Voriconazole Toxicity in Multiple Penguin Species

Abstract

Aspergillosis is a common respiratory fungal disease in penguins managed under human care. Triazole antifungal drugs, including itraconazole, are most commonly used for treatment; however, itraconazole treatment failures from drug resistance are becoming more common, requiring newer treatment options. Voriconazole, a newer triazole, is being used more often. Until recently, no voriconazole pharmacokinetic studies had been performed in penguins, leading to empiric dosing based on other avian studies. This has led to increased anecdotal reporting of apparent voriconazole toxicity in penguins. This report describes 18 probable and 6 suspected cases of voriconazole toxicity in six penguin species from nine institutions: 12 African penguins (Spheniscus demersus), 5 Humboldt penguins (Spheniscus humboldti), 3 Magellanic penguins (Spheniscus magellanicus), 2 gentoo penguins (Pygoscelis papua papua), 1 macaroni penguin (Eudyptes chrysolophus), and 1 emperor penguin (Aptenodytes forsteri). Observed clinical signs of toxicity included anorexia, lethargy, weakness, ataxia, paresis, apparent vision changes, seizure-like activity, and generalized seizures. Similar signs of toxicity have also been reported in humans, in whom voriconazole therapeutic plasma concentration for Aspergillus spp. infections is 2-6 μg/ml. Plasma voriconazole concentrations were measured in 18 samples from penguins showing clinical signs suggestive of voriconazole toxicity. The concentrations ranged from 8.12 to 64.17 μg/ml, with penguins having plasma concentrations above 30 μg/ml exhibiting moderate to severe neurologic signs, including ataxia, paresis, and seizures. These concentrations were well above those known to result in central nervous system toxicity, including encephalopathy, in humans. This case series highlights the importance of species-specific dosing of voriconazole in penguins and plasma therapeutic drug monitoring. Further investigation, including pharmacokinetic studies, is warranted. The authors recommend caution in determining voriconazole dosages for use in penguin species.

Application of different pharmacokinetic models to describe and predict pharmacokinetics of voriconazole in magellanic penguins following oral administration

“…These differences may result in drug toxicity in individuals due to large differences in achieved voriconazole plasma concentrations. Twenty‐four cases of suspected voriconazole toxicity in six species of penguin have been reported by Hyatt and co‐workers (Hyatt et al., ). Clinical signs of toxicity included anorexia, abnormal behavior (lethargy, changes in mentation, depression, isolating self, staring off into the distance), or neurologic signs (weakness, ataxia, paresis, apparent changes in vision, seizure‐like activity, and seizures) in penguins and elevated liver enzymes and bile acids in other birds (Hyatt et al., ).…”

“…In the Hyatt et al. (), signs of toxicity in penguins occurred within 4 to 99 days of start of treatment in animals dosed at least once daily and after 448 and 511 days of treatment in penguins treated every 72 hr and doses in excess of 5 mg/kg were used in all cases. Plasma voriconazole in the affected penguins ranged from >10 to 64.17 μg/ml.…”

Voriconazole

“…32 Treatment for aspergillosis with VCZ was associated with neurologic events and death in multiple individuals from six penguin species. 37 The authors observed the following adverse clinical signs in the VCZ treated penguins: anorexia, lethargy, weakness, ataxia, paresis, apparent vision changes, seizure-like activity, and generalized seizures. 37 The penguins' plasma concentration levels ranged from 8 to 64 μg/ml, and the birds that had levels above 30 μg/ml exhibited more severe neurologic events.…”

Aspergillosis, Avian Species and the One Health Perspective: The Possible Importance of Birds in Azole Resistance

“…The taxonomy of Aspergillus is in flux, and four to eight subgenera, and from 16 to 25 sections, has been proposed by different authors, and more than 350 species. Most species are found in the Azoles such as itraconazole (ITC), voriconazole (VRC), posaconazole (POS) and isavuconazole (ISA) are the drugs of choice for prophylaxis and treatment of aspergillosis both in humans and animals [7][8][9][10][11][12]. Because of the difficulty on designing antifungal drugs that lack side effects in humans, effective therapeutic options to treat mycoses presently are limited [13].…”