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Aspects of the pharmacokinetics of itraconazole and voriconazole in the tuatara (Sphenodon punctatus) and application in the treatment of an emerging fungal disease

Alexander, Sarah (2017) Aspects of the pharmacokinetics of itraconazole and voriconazole in the tuatara (Sphenodon punctatus) and application in the treatment of an emerging fungal disease. Professional Doctorate thesis, Murdoch University.

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Abstract

Tuatara (Sphenodon punctatus) are unique, cold-adapted reptiles endemic to New Zealand. Recently, captive tuatara have been found to be affected by an emerging fungal pathogen, Paranannizziopsis australasiensis. P. australasiensis causes dermatitis in tuatara, and has caused fatal systemic mycosis in a bearded dragon (Pogona vitticeps), and in aquatic file snakes (Acrochordus spp). The discovery of P. australasiensis infections has prevented the release of tuatara from several captive institutions to offshore islands, and has negative implications for the long-term health and welfare of the animals.

A review of the literature revealed that infections caused by organisms related to P. australasiensis are being recognised worldwide as emerging pathogens of reptiles. Little is known about the epidemiology of these often-fatal infections, and treatment with a range of antifungals has met with varying success. There has been little research on antifungal use in reptiles, and none on how environmental temperature affects the pharmacokinetics of antifungals.

This study investigated the microbiological characteristics of P. australasiensis, primarily the growth rate of the fungus at different temperatures, and the Minimum Inhibitory Concentration (MIC) of various antifungal agents for P. australasiensis. It was determined that the optimal growth temperature for P. australasiensis encompasses the range from 20oC-30oC, with scant growth at 12oC, moderate growth at 15oC, and no growth at 37oC. The MICs of antifungals were tested at room temperature and at 37oC, and were not found to be significantly different. MICs of itraconazole and voriconazole for three isolates of P. australasiensis were found to be low, at 0.12mg/L for itraconazole and <0.008mg/L for voriconazole.

The single and multiple dose pharmacokinetics of itraconazole and voriconazole in tuatara were investigated at 12 and 20oC; these are the high and low ends of the tuatara’s preferred optimal temperature zone (POTZ). Results showed statistically significant differences in antifungal elimination half-life between temperatures. With the aid of population pharmacokinetic modelling, optimal dosing regimes for both antifungals were developed for tuatara of different weights. It was established that tuatara should be treated at 20oC, at the high end of POTZ, to facilitate rapid attainment of therapeutic antifungal concentrations, improve clinical outcomes and reduce the risk of adverse effects.

While itraconazole demonstrated more predictable pharmacokinetics than voriconazole in tuatara, itraconazole treatment was associated with significant adverse effects. These included elevated bile acids and uric acid concentrations, and weight loss. While voriconazole appears to be safer, its pharmacokinetics are less predictable, with high inter-individual variability in tuatara administered the same dose rate (a phenomenon also observed in humans). While voriconazole may be a useful antifungal in clinically affected tuatara where dosage can be adjusted based on the response to treatment, its use in an asymptomatic quarantine setting may be limited. The use of higher voriconazole doses may increase the likelihood of maintaining therapeutic concentrations in all treated animals, however the risk of adverse effects increases concomitantly. Furthermore, there are currently no published reports of successful treatment of P. australasiensis in tuatara with voriconazole.

This study also established haematologic and biochemical reference ranges in a group of tuatara. These demonstrated variability in several parameters based on sex and season, and will be a useful tool for assessing health and disease in these and other tuatara.

Publication Type: Thesis (Professional Doctorate)
Murdoch Affiliation: School of Veterinary and Life Sciences
Supervisor: Warren, Kristin
URI: http://researchrepository.murdoch.edu.au/id/eprint/39938
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