Exotic animals are typically non-domesticated and non-indigenous to the geographical region they inhabit [1]. Fungal diseases are widespread and have led to the decline of multifarious exotic animals. Fatal dermatomycoses caused by Nannizziopsis spp. have been reported in captive reptiles, despite treatment with antifungals [2]. Dermatomycoses such as those caused by the fungal complex Chrysosporium anamorph of Nannizziopsis vriesii (CANV) are emerging infectious diseases in reptiles, with increasing prevalence and spread across geographical regions and, unfortunately, increasing antifungal resistance patterns [3]. Likewise, the most common fungal disease in avians, aspergillosis, has a high mortality rate [4]. Other than the avian anatomical and physiological characteristics which predisposes them to aspergillosis, azole resistance, especially in Aspergillus fumigatus, is a rising global concern requiring stricter epidemiological surveillance to reduce treatment failures [5]. Limited studies were collated for other fungal diseases, such as candidiasis and cryptococcosis, in avians. Candida albicans is the most notorious pathogen for candidiasis, while the pathogenic agents for cryptococcosis are Cryptococcus neoformans and Cryptococcus gattii [6]. Although some antifungals were studied for candidiasis and cryptococcosis, the sample sizes were not statistically significant for recommendations to be made. With rising mortality and morbidity rates in these exotic animals, there is a need to refine the currently inadequate armamentaria of antifungals used in the treatment of fungal diseases.

Antifungals are often used in the treatment of fungal diseases in exotic animals to eliminate fungal pathogens and resolve clinical symptoms. Different classes of antifungals such as azoles, allylamines, echinocandins, nucleoside analogues and polyenes with different mechanism(s) of actions have been used [7]. Veterinarians commonly adopt recommendations from formularies such as the Exotic Animal Formulary (EAF) to guide dosing regimens of antifungals. Due to the lack of pharmacological data in some exotic animals, such as those from the crocodylia or phoenicopteriformes order, veterinarians often extrapolate doses from closely-related or sometimes even distantly related species. This may not be ideal due to marked interspecies differences in metabolic rates and physiological features, even within closely-related species, which may affect the pharmacological profile of antifungals and ultimately therapeutic outcomes. When inappropriate dose extrapolations are made, suboptimal treatment outcomes may arise in the form of increased risk of toxicity, subtherapeutic dosing or treatment failure, subsequently contributing to the decline of exotic animals [8].

Seventy studies or case reports on the efficacy and/or safety of antifungals in avians were found, with itraconazole (n = 20) and voriconazole (n = 17) being the most commonly used antifungal, especially in Psittaciformes and Sphenisciformes. In reptiles, 30 such reports were found, with itraconazole (n = 13), terbinafine (n = 5) and voriconazole (n = 5) being the most commonly used antifungal, especially in Squamata. 

Clinical resolution of lesions or symptoms are often used to assess the efficacy of antifungals in treating fungal diseases. Objective measures of efficacy include the use of MIC data to determine the susceptibility of fungal pathogens to antifungals, or to maintain therapeutic plasma concentrations above MIC. Determination of MIC of fungal isolates were limited and often relied upon comparisons with reported values in human studies or other related species. AST is recommended, when possible, to attain specific MIC values, especially for causative pathogens with MIC yet to be determined and also to look out for emerging resistance patterns.

The type of fungal pathogens is pivotal in the selection of antifungals to optimise treatment efficacy in exotic animals. The evaluation on the use of different antifungals for the more common fungal diseases in avian and reptiles are summarised in Table 2 and Table 3.

Aspergillosis commonly involves the respiratory tract, with Aspergillus fumigatus being the most common causative pathogen. Voriconazole appears to be efficacious in treating Aspergillus fumigatus infections in Japanese quails and racing pigeons (Table 2), and the large sample size provides further credibility. AST conducted on racing pigeons revealed an MIC of 0.25µg/mL for Aspergillus fumigatus, showing susceptibility to voriconazole, which could explain the efficacy observed. However, not all studies performed AST, and many used MIC data from other species to evaluate the efficacy of antifungals [32]. Additionally, Aspergillus fumigatus can be easily confused with more than 11 other Aspergillus spp. based on their conidial morphology [33], including Aspergillus lentulus, which is typically known to be resistant to triazoles and amphotericin B [34]. Accurate identification of the causative pathogen and its susceptibility to different antifungals is crucial to ensure efficacy in treatment. AST is recommended, especially for severely ill exotic animals, where time is critical and using antifungals that are resistant to the causative fungal isolates may result in poor clinical outcomes.

For Aspergillus flavus infections, itraconazole proved efficacious in turkeys by reducing the lung lesion score (Table 2). In Okinawa rails, however, though MIC revealed susceptibility of Aspergillus flavus to itraconazole, inefficacy was observed, possibly due to low concentrations in the air sacs. Voriconazole might also be efficacious for Aspergillus flavus infections, but this is inconclusive due to the small sample sizes of studies.

CANV infections in reptiles are the rising cause of mortality, especially in bearded dragons (n = 7) [35], which also have the most studies/case reports collated (Table 3). Numerous pathogens under the CANV denomination were identified and have been subsequently renamed to include three genera: Nannizziopsis spp., Ophidiomyces spp. and Paranannizziopsis spp. Formerly termed “yellow fungus disease” has been replaced by “nannizziomycosis” and “paranannizziomycosis”; thus, careful interpretation of older literature is warranted [3]. With the limited reports of antifungal therapy in CANV-related infections, itraconazole did not show efficacy in most reptiles, except the tuataras infected by Paranannizziopsis spp. (Table 3). In a direct comparison study, voriconazole demonstrated better efficacy in clearing CANV infection and had a higher survival rate (Table 3). In another giant girdled lizard, voriconazole used at the same dose cleared CANV infection and AST revealed the lowest MIC (0.25µg/mL) for voriconazole amongst the other antifungals tested [36]. Hence, voriconazole shows promising potential for the treatment of CANV infections, but further studies should be conducted in other reptile species to ensure the efficacy and safety of the dosing regimens [36].

Ophidiomycosis, previously termed “snake fungal disease” appears to only cause disease in snakes, though the reasons are unclear [3]. Studies on antifungal therapy for ophidiomycosis are scarce, with inconclusive efficacy (Table 3). Unconventional methods with terbinafine using subcutaneous implants and nebulization have been described to be possibly efficacious based on plasma-concentration studies, but further studies on actual diseased snakes are required to confirm these findings. Such methods are preferred, especially when venomous snakes are involved and also due to their bimonthly feeding, which makes oral administration of antifungals unfavourable [37]. Though voriconazole may also be a possible option, efficacy is unclear.

While MIC data is important for assessing efficacy, efficacy is not guaranteed, even when the pathogen is susceptible to the antifungal in vitro. Other reasons for the lack of efficacy may be insufficient concentrations at the site of infection, acquired resistance, interspecies differences affecting the disposition of antifungals, or poor condition of species at initial presentation. Such factors should also be considered when assessing the efficacy of antifungals.

The site of infection plays a crucial role in the selection of appropriate antifungals. Fungal diseases in reptiles commonly occur in the cutaneous layers, and their much thinner hypodermis can predispose them to subsequent invasion of deeper tissues, such as the bones or muscles, requiring systemic antifungals [38]. The common sites of infection in avians preferentially involve the respiratory tract, possibly because the primary route of fungal invasion is via inhalation [39].

Tissue concentrations of antifungals are more clinically relevant and reflective of the efficacy of the antifungal rather than the plasma concentrations, though they are not commonly measured in PK studies. A typical dose of itraconazole 10 mg/kg seems to be efficacious in different species, such as the African grey parrots and red-tailed hawks, but not in Okinawa rail or Pesquet’s parrots (Table 2). A possible reason for this could be that the tissue concentrations were not high enough to eliminate the fungal pathogens. In mallard ducks and racing pigeons, itraconazole concentrations in lung and brain tissues were the lowest, and it was posited that a significantly higher dose would be required to have a fungicidal effect in lung tissues [39,40]. Voriconazole tissue concentrations were not measured in any studies during our search. In reptiles, the keratinophilic nature of terbinafine makes it ideal for the treatment of dermatomycoses, due to accumulation in keratinized tissues [41].

Tissue concentration studies were scarce, and future studies should focus on methods to predict tissue concentrations with plasma concentrations in specific species to better assess the therapeutic efficacy of antifungals.

Species-specific data are crucial when assessing the safety of antifungals. Itraconazole, voriconazole and terbinafine had more extensive safety data reported in avians and reptiles. Variable manifestations of neurotoxicity were observed for voriconazole in the form of lethargy, anorexia, ataxia and seizure-like symptoms in multiple penguin species such as Humboldt, African or Macaroni penguins, hind limb paresis in red-eared slider turtles and torticollis in cottonmouths, but not in African grey parrots or Japanese quails, despite using significantly higher doses. Possible hepatotoxicity from voriconazole administration was seen in the form of mild increases in aspartate aminotransferase in African grey parrots and a few inland bearded dragons. Similar adverse events have been observed in humans, and high trough concentrations are reported to increase the risk of neurotoxicity and hepatotoxicity [42], though the target trough concentrations in specific exotic species are unclear. Adverse events in itraconazole were observed as hepatotoxicity mainly in the form of increases in aspartate aminotransferase in bearded dragons and a Parson’s chameleon, but not in tuataras, despite being given similar doses. Terbinafine was generally found to be safe in both avians and reptiles. For the other antifungals, there were either no adverse events reported or insufficient sample sizes to evaluate safety accurately.

Though many single-dose studies reported no adverse events, safety cannot be accurately concluded as toxicity may sometimes only be observed upon chronic administration. This was evident in the numerous penguin species which showed neurotoxicity in multiple-dosing regimens but not in single-dosing regimens. Furthermore, the deranged physiology in immunocompromised animals may further predispose them to adverse events that healthy animals are not subjected to. Adverse drug reactions may be unpredictable and therefore hard to predict in specific species [43]. Hence, close therapeutic drug monitoring is recommended, especially for the azoles, to ensure safe dosing regimens.