Session #3001
Abstract
The use of antifungal drugs in birds is characterized by major challenges such as a large interspecies and interindividual variability in the pharmacokinetics, which can significantly affect drug safety and efficacy, and limited knowledge on avian antifungal treatment protocols. Therefore, different factors need to be considered in the rational drug selection of antifungal therapy in birds. This masterclass is aimed to provide insight into the interrelation of antifungal drug formulation, administration route, therapeutic-toxic range, antifungal resistance, and treatment outcome in fungal diseases, focusing in particular on aspergillosis in birds. The antifungal activities of the three major antifungal drugs used in avian medicine, azole derivatives, polyenes, and allylamines, are related to the synthesis or direct interaction with ergosterol. Conventional antifungal therapies in avian medicine are frequently associated with a lack of efficacy and high toxicity. Innovative drug formulations can help to reduce the intrinsic toxicity and enhance efficacy. Because the majority of systemic fungal infections require long-term therapy, oral administration of antifungal drugs is preferred, with intravenous administration being reserved for the initial phase of treatment in cases of acute aspergillosis or severely debilitated birds. Finally, alternative treatment strategies including topical administration of antifungals, such as through nebulization, and combining different antifungal drugs in treatment protocols show promising results in birds.
Introduction
An antifungal drug is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis, such as aspergillosis, megabacteriosis, and candidiasis. The use of antifungals in birds is characterized by interspecies and interindividual variability in the pharmacokinetics, affecting drug efficacy and toxicity. In the last decades, newer and less toxic antifungals, including the azoles and echinocandins, have been developed. Aside from the chemical structure, treatment safety is also affected by antifungal drug formulation, route, and frequency of administration; however, the knowledge of avian antifungal treatment is limited, therefore treatment protocols are often developed empirically, based on case reports or extrapolated from humans or other animal species. Rational usage of antifungal drugs in avian species is much more than only selecting an appropriate dosage.1 The objective of this masterclass is to discuss the mechanism of action and toxicity of different antifungal drugs, the impact of different formulations and drug delivery strategies on antifungal treatment, antifungal resistance, and some practical guidelines on administration and treatment.
Mechanism of Action of Different Antifungals
The mechanism of action of all three major groups of antifungal agents used in avian practice (i.e., polyenes, azole derivatives, and allylamines) involves the inhibition of synthesis or direct interaction with ergosterol, the predominant component of the fungal cell membrane. The polyene macrolide antibiotics, such as amphotericin B, nystatin, and pimaricin (or natamycin), act primarily by binding to ergosterol and forming pores in the plasma membrane, increasing membrane permeability, eventually leading to cell death. Polyenes can be fungistatic or fungicidal, depending on the dosage. Polyenes have a broad antifungal spectrum, including a variety of yeasts (e.g., Macrorhabdus ornithogaster, Candida spp., Rhodotorula spp.) and molds (e.g., Aspergillus spp., Mucor spp., Penicillium spp.). Azoles inhibit the enzyme cytochrome P450-dependent 14α-sterol demethylase, a key enzyme in ergosterol biosynthesis, resulting in a disruption of fungal membrane structure and function. Azoles are classified into two groups: the imidazoles with two nitrogens in the azole ring (such as clotrimazole, miconazole, enilconazole, and ketoconazole) or triazoles (such as itraconazole, fluconazole, posaconazole, and voriconazole). Most azoles have a broad-spectrum activity against most yeasts and filamentous fungi, and except voriconazole, most azoles used in avian medicine are fungistatic at the doses used in birds and need several days to reach steady-state concentrations. Allylamines, such as terbinafine, inhibit the enzyme squalene epoxidase, resulting in an ergosterol depletion and squalene accumulation. Allylamines have fungicidal activity against dermatophytes, molds, and certain dimorphic fungi and fungistatic activity against yeasts.1,2
Besides the antimicrobial agents affecting fungal sterols, inhibitors of glucan synthesis, such as echinocandins (e.g., caspofungin, micafungin, and anidulafungin), also affect the fungal cell wall. Echinocandins exhibit fungicidal activities against Candida spp., but are fungistatic for Aspergillus spp. Finally, 5-fluorocytosine is a fluorinated pyrimidine with inhibitory activity against many yeasts, including Candida spp. and Cryptococcus neoformans, and against Aspergillus spp.1,2
Toxicity
Amphotericin B is characterized by a dose-dependent nephrotoxicity in mammals as a result of renal vasoconstriction, reduced glomerular filtration rate, and direct toxic effect on the membranes of the renal tubule cells. In contrast to mammals, nephrotoxicity is lessened in birds due to their faster elimination rate; however, systemic use of amphotericin B deoxycholate should be limited and reserved for severe cases of aspergillosis. Nystatin is used primarily to treat Candida infections of mucosa, skin, and the gastrointestinal tract. Nystatin should not be given if gastrointestinal epithelium is not intact as systemic absorption may occur.1
The most common observed side effects associated with azole administration in avian patients are gastrointestinal signs, such as anorexia and vomiting, and liver dysfunction. Toxicity of azoles is associated with the drug-specific binding to the fungal cytochrome P450 enzyme instead of the vertebrate analogue. In general, azoles are well tolerated in birds; however, remarkable species differences are observed. The apparent sensitivity to azoles experienced by different bird species might be explained by differences in the drug’s pharmacokinetics.1,2 Of the imidazoles, enilconazole and clotrimazole rarely cause side effects when used topically; however, in humans it has been reported that clotrimazole induces edema, erythema, vesication, desquamation, pruritus, and urticaria after cutaneous application. Prudent usage of ketoconazole is recommended since adverse liver, renal, gastrointestinal, and circulatory side effects have been reported following parental application.2
The use of terbinafine is generally associated with limited side effects. These side effects can include mild gastrointestinal symptoms and hepatobiliary dysfunction.3
Drug Formulation
Several antifungal drugs are characterized by their insolubility in water at physiologic pH, poor oral bioavailability, and limited formulation approaches. Different formulations and drug delivery strategies have been developed to improve the antifungal pharmacokinetics with targeted delivery, rapidly followed by sustained release and prolonged retention of high drug concentration localized at the infection site. For example, to reduce the intrinsic toxicity and to enhance efficacy of amphotericin B, different lipid formulations have been developed (i.e., amphotericin B lipid complex, liposomal amphotericin B, and amphotericin B colloidal dispersion).1,4 However, in-depth information on the pharmacokinetics, pharmacodynamics, and clinical use of amphotericin B lipid formulations in birds is lacking. In addition, nanotechnology holds great promise to overcome the limitations of antifungal drug solubility and toxicity. In falcons, it was demonstrated that itraconazole-loaded nanostructured lipid carriers penetrate deeply in the lungs and air sacs, which is a prerequisite for pulmonary treatment of aspergillosis.5
Drug Resistance
Antifungal susceptibility testing may be helpful for monitoring therapy in avian species. Acquired resistance of A. fumigatus strains, isolated from companion and wild birds, is reported for amphotericin B, itraconazole, voriconazole, and caspofungin. With even some isolates being resistant to more than one antifungal drug.6 Although historically used, significant resistance of C. albicans to itraconazole has been reported. Finally, evidence of nystatin and of amphotericin B resistance in Macrorhabdus ornithogaster have been reported.7
Combined Antifungal Treatment
Treatment of fungal diseases is often complicated by poor response and high toxicity. Therefore, double-drug combinations might be promising to enhance efficacy. For example, synergistic interaction between terbinafine and itraconazole has been observed in vitro for A. fumigatus, resulting in a reduced MIC and MFC.8 However, since amphotericin B and the azoles target the same site, simultaneous administration might result in an antagonistic interaction, where azoles prevent the synthesis of ergosterol, making the amphotericin B that usually binds the ergosterol in the cell membrane inactive. In avian medicine, the use of certain aerosolized disinfectants such as F10 (a blend of quaternary ammonium and biguanide compound; Health and Hygiene (Pty) Ltd, Johannesburg, South Africa) and lufenuron has been reported as an effective addition to the inhalation therapy with azoles (e.g., enilconazole), but scientific studies on the safety and efficacy of these substances are lacking.9 Finally, different routes of administration can also be combined, such as systemic triazole therapy (itraconazole or posaconazole) combined with inhalation therapy or topical intranasal clotrimazole or enilconazole.10
Practical Guidelines on Administration and Treatment
Drug selection and administration route is mainly dependent on the course and the severity of the disease. Depending on the drug formulation, antifungal drugs need to be given regularly, once (q 24 h) or twice (q 12 h) daily, to achieve a systemic effect. In most cases, treatment needs to be continued for at least 3–4 weeks, in severe cases for 3 months or even longer. Furthermore, a combination of several approaches is usually required. Antifungal drugs may be administered orally, via nebulization, intratracheally, intramuscularly, subcutaneously, intravenously, and topically on fungal lesions.
Oral treatment is the most common drug application for systemic treatment of aspergillosis or microsporidia infections as well as for the treatment of gastrointestinal yeast. For the treatment of aspergillosis, the oral formulations of itraconazole and voriconazole are mostly used, which are reabsorbed from the gastrointestinal tract following oral administration. In contrast, gastrointestinal yeast infections, such as Candida spp. and megabacteria (Macrorhabdus ornithogaster) infections, are usually treated with formulations which are not absorbed from the gastrointestinal tract but act locally.2
Nebulization of antimycotic drugs (e.g., amphotericin B, terbinafine, or the triazole drugs enilconazole and clotrimazole) has been regularly reported for the treatment of aspergillosis and is a valuable and stress-free addition to the therapeutic regime in absence of major side effects. The antifungal medication is mixed with saline solution and nebulized using a commercial inhalation device, providing sufficiently fine and respirable aerosol droplets, able to enter air capillaries.1,2,11,12
In severe cases of systemic fungal infections, antifungal drugs may also be administered parenterally via the subcutaneous, intramuscular, or intravenous routes. Likewise, parenteral injections are an alternative administration route to oral medication in patients with vomiting or regurgitation, those with acute courses of aspergillosis, or individuals with unusual localizations of fungal infections (e.g., in joints, bones, or the spinal cord). Parenteral solutions are available for amphotericin B, fluconazole, and voriconazole, but the therapeutic effect of fluconazole against Aspergillus spp. has been reported to be low. Voriconazole has been used in recent years successfully in various species, with less side effects and larger clinical utility compared to amphotericin B; however, a faster onset of therapeutic action has been reported for amphotericin B compared to the triazole drugs. This may explain why this agent is often used in the initial phase of medical therapy of aspergillosis but not for a prolonged period.1
Topical administration of antifungal drugs by applying injectable solutions directly to the fungal lesion is suggested in addition to nebulization for the treatment of fungal lesions inside the trachea or syrinx. Therefore, parenteral solutions such as amphotericin B or voriconazole may be applied intratracheally, orthograde via the glottis using plastic catheters. In some cases of tracheal aspergillosis, also surgical debridement may be required. Likewise, topical treatment and surgery may be required for the treatment of air sac aspergillomas. Furthermore, a topical antifungal treatment may also be applied to the mucous membranes of the oropharynx in cases of candidiasis, to the outer skin and feather follicles in cases of fungal dermatitis and folliculitis, as well as to eyes and nose in cases of ocular fungal infection, rhinitis, or sinusitis.1
Finally, ocular fungal infections including diseases of conjunctiva, cornea, and/or anterior eye chamber are treated using antifungal eye drops, even though they are usually not commercially available but may be prepared by a pharmacist on request. Similar formulations may be used for the treatment of fungal rhinitis and sinusitis in addition to inhalation therapy and systemic antifungal medication; however, nasal flushes using enilconazole or F10 SC solutions have been reported as beneficial additions to the treatment of fungal rhinitis and sinusitis.9
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Adapted from: Antonissen G, Martel A, Fischer D. Antifungal drugs. In: Current Therapy in Avian Medicine and Surgery. Elsevier; In prep.
References
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