of the clinical signs. Seventeen days later, the cat was evaluated by another veterinarian and hospitalized for fluid therapy because of increased blood urea nitrogen (BUN) (36 mg/dL; reference range, 16–36 mg/dL) and serum creatinine (3.2 mg/dL; reference range, 0.8–2.4 mg/dL) concentrations with urine specific gravity of 1.014. The cat was still azotemic at reevaluation 2 weeks later (serum creatinine concentration 3.0 mg/dL; BUN concentration 39 mg/dL), but was doing well clinically. The cat was walking normally again when evaluated 2.5 months later by a veterinary internist. Itraconazole was instituted for the retrobulbar Aspergillus infection, and the cat was subsequently lost to follow-up.

Voriconazole inhibits the cytochrome P450-dependent enzyme 14-α-sterol demethylase, which disrupts the fungal cell membrane and halts growth.1 Voriconazole is fungistatic against Candida sp. and Cryptococcus sp. and fungicidal against Aspergillus sp. It has better activity against Candida sp. than fluconazole and better activity against Aspergillus sp. than either itraconazole or amphotericin B.1 Bioavailability is high (> 75%) based on initial pharmacokinetic studies in rat, dog, rabbit, and guinea pig models.2 The drug does not display linear pharmacokinetics in any species studied, and thus higher doses result in greater drug accumulation. In humans, there appears to be marked individual variability in drug serum concentration and, as a result, therapeutic drug monitoring is encouraged.3

Very few reports are available on the use of voriconazole in cats, and to the best of the authors' knowledge there are no reports regarding adverse events associated with the use of the drug in cats. In one report, 5 mg/kg voriconazole was given IV to a cat with systemic Cryptococcus albidus infection, but the cat was extremely debilitated and died after 3 days.4 Voriconazole ophthalmic ointment (1%) has been prescribed for Aspergillus flavus keratomycosis in a cat and resulted in resolution of the condition.5 Information is available about the drug from the initial toxicity studies and several clinical trials in humans, and the clinical signs seen in the cats described here appear consistent with previously reported adverse effects in humans and other species.2,3,6–8

Two of the cats described here had visual abnormalities including mydriasis, decreased to absent PLRs, and decreased menace response. All 3 cats had ataxia, which in 2 cats progressed to paraplegia of the rear limbs. Toxicity studies using rodent models showed that high dosages (100 mg/kg) resulted in central nervous system signs such mydriasis, loss of balance, lethargy, prostration, and rigid extended limbs.2 In humans, the most commonly reported adverse effect (30%) is visual disturbances.1 However, this reaction often is described as mild and transient in nature, rarely resulting in cessation of therapy. More recently, a peripheral neuropathy was reported in association with the use of the drug.6,7 The patients developed extreme pain in their extremities with the loss of proprioception and sensation. The signs could not be attributed to any other disease, and the results of electromyographic and nerve conduction studies were suggestive of a neuropathy. The condition resolved rapidly after discontinuation of the drug in all cases. The clinical signs seen in 2 of the cats of this report were consistent with peripheral neuropathy, but neurolocalization was not possible because of the limited nature of the neurological assessment and no advanced diagnostic tests were done to explore this possibility. The neurologic assessment of the 1st cat was more consistent with a central lesion. Hypokalemia as seen in Case 2 and arrhythmias as seen in Case 1 also have been reported at adverse effects associated with the drug.2,9 Hepatotoxicity associated with increases in liver enzyme activity is another commonly reported adverse event in humans,1 but liver function abnormalities were not observed in the cats described here. The vomiting, anorexia, and azotemia seen in Case 3 may have been more consistent with meloxicam administration than voriconazole.

In people, higher plasma voriconazole concentrations have been correlated with increased incidence of visual and neurologic adverse events including painful peripheral neuropathy, blurred vision, visual hallucinations, confusion, impaired concentration, anxiety, nystagmus, dysarthria, and insomnia.3,8,10 In one study, 31% of patients with a voriconazole trough concentration >5.5 mg/L presented with neurologic signs, in contrast to no patients with concentrations <5.5 mg/L exhibiting such clinical signs.8 In the cats presented here, various dosages of voriconazole were administered ranging from 10 to 13 mg/kg/d. Although it is possible that a lower dosage would not have resulted in the observed clinical signs, similar adverse effects have been reported even in cats administered 5 mg/kg PO every 24 hours (Barrs, personal communication). Therefore, it is possible that the dosage currently used is too high, or that cats, like humans, may have variable blood concentrations, and therapeutic monitoring of drug concentrations may be warranted.

Toxicity was not definitively proven in the cats of this report because serum drug concentrations were not measured. However, the similarity of the adverse events to those reported in other species, the rapid onset after initiation of medication, and resolution of signs after discontinuation of the medication lead us to strongly suspect that voriconazole was responsible for the clinical signs noted. The purpose of this report is to alert clinicians to potential neurologic adverse effects of this medication in cats. The efficacy of voriconazole against fungal organisms shows great potential, but if it is to be safely used in cats, additional information regarding pharmacokinetics of the drug in this species must be gathered to help determine how it can be dosed most effectively with minimal adverse effects.

Acknowledgment

This study was not supported by a grant and has not been previously presented in any form.

Footnotes

aCALAS, Meridian Diagnostics Inc, Cincinatti, OH

bFluconazole, IVAX Pharmaceuticals, Miami, FL

cCLDC, Colorado State University, Fort Collins, CO

dVFEND, Pfizer Animal Health, New York, NY

eSporanox Oral Solution, Janssen Pharmaceutical, Raritan, NJ

fTumil-K, Virbac AH Inc, Fort Worth, TX

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