Antifungals Used in Exotic Avian and Reptile Species

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1		Shangzhe Xie	--	7173	2023-08-10 03:30:47	\|
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3	layout	Jessie Wu	Meta information modification	7173	2023-08-10 05:21:08	\|

This entry is adapted from the peer-reviewed paper 10.3390/jof9080810

Exotic animals are typically non-domesticated and non-indigenous to the geographical region they inhabit. 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. 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. Likewise, the most common fungal disease in avians, aspergillosis, has a high mortality rate.

antifungal avian efficacy exotic species fungal diseases pharmacodynamic pharmacokinetic reptile safety

1. Introduction

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].

2. Pharmacodynamic Variabilities in Avians and Reptiles

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.

2.1. Evaluation of Dosing Regimens in Relation to Efficacy

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.

2.1.1. Type of Fungal Pathogens/Disease

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 1 and Table 2.

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 1), 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 ^[9]. Additionally, Aspergillus fumigatus can be easily confused with more than 11 other Aspergillus spp. based on their conidial morphology ^[10], including Aspergillus lentulus, which is typically known to be resistant to triazoles and amphotericin B ^[11]. 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 1). 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) ^[12], which also have the most studies/case reports collated (Table 2). 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 2). In a direct comparison study, voriconazole demonstrated better efficacy in clearing CANV infection and had a higher survival rate (Table 2). 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 ^[13]. 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 ^[13].

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 2). 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 ^[14]. 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.

2.1.2. Site of Infection

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 ^[15]. The common sites of infection in avians preferentially involve the respiratory tract, possibly because the primary route of fungal invasion is via inhalation ^[16].

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 1). 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 ^[16]^[17]. Voriconazole tissue concentrations were not measured in any studies during the search. In reptiles, the keratinophilic nature of terbinafine makes it ideal for the treatment of dermatomycoses, due to accumulation in keratinized tissues ^[18].

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.

2.2. Evaluation of Dosing Regimens in Relation to Safety

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 ^[19], 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 ^[20]. Hence, close therapeutic drug monitoring is recommended, especially for the azoles, to ensure safe dosing regimens.

Table 1. Summary of efficacy and safety data in avian species accompanied by a critical analysis of the study findings.

Site of Infection	Antifungal Used	Dosing Regimen	Species	Evaluation of Dosing Regimens in Relation to Efficacy and Safety	References
Aspergillus spp.^a
Respiratory tract	Clotrimazole Itraconazole	10 mg/mL NEB SID for 30–45 min on 3 day on–2 day off schedule PO 10 mg/kg SID × 1 month	African grey parrots (n = 1) Citron-crested cockatoo (n = 1) Gyrfalcon (n = 1) Red-tailed hawk (n = 1) Yellow-naped Amazon (n = 1)	Clotrimazole: • Efficacy observed for all species studied. • Common mild adverse event of regurgitation for citron-crested cockatoo and Yellow-naped Amazon. • Potential for clotrimazole nebulisation to be efficacious for aspergillosis in avians. Despite small sample size, efficacy was apparent for a range of avian species from different avian orders. Itraconazole: • Efficacy in terms of responsiveness to treatment. However, there was no specificity as to how efficacy was seen (e.g., resolution of lesions, improvement of symptoms, etc.). Hence, such efficacy data may be less reliable. • Safety observed.	^[21]
Respiratory tract	Amphotericin B Flucytosine	Intratracheal 1 mg/kg BID × 3 days IV 1.5 mg/kg TID × 3 days NEB 1 mg/mL of saline BID × 20 days PO 120 mg/kg QID × 20 days	Gyrfalcon (n = 1)	• Efficacy in terms of stabilisation of condition was not specific enough to accurately assess efficacy of amphotericin B in treating aspergillosis. • Safety observed.	^[21]
Respiratory tract	Amphotericin B	NEB 1 mg/mL of saline BID × 31 days	Yellow-naped Amazon (n = 1)	• Efficacy in terms of dramatic response to therapy was not specific enough to accurately assess efficacy of amphotericin B in treating aspergillosis. • Safety observed.	^[21]
NR	Clotrimazole	NEB 40 mg for 1 h a day	Micronesian kingfisher (n = 1)	• Efficacy and safety observed.	^[22]
NR	Fluconazole	PO 15 mg/kg q12 h × 5–75 days	African grey parrots (n = 23)	• Efficacy and safety observed.	^[23]
Eyelids, head	Itraconazole Miconazole	PO 15 mg/kg q12–24 h × 3 months Topical BID on lesions	Falcon peregrinus × Falcon rusticolus (n = 1)	• Efficacy and safety of itraconazole was observed when given PO 15 m/kg q12 h. • Efficacy and safety of miconazole was not reported.	^[24]
NR	Itraconazole	PO 10 mg/kg SD	Lesser flamingo (n = 17)	• Efficacy was inconclusive because it was a single-dose study. Multiple dosing should be conducted as they are more clinically relevant. • Large sample size supports safety of itraconazole in lesser flamingo.	^[25]
NR	Voriconazole	PO 12.5 mg/kg q12 h × up to 91 days	Gyrfalcons × peregrine falcon hybrid (n = 1) Saker falcons (n = 2)	• Efficacy was not reported. • Safety was observed.	^[26]
NR	Voriconazole	PO 20 or 40 mg/kg SD	Japanese quail (n = 38 for each dosing)	• Efficacy and safety were observed.	^[27]
Respiratory tract	Amphotericin B	IV 0.5–0.75 mg	Prairie falcons (n = 2)	• Lack of efficacy might be due to critical condition for falcons at initial presentation, and not the inefficaciousness of amphotericin B.	^[28]
Respiratory tract and hematogenous involvement	Flucytosine	PO 60 mg/kg BID	Crested wood partridges (n = 4)	• Lack of efficacy was observed. • Safety was not reported.	^[29]
^a Evaluation of antifungal therapy: • General site of infection was observed to involve the respiratory tract. • Although only two papers were collated on clotrimazole nebulisation, the studies showed efficacy of the drug in a range of avian species. Together with only mild adverse events observed across species, clotrimazole might be a potential antifungal for treating respiratory aspergillosis. Use of clotrimazole has not been widely studied, hence more studies can be conducted to assess its efficacy and safety. • Fluconazole showed efficacy and safety in African grey parrots and Falcon peregrinus and Falcon rusticolus. Large sample size in the study on African grey parrots further supports fluconazole’s efficacy and safety in treating aspergillosis in avian species. Site of infection was not reported. • Voriconazole showed efficacy in the study on Japanese quails where a large sample size was used, but the site of infection was not reported. Voriconazole showed safe use in Japanese quails and falcon species. Hence, it is likely to be safe when used to treat aspergillosis in avian species. However, more studies are still needed to assess its efficacy and safety in other avian species. • There were insufficient data to assess the efficacy and safety for itraconazole, amphotericin B, flucytosine and miconazole in avian species.
Aspergillus flavus ^b
Lungs	Ketoconazole Enilconazole Itraconazole	PO 50 mg/kg PO 150 mg/kg Aerosol spray: 50 mg/kg PO 6 mg/kg	Turkeys (n = 20–40)	• Efficacy seen for PO itraconazole and enilconazole aerosol spray, where PO itraconazole was more efficacious because it resulted in the reduction of lesion score in both lungs and air sacs by more 90% and a lower re-isolation rate of fungi of 30% (trial 2). Enilconazole aerosol spray efficacy was seen in the reduction of lesion score in only the lungs (>50%), and re-isolation rate was 80–100%. • PO ketoconazole and PO enilconazole were inefficacious. • Safety was not reported.	^[30]
Air sac	Voriconazole Micafungin Itraconazole	IM 23.5 mg/kg q12–24 h SC 11.6 or 22.7 mg/kg q12–24 h PO 10 mg/kg q12 h × 162 days	Okinawa rail (n = 1)	• Lack of efficacy was observed despite the use of these three antifungals. • MIC testing was conducted, and the pathogen showed low susceptibility to voriconazole and micafungin. • Safety was not reported. • Likely reasons for the lack of efficacy of itraconazole, even though the fact that the pathogen showed susceptibility to itraconazole was not mentioned in the paper, might include the dose being too low or not high enough to reach the air sacs, the long-term nature of antifungal regimen might have resulted in antifungal resistance, or critical condition at initial presentation.	^[31]
^b Evaluation of antifungal therapy: • Based on the study on 40 turkeys, itraconazole proved its efficacy in reaching the lungs and air sacs. Even though safety was not reported, there is evidence that itraconazole is potentially a recommended antifungal for treating Aspergillus flavus infections. Even though itraconazole was inefficacious in treating the air sac infection in Okinawa rail, only one subject was studied. Voriconazole may still be efficacious, but due to the small sample size and critical condition of the rail at initial presentation, it showed inefficacy in treating the infection. • Enilconazole aerosol spray may be the next antifungal choice for treating Aspergillus flavus infection of the lungs in turkeys, but the route of administration is not as convenient as the oral route. However, oral enilconazole was seen to be inefficacious in the same study. • Hence, the most appropriate antifungal for treating Aspergillus flavus infection of the lungs in turkeys would be PO itraconazole. Because safety was not reported, more studies could be done to evaluate its safe use so that better antifungal recommendations can be made. • With only two papers on Aspergillus flavus infections, more studies should be conducted to assess the efficacy and safety of different antifungals, especially itraconazole, across different avian species.
Aspergillus fumigatus ^c
Pectoral muscle	Itraconazole Miconazole Amphotericin B (liposomal formulation)	PO 20 mg/kg q12 h × 50 days Topical twice weekly Topical 1.35 mg/kg q24 h × 30 days → discontinued for 15 days → q24 h × 14 days → every 3/4 days × 16 days → every 5–7 days × 60 days	Goliath heron (n = 1)	• Lack of efficacy for both PO itraconazole and topical miconazole. • Efficacy was observed when liposomally encapsulated amphotericin B was administered topically. • Liposomal formulation of amphotericin B has reduced nephrotoxicity and longer duration of activity related to conventional formulation.	^[32]
Trachea	Itraconazole	10% NEB SID for 30 min × 6 days 4% NEB SID for 30 min × 6 days	Japanese quail (n = 40)	• 10% suspension was more efficacious than 4% suspension. • Safety was observed for both suspensions. • 4% suspension was inefficacious, which is likely due to reduced deposition of itraconazole and hence reduced availability of parent drug for dissolution and metabolism to form the metabolite, hydroxy-itraconazole (OH-ITRA).	^[33]
Respiratory tract	Itraconazole	PO 10 mg/kg/day × 7 days	Japanese quail (n = 60)	• Reduction in mortality may not be a good marker for evaluating the efficacy of antifungal in treating fungal disease. • Safety was not reported.	^[34]
Trachea	Voriconazole	PO 20 mg/kg SD PO 20 mg/kg q24 h PO 40 mg/kg SD PO 40 mg/kg q24 h	Japanese quail (n = 76 for single dose) (n = 40 for multiple dose)	• Single dose (40 mg/kg): plasma concentrations remained above 0.5 µg/mL (concentration where improved treatment success was reported) for longer duration (12 h). • 40 mg/kg q24 h showed efficacy in terms of longer drug exposure, prolonged survival and fewer colony forming units, which was previously validated and discussed; safety was reported.	^[27]
Ocular	Voriconazole	Topical 1 drop OS q4–6 h PO 20 mg/kg q12 h × 35 days	Khaki Campbell duck (n = 1)	• PO voriconazole showed better efficacy than topical formulation due to better penetration into the cornea through the presence of corneal vascularisation in this case. • Mild toxicity was observed. • PO voriconazole was seen to be able to reach the physiologically privileged site (eye) in this case, hence this dosing regimen is likely to be efficacious for ocular Aspergillus Fumigatus infection in this species.	^[35]
NR	Voriconazole	PO 8 mg/kg SID → 5 mg/kg SID → 5 days on treatment followed by 2-day off period × several years	Magellanic penguin (n = 1)	• Safety was apparent when voriconazole was given via 5 days on–2 days off dosing regimen. Additionally, safety was observed even when this dosing regimen was used for several years, which shows the safety of voriconazole during long-term treatment. Multiple dosing or long-term dosing of antifungals are more clinically relevant. • Efficacy was unclear. • Because voriconazole has shown a range of variable toxicities across avian species, the use of n day on–n day off dosing intervals might be useful to avoid overdosing and toxicity issues.	^[36]
Respiratory tract, air sac	Amphotericin B	IM 2.0 mg/kg SID	Peruvian penguins (n = 1)	• Lack of efficacy was observed. • Safety was not reported.	^[37]
Lung	Voriconazole	PO 10 mg/kg q12 h × 14 days PO 20 mg/kg q24 h × 14 days	Racing pigeons (n = 10 for each dosing)	• MIC = 0.25 µg/mL (isolate was susceptible to voriconazole). • 10 mg/kg q12 h proved to be more efficacious than 20 mg/kg q24 h but toxicity was slightly more severe. • Shorter dosing interval might provide sufficient or high enough plasma concentrations (>0.5 µg/mL) to achieve therapeutic efficacy.	^[38]
^c Evaluation of antifungal therapy: • Liposomal amphotericin B might be efficacious for Aspergillus Fumigatus infection of the pectoral muscle in goliath heron but only one subject was studied. • Itraconazole (NEB/PO) and PO voriconazole (40 mg/kg q24 h) were observed to be efficacious and generally safe in treating Aspergillus Fumigatus infection involving the respiratory tract in Japanese quails. PO voriconazole (10 mg/kg q12 h) was efficacious in treating infection involving the lungs in racing pigeons but mild toxicity was reported. The large sample size in these studies improves the credibility of such data. Higher dose was used in Japanese quail than in racing pigeons, but no toxicity was observed. This is likely due to the interspecies differences across different avian species, even across closely-related species. • PO voriconazole might be a useful antifungal when Aspergillus Fumigatus infection involves physiologically privileged sites such as the eye. Efficacy was apparent in Khaki Campbell duck, but only one subject was studied. • PO voriconazole was safe, even when long-term dosing was administered to magellanic penguin. Long-term dosing of antifungals is more clinically relevant in the treatment of fungal diseases. Use of n day on–n day off dosing regimen may be useful in reducing the risk of accumulation, overdosing and toxicity, especially because voriconazole has shown variable toxicity across different avian and reptile species.
Candida albicans ^d
Respiratory tract	Nystatin Itraconazole Amphotericin B Fluconazole	PO 400,000 units/kg q12 h PO 10 mg/kg q12 h × 30 days Intralesional: 1 mg/kg NEB 1 mg/mL of saline for 15 min q8 h × 2 days PO 5 mg/kg q12 h × 1 month	Sun conure (n = 1)	• Bird improved clinically after initiating itraconazole and amphotericin B but repeat complete blood count 1 week later showed increased leucocytosis with increased heterophilia and monocytosis. • Based on the hematologic results, and amid concerns of drug resistance, treatment regimen was changed from itraconazole to fluconazole. • Isolated pathogen was susceptible to fluconazole, itraconazole and voriconazole. • Fluconazole showed efficacy in terms of significant signs of improvement (increased appetite, normal body weight). • Safety was not reported.	^[39]
Gnathotheca, mandibular bone	Itraconazole	PO 10 mg/kg q24 h × 10 days	Lesser flamingo (n = 1)	• Lack of efficacy was observed. • Safety was not reported.	^[40]
Proventriculus	Ketoconazole	PO 10 mg/kg q12 h × 3 weeks	Lesser sulphur-crested cockatoo (n = 1)	• Efficacy was observed. • Safety was not reported.	^[41]
Membrane nictitans, cornea	Amphotericin B Flucytosine	Topical, subconjunctival injection, PO (dosing NR) Parenteral: 400 mg/kg/24 h given as two divided doses over a period of 3 weeks	Barrow’s goldeneye, common scoter, red-breasted merganser, long-tailed duck (n = NR)	• Efficacy was observed when amphotericin B was given topically, provided the infection was not within the globe, but safety was not reported. • Flucytosine given via parenteral routes was efficacious, but no specific route of administration was mentioned. • Safety of Flucytosine was reported.	^[42]
^d Evaluation of antifungal therapy: • Papers collated only studied on Candida albicans for the candidiasis infection. • Fluconazole was efficacious in sun conure when pulmonary sites were involved, but only one subject was studied. • Ketoconazole was efficacious in Lesser-sulphur crested cockatoo when the site of infection was proventriculus, but only one subject was studied. • Amphotericin B was efficacious in a range of ornamental ducks when given topically when the site of infection did not involve the globe, but topical administration might not be feasible due to stress from excessive handling. • Flucytosine was efficacious and safe in ornamental ducks when the site of infection is the membrane nictitans and cornea, but the parenteral route of administration was not specified. Although the dosing regimen might be efficacious in these species, there is a need to confirm the route of administration for better recommendations to be made. Additionally, the number of subjects in the study was not mentioned, hence the efficacy and safety data may be less reliable. • As such, fluconazole, ketoconazole and flucytosine may be efficacious for the respective sites of infection, but more studies with larger sample size are needed to confirm their efficacy.
Cryptococcus neoformans ^e
Respiratory tract, globe, periocular tissues, and brain	Voriconazole	1 drop of 1% reconstituted topical ophthalmic drops OS q6 h	African grey parrots (n = 1)	• Efficacy in local (intraocular) fungal infections is unclear because of discontinuation within 5 days due to possible toxicity or systemic spread, hence systemic antifungal therapy is required. • Presented with ataxia, lethargy, anorexia and lack of ability to perch, which could be due to voriconazole toxicity or worsening disease due to systemic fungal invasion.	^[43]
Respiratory tract, globe, periocular tissues, and brain	Terbinafine Fluconazole	PO 20 mg/kg q12 h for 1 week → 15 mg/kg q12 h PO 15 mg/kg q12 h	African grey parrots (n = 1)	• Antifungal therapy may be efficacious depending on site and severity of infection. • Despite treatment for 1 month, radiographs still showed severe and progressive exophthalmos and buphthalmias and minimal changes to the coelomic mass. Cytologic examination of intraocular fluid revealed appearance consistent with Cryptococcus spp., even though fungal cultures were negative. • Though it was highly effective in decreasing the size of the air sac mass, it was not able to reduce the progression of the disease to the eye. • No adverse effects were reported.	^[43]
Respiratory tract, globe, periocular tissues, and brain	Amphotericin B Terbinafine Fluconazole	Intraocular infusion: 1.5 mg/kg 3 doses into the globe × 4 months PO 15 mg/kg q24 h PO 15 mg/kg q24 h	African grey parrots (n = 1)	• Antifungal therapy was generally inefficacious, despite mild improvements. • Even with intraocular infusion of amphotericin B, persistently elevated beta-globulin levels were observed (though improved from the previous measurement), showing continuous acute inflammation and radiographs showed a decrease in size of the coelomic mass. • Dosing intervals for terbinafine and fluconazole were increased to q24 h (from q12 h), after which exophthalmia and buphthalmia in the left globe of the eye continued to increase.	^[43]
Respiratory tract, globe, periocular tissues, and brain	Amphotericin B	IV 1.5 mg/kg	African grey parrots (n = 1)	• Antifungal therapy was generally inefficacious. • Some mild improvements in activity levels and response were present, but the bird eventually presented with seizures and died shortly after recovery, which was suggested to be due to fungal spread to the brain, causing seizures. Histopathological findings revealed Cryptococcus spp. in the cerebrum with multifocal areas of haemorrhage. • Given the poor penetration of amphotericin B into the cerebrospinal fluid (CSF) ^[44], insufficient tissue concentrations may have been reached in the CSF, leading to subtherapeutic treatment.	^[43]
Respiratory tract, globe, periocular tissues, and brain	Flucytosine Fluconazole	PO 150 mg/kg q12 h PO 15 mg/kg q24 h	African grey parrots (n = 1)	• Antifungal therapy was generally inefficacious. • Despite combination therapy, the size of the periocular swelling and swelling on the globe only decreased minimally, even though both flucytosine and fluconazole are able to penetrate into the vitreous and aqueous humours of the eye ^[44].	^[43]
^e Evaluation of antifungal therapy: • Interpretations are not statistically significant due to small sample sizes (n = 1), and there are scarce reports of the outcomes of antifungal therapy in different species. More studies on a larger sample size are required to assess the efficacy of such dosing regimens more accurately in these species. • Cryptococcus neoformans is an opportunistic pathogen which causes disease, mainly in immunocompromised birds due to their unfavourable high body temperatures for the growth of Cryptococcus spp. ^[43], unlike Cryptococcus gattii, which causes disease even in immunocompetent birds ^[43]. Given the severe disease of the African grey parrot at initial presentation, it is possible that the physiological derangements may have altered the disposition of antifungals and pharmacodynamic interactions of the antifungals. Poor treatment outcomes may have been due to deteriorating immune functions and not necessarily inefficacious antifungal therapy. • Inefficacy for amphotericin B may have likely arisen from low concentrations at the site of infection. • Flucytosine and fluconazole were used in combination to reduce the development of resistance ^[43]. Despite their wide distribution in tissues (including the eye), they were inefficacious in coping with the fungal load in the eye or preventing systemic spread to other tissues (brain). • Safety profiles from these dosing regimens are unclear as symptoms reported may have been due to the clinical deterioration of fungal disease rather than drug toxicity. • Recommendations on the dosing regimens to adopt in Cryptococcus infections remain inconclusive. Furthermore, Cryptococcus neoformans infections seem to be more invasive and result in disseminated infections, unlike Cryptococcus gattii spp., which would require potent systemic antifungals ^[45].
Cryptococcus neoformans var. gattii ^f
Beak, infraorbital sinus	Fluconazole	PO 8 mg/kg q24 h × 30 days	Goldie’s lorikeet (n = 1)	• Antifungal therapy was inefficacious due to resistance of isolate to fluconazole. • Agglutination tests showed Cryptococcus neoformans var. gattii to be of serotype B, and all strains were determined to be resistant to fluconazole. • Both birds died within 3 weeks of initiation of oral therapy. • Intralesional injections of fluconazole were administered with another biotherapeutic (Cryptococcus 30CH), which seemed to eliminate the gelatinous mass, and thus interpretations of the efficacy of fluconazole is inconclusive.	^[46]
Choana	Fluconazole	Intralesional injection 8 mg/kg SID × 30 days, → PO 8 mg/kg q24 h × 30 days	Papua lori (n = 1)		^[46]
Cryptococcus gattii ^f
Rhamphotheca of lower beak (and underlying bones), lungs, spleen, and brain	Fluconazole	PO 15 mg/kg q12 h	Citron-crested cockatoo (n = 1)	• Cryptococcus gattii VGIIA subtype. • Antifungal therapy was generally inefficacious. • Amongst the antifungals for susceptibility, fluconazole showed the highest MIC (50% inhibition) of 8 µg/mL. • Bird eventually died, and upon necropsy, disseminated infection to various tissues was concluded. • As plasma concentration studies were not performed, it is inconclusive if therapeutic concentrations were achieved in these species. • Safety was not reported.	^[47]
Humerus	Itraconazole	PO 10 mg/kg q24 h	Pesquet’s parrot (n = 1)	• Antifungal therapy was inefficacious. • Cryptococcus gattii sp. showed susceptibility to itraconazole (MIC: 0.125 µg/mL) but to fluconazole at a higher MIC (2.0 µg/mL). • Itraconazole plasma concentrations were found to be undetectable. • Inefficacy was postulated by the authors to be due to use of compounded itraconazole formulations which lack cyclodextrin, which typically facilitates absorption across the gut. Reduced drug absorption could explain the lack of detection of itraconazole in plasma.	^[48]
Humerus	Fluconazole	PO 10 mg/kg BID	Pesquet’s parrot (n = 1)	• Antifungal therapy was generally inefficacious. • No clinical progression of disease over the few months of therapy, and tracheal lesions reduced in size, but glottal lesions remained. • Though fluconazole plasma concentrations measured were above the MIC, bone biopsy revealed persistent cryptococcal infection. Knowledge on the site of infection is crucial, and the plasma concentration is not truly reflective of tissue concentrations.	^[48]
Humerus, Glottis, trachea	Fluconazole Flucytosine Fluconazole	PO 10 mg/kg q12 h PO 50 mg/kg q12 h PO 15 mg/kg q24 h	Pesquet’s parrot (n = 1)	• Fluconazole at lower doses + Flucytosine was minimally effective due to eventual increase in Cryptococcus latex agglutination titres despite an initial decrease. This change in titre values may have been due to resistance. Furthermore, flucytosine was not detected in plasma (0 µg/mL), which led to discontinuation and initiation of higher doses of fluconazole. • Efficacy and safety were observed when higher dose of fluconazole was used.	^[48]
Glottis, trachea	Amphotericin B	1 mg/kg topical administration via atomisation syringe of reconstituted 5 mg/mL injectable q24 h × 2 weeks → q48 h × 2 weeks	Pesquet’s parrot (n = 1)	• Localised therapy for the glottis and trachea, which reduced the lesions, but there was no complete resolution. • Safety was observed.	^[48]
^f Evaluation of antifungal therapy: • Interpretations are not statistically significant due to small sample sizes (n = 1), and there are scarce reports of the outcomes of antifungal therapy in different species. More studies on a larger sample size are required to assess the efficacy of such dosing regimens more accurately in these species. • Serology testing has shown different serotypes of Cryptococcus spp. with Cryptococcus neoformans and Cryptococcus gattii (Cryptococcus neoformans var. gattii is the former term for Cryptococcus gattii), which can also be further differentiated by molecular typing techniques into different genotypes ^[47]. The antifungal therapy used for these different subtypes varies and determining the Cryptococcus spp. causing fungal disease may guide decision making in selecting the appropriate antifungal to use. • Limited findings with fluconazole have shown resistance to Cryptococcus gattii spp. in psittacine birds ^[46]^[47], and it is not recommended because it is likely to result in poor therapeutic outcomes. Higher doses of fluconazole (15 mg/kg) showed efficacy in a Pesquet’s parrot but not in the Citron-crested cockatoo. However, this could have been due to a more severe disseminated infection in the Citron-crested cockatoo, especially because the dosing interval was shorter in the Citron-crested cockatoo. Another possible cause for the lack of efficacy in the Citron-crested cockatoo could be due to a more resistant isolate (higher MIC) than that in the Pesquet’s parrot. • Fluconazole is reported to reach physiologically privileged sites such as the brain and eye but lower concentrations in the bone ^[44]. Despite this, efficacy was poor in the Citron-crested cockatoo, where infections involved the brain. Bone biopsy showed Cryptococcus spp. present in the bone in the Pesquet’s parrot, but fluconazole was still useful in the treatment of cryptococcal infection. Hence, while site of infection is crucial, the severity of the disease can affect clinical outcomes, and veterinarians should be mindful of the clinical condition of the bird. Future studies should aim to elaborate on the dosing regimens with the severity of the disease in mind.

BID = twice daily; TID = thrice daily; IM = intramuscular; IV = intravenous; MIC = minimum inhibitory concentration; n = number of (animals); NEB = nebulization; NR = not reported; OS = left eye; PO = oral; QID = four times daily; SC = subcutaneous; SD = single dose; SID = once daily; spp. = species.

Table 2. Summary of efficacy and safety data in reptile species accompanied by a critical analysis of the study findings.

Site of Infection	Antifungal Used	Dosing Regimen	Species	Evaluation of Dosing Regimens in Relation to Efficacy and Safety	References
Chrysosporium anamorph of Nannizziopsis vriesii (CANV and related spp.) infections ^a
Chrysosporium anamorph of Nannizziopsis vriesii (CANV)
Skin	Itraconazole	PO 5 mg/kg q24 h + 1% topical silver sulfadiazine cream q12 h	Boa constrictor (n = 1)	• Lack of efficacy as snake still died after 3 weeks of itraconazole treatment. • Safety was not reported.	^[49]
Skin	Itraconazole	PO 5 mg/kg q24 h	Coastal bearded dragon (n = 1)	• Lack of efficacy as bearded dragon was euthanised due to persistent systemic mycoses, with several granulomas indicating the presence of fungal infections. • Safety was not reported.	^[50]
Skin	Itraconazole	PO 5 mg/kg q24 h	Inland bearded dragon (n = 7)	• Possibly efficacious as the fungus was not re-isolated from the dermal lesions after approximately 4 weeks in 2/7 of the bearded dragons. • 5/7 of the other bearded dragons did not survive, and upon post-mortem culture, CANV was cultured in 2/5 of these bearded dragons. • Possible drug toxicity was apparent.	^[51]
Skin	Itraconazole	PO 5 mg/kg q48 h × 14 days + 20 mg/kg SC ceftazidime q72 h × 12 days	Inland bearded dragon (n = 1)	• Efficacy was observed. • Safety was not reported.	^[12]
Skin	Itraconazole	PO 10 mg/kg q24 h × 6 weeks + 0.125% chlorhexidine topical solution	Inland bearded dragon (n = 1)	• Lack of efficacy was observed. • Possible drug toxicity was apparent.	^[12]
Skin	Itraconazole	PO 10 mg/kg q24 h × 10 weeks + daily baths in dilute povidone-iodine solution	Inland bearded dragon (n = 1)	• Lack of efficacy was observed. • Post-mortem examination revealed an extensive ulcerative dermatitis of the ventral abdomen and a focal hepatic granuloma. Bacterial rods and fungal hyphae were found within the granuloma.	^[12]
Systemic	Itraconazole	PO 10 mg/kg q24 h × 21 days	Jewel chameleon (n = 1)	• Lack of efficacy was observed. • Safety was observed during the course of treatment, but the duration of therapy was too short for toxicity to be observed.	^[52]
Skin	Itraconazole	PO 10 mg/kg q24 h × 21 days	Parson’s chameleon (n = 1)	• Possibly efficacious despite the general loss of condition, but the chameleon’s overall clinical condition improved months later. However, the chameleon still died a year later. Autopsy indicated that death was due to cholecystitis and septicaemia, and no evidence was mycosis was seen. • Possible drug toxicity was apparent.	^[52]
Skin	Voriconazole	PO 10 mg/kg q24 h	Giant girdled lizard (n = 1)	• Efficacy was observed. • Voriconazole had the lowest MIC upon antifungal susceptibility testing (0.25µg/mL) amongst the other antifungals tested. • Safety was observed.	^[13]
Skin	Voriconazole	PO 10 mg/kg q24 h	Inland bearded dragon (n = 7)	• Efficacy was observed. • Possible drug toxicity was apparent.	^[51]
Chrysosporium spp.
Skin	Ketoconazole	PO 20 mg/kg q24 h + 2% chlorhexidine solution + topical terbinafine	Green Iguana (n = 1)	• Efficacy was observed. • Safety was not reported.	^[53]
Skin	Ketoconazole	PO 20 mg/kg q24 h × 14 weeks + 2% chlorhexidine solution + topical terbinafine	Green Iguana (n = 1)	• Efficacy was observed. • Safety not reported.	^[53]
Nannizziopsis guarroi
Skin	Terbinafine	PO 20 mg/kg SD	Inland bearded dragons (n = 8)	• Efficacy was inconclusive. • Multiple-dosing studies on actual diseased bearded dragons are required to demonstrate efficacy. • Safety was observed.	^[54]
Paranannizziopsis australasiensis
Skin	Itraconazole	PO 5 mg/kg q24 h × 28 days + topical 1% terbinafine ointment × 21 days	Tuatara (n = 1)	• Efficacy was inconclusive. • Safety was not reported.	^[55]
Skin	Itraconazole	PO 5 mg/kg q24 h × 29 days	Tuatara (n = 1)	• Efficacy was observed. • Safety not reported.	^[55]
^a Evaluation of antifungal therapy: • Interpretations are not statistically significant due to small sample sizes and scarce reports of the outcomes of antifungal therapy in different species. More studies on a larger sample size are required to assess the efficacy of such dosing regimens more accurately in different reptile species. • Complications arise in the evaluation of therapeutic efficacy due to the changing nomenclature of CANV spp. Molecular testing has revealed numerous subgroups within CANV that are yet to be accurately identified ^[50]. In the past, identification of CANV-related species has also been confused with morphologically similar looking species, such as the Trichophyton spp. ^[50]. Hence, even with case reports showing efficacy for CANV-related infections, it is unclear if the fungal pathogens involved were indeed CANV-related spp. • Itraconazole has been widely used, with a typical dose ranging from 5 to 10 mg/kg in different reptile species. Lack of efficacy was observed for most of the species, and possible itraconazole-induced hepatoxicity was observed in bearded dragons and a Parson’s chameleon. However, it did seem to show efficacy in another distinctly related species, the tuatara, though the sample size was small. • Voriconazole seems to be much more potent in vitro (based on antifungal susceptibility testing) than itraconazole, and it also shows better therapeutic efficacy in bearded dragons and a giant girdled lizard. Though these findings are preliminary, voriconazole seems to have a better efficacy and safety profile than itraconazole. However, species-specific voriconazole toxicity has been observed and caution should be taken through close monitoring upon initiation of therapy. • Although ketoconazole seems efficacious, the small sample size (n = 1) in a single species, the Green Iguanas, the superior pharmacokinetics, and potency of voriconazole is still likely to make it the more favourable antifungal for the treatment of CANV-related infections.
Ophidiomyces ophiodiicola ^b
Skin	Itraconazole	10 mg/kg SD per cloaca	Cottonmouth (n = 7)	• Efficacy is inconclusive but predicted to be inefficacious as the therapeutic concentrations of itraconazole and hydroxyitraconazole (bioactive metabolite) in both plasma and tissues were not reached. • Multiple-dosing studies on actual diseased snakes are required to demonstrate efficacy. • No adverse events were observed.	^[56]
Skin	Voriconazole	SC 5 mg/kg SD	Cottonmouth (n = 6)	• Efficacy is inconclusive. Multiple-dosing studies on actual diseased snakes are required to demonstrate efficacy. • Even though two of the six the cottonmouths survived with no adverse events, the other four died and presented with a range of symptoms—lethargy, depression, loss of righting reflex, and even torticollis in one of the cottonmouths. This could be suggestive of potential voriconazole-induced neurotoxicity.	^[56]
Skin	Voriconazole	SC 10 mg/kg SD	Cottonmouth (n = 1)	• Efficacy is inconclusive. Multiple-dosing studies on actual diseased snakes are required to accurately predict efficacy in cottonmouths. • Safety was observed despite given a higher dose of voriconazole, but sample size (n = 1) is too small to make conclusions on the safety profile.	^[56]
Skin	Voriconazole	SC osmotic pump 22.2 mg/mL (1.02–1.6 mg/kg/h)	Eastern massasauga (n = 2)	• Efficacy was not observed. • However, sample size is too small to make any generalised conclusions on efficacy. • Safety was not reported.	^[56]
Skin	Voriconazole	SC osmotic pump 10 mg/mL (12.1–17.5 mg/kg/h)	Timber rattlesnake (n = 1)	• Efficacy is inconclusive. Therapeutic efficacy cannot be concluded due to small sample size. • Safety was not reported.	^[56]
Skin	Terbinafine	2 mg/mL (18 mg total dose) × 30 min via nebulisation	Cottonmouth (n = 7)	• Efficacy was inconclusive. • In vitro susceptibility concentration (0.015 µg/mL) was maintained for at least 12 h in four of the nebulized cottonmouths. The author recommends using a dose of 2 mg/mL (16 mg total dose) × 30 min via nebulisation once a day for the treatment of snake fungal disease. However, further studies need to be carried out to ensure that this recommendation is clinically relevant in actual diseased cottonmouths. • No adverse effects were observed, but all snakes non-significantly gained weight.	^[14]
Skin	Terbinafine	24.5 mg (75–190 mg/kg) SC implant cranial to midbody point	Cottonmouth (n = 7)	• Efficacy was inconclusive. • In vitro susceptibility concentration (0.015 µg/mL) was maintained for > 5 weeks in implanted snakes (peak concentration of 100 ng/mL at 3 weeks). The author recommends giving a 24.5 mg subcutaneous implant every 5–6 weeks for the treatment of snake fungal disease. However, further studies need to be carried out to ensure that this recommendation is clinically relevant in actual diseased cottonmouths. • No adverse effects were observed, but all snakes non-significantly gained weight.	^[14]
Mandible and eye	Ketoconazole	PO 50 mg/kg q24 h	Black ratsnake (n = 1)	• Reported as Chrysosporium ophiodiicola. • Efficacy was not observed. • Safety was not reported.	^[57]
^b Evaluation of antifungal therapy: • Interpretations are not statistically significant due to small sample sizes and scarce reports of the outcomes of antifungal therapy in different species. More studies on a larger sample size are required to assess the efficacy of such dosing regimens more accurately in different reptile species. • Therapeutic recommendations are unclear given the limited studies. Given that some of the studies were single-dose studies, efficacy cannot be concluded as the disposition of the drug may vary in multiple-dose studies and clinical disease state of the snake. • Voriconazole and terbinafine appear to be favourable options given that therapeutic plasma concentrations were reached when using different routes of administrations such as SC osmotic pumps or implants and nebulisation. These are especially critical in the treatment of venomous snakes as oral administration is not favourable given that they feed twice a month and the danger posed to the administrator (s10). SC implants are safer and more practical as the snake can be released back into the wild and be captured back weeks later to monitor the outcomes of the treatment. However, multiple-dose studies are required to supplement the results of the single-dose studies and determine if they are indeed appropriate for the treatment of snake fungal disease. • Voriconazole also appears to exhibit species-specific neurotoxicity, in this case the cottonmouths but not the Eastern massasaugas or Timber rattlesnake. Hence, caution needs to be made when using voriconazole in snakes as the mechanism of this toxicity is still unclear. Terbinafine might be favoured given its better safety profile, but the only studies available were in cottonmouths, and it is unclear if the same safety profile will be observed in other snake species. Nevertheless, it is recommended to closely monitor the snake upon drug administration, especially if voriconazole is being used.

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Naresh Visvanathan

Jolise Yi An Lim

Hui Ting Chng

Shangzhe Xie

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Update Date: 10 Aug 2023

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