Keith E. Baptiste Increasing incidences of fatal human fungal infections and rising antifungal resistance have become major global public health issues. Advances in patient management technologies and therapies such as bone marrow and solid organ transplants, new and more effective chemotherapeutic agents, more aggressive use of chemotherapy, and the rise in the numbers of immunocompromised patients (e.g., HIV infection, chronic disease) are all factors contributing to global increases in fungal infections in people. Similar factors are likely contributing to an increase in the incidence of fungal infections in domestic animals as well. Fungi are also emerging as important nosocomial pathogens causing considerable morbidity and mortality in hospitalized patients. In addition to immunosuppression, risk factors common to many hospitalized veterinary patients include malnutrition, indwelling catheters, and disruption of normal microbial flora by potent broad‐spectrum antimicrobial drugs. To highlight these global issues, the World Health Organization (WHO) has published a fungal priority pathogens list, noting that cases of invasive fungal disease are rising as at‐risk populations continue to expand (WHO, 2022). The list is focused on fungal pathogens responsible for acute, subacute systemic fungal infections for which drug resistance contributes to serious risk of morbidity and/or mortality. Four “critical threat” fungal pathogens were identified (Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, and Candida albicans). These fungi also cause disease in animals, along with Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis, and Cryptococcus neoformans. Of these, C. auris has received a lot of focus as a major public health threat. C. auris is a globally distributed yeast that can cause life‐threatening invasive candidiasis and is associated with high mortality in humans. C. auris has high outbreak potential and was responsible for several nosocomial hospital outbreaks. C. auris has been isolated from the ear canals of stray dogs. While C. auris spreads easily from human to human, the route of transmission among animals or from animals to humans is much less clear and further investigation is required. C. auris can survive in harsh conditions as it has been discovered on the surface of stored apples, in tidal marshes, in environments with extremely high salinity, and in wastewater. Preventive measures are not well established. C. auris is heat resistant and partially resistant to commonly used disinfectants. It is intrinsically resistant to most available antifungal medicines and some strains are panresistant. Initially, the range of antifungal drugs available for systemic use was limited to a few agents, the most effective of which was the highly toxic amphotericin B. Currently, only four classes of systemic antifungal medicines (azoles, echinocandins, pyrimidines, and polyenes) are used in human and veterinary medicine and horticulture. Despite continued efforts, the number of antifungal agents for systemic use remains limited (Table 19.1). Humans and animals and their fungal pathogens have many common cellular characteristics, resulting in a lack of potential drug targets that are unique to the fungus but not the host. Although existing antifungal medicines are effective, they are associated with a plethora of adverse effects. The use of these medicines also requires expertise and drug–drug interactions are common. Such interactions, along with the requirement for lengthy courses of therapy, further impact patient safety, prognosis and antifungal resistance. Table 19.1 Systemic and topical antifungal agents in use. O, oral; IV, intravenous; T, topical. a Broad spectrum: dermatophytes, yeasts, Aspergillus, dimorphic fungi. b Yeasts: Candida spp., Cryptococcus neoformans, Malassezia pachydermatis. c Dimorphic fungi: Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis, and Sporothrix schenckii. d Many other imidazoles such as bifonazole, butoconazole, oxiconazole, sulconazole, terconazole, and tioconazole are available for topical use. e The parenteral formulation is not available in the United States. The primary base of knowledge and clinical experience with antifungals comes from human medicine and is extrapolated to veterinary medicine. The modes of action for various antifungals target the cytoplasmic membrane (polyenes, azoles); cell wall (ecchinocandins, nikkomycins); and DNA and protein synthesis machinery (flucytosin, sordarins) (Figure 19.1). Figure 19.1 Action of antifungal agents on the fungal cell. The global escalation of fungal resistance is partly driven by inappropriate antifungal use across the One Health spectrum. For example, agricultural use is responsible for rising rates of azole‐resistant Aspergillus fumigatus infections, with azole resistance rates of 15–20% reported in parts of Europe and over 80% in environmental samples in Asia (WHO, 2022). Although there is general overuse and misuse of antimicrobials in veterinary medicine, antifungal use is considerably lower. Accelerations in azole resistance mechanisms are thought to have been driven by use of azole fungicides on crops. Based on Eurostat data, at least 10 000 tonnes of imidazole/triazole‐based fungicides were used as plant protection products in the EU in 2018. From the perspective of One Health, there should be discussion of antimicrobial stewardship for antifungal therapy in veterinary medicine. For dogs and cats, the need for broad‐spectrum antifungals for Malassezia pachydermatis dermatitis and external ear canal infections is unclear. While patients may be immunocompromised, typically treating the underlying allergy along with topical disinfectants has the same therapeutic effect as antifungals. Similarly, the need for broad‐spectrum antifungals for dermatophytosis (“ringworm”) infections in domestic mammals and candidiasis in poultry is unclear. In vitro antifungal susceptibility tests differ from those performed against bacteria because a given fungal isolate may be in the form of yeast or of filamentous fungi. The Clinical and Laboratory Standards Institute (CLSI) has described standardized testing methods for both of these forms of fungi, M27 and M38, respectively. The M27 document is intended for the susceptibility testing of yeasts that cause invasive infections and include organisms such as Candida spp. and Cryptococcus neoformans. The M38 document describes testing methods for common filamentous fungi that cause invasive infections such as Aspergillus, Fusarium, Rhizopus, Pseudallescheria, and the mycelial form of Sporothrix schenckii. The methods described in these CLSI documents have not been standardized for testing the yeast forms of the dimorphic fungi such as Blastomyces, Coccidioides, and Histoplasma. For specific details on how to perform antifungal susceptibility tests, the reader is referred to these documents. Since antifungal susceptibility testing is not routinely performed in veterinary clinical microbiology laboratories, referral of isolates to laboratories that specialize in antifungal testing is recommended in most instances. This results in increased costs and an additional delay in obtaining the results. Thus, it is prudent for the clinician to be familiar with the types of pathogenic fungi most likely to be encountered and the typical susceptibility of those fungi to the available antifungal agents. Such knowledge facilitates appropriate empirical therapy. However, the susceptibility of fungi, as with bacteria, is not always predictable. In order to be useful clinically, in vitro susceptibility testing needs to reliably predict the clinical outcome of therapy. Many factors may affect this outcome, including drug pharmacokinetics, drug interactions, host immune response, patient management, and virulence of the infecting microorganism. Since so many factors can affect the outcome of antifungal therapy, a low MIC does not necessarily predict clinical success. Similarly, a report that indicates that a fungus is resistant to an antifungal agent does not always mean that the use of that antifungal agent will result in an unfavorable clinical outcome. Nevertheless, many studies have provided evidence that in vitro antifungal susceptibility tests correlate with the outcome of therapy in human medicine (Rex and Pfaller, 2002). In the absence of specific veterinary criteria, the standards developed in human medicine may be useful. Antifungal drug resistance can be intrinsic or acquired. Intrinsic resistance is an inherited characteristic of a species or strain. In contrast, acquired resistance occurs when a previously susceptible isolate develops a resistant phenotype, usually as a result of prolonged exposure to antifungals. The precise mechanism associated with acquired resistance depends on the mode of action of the class of antifungal drug, and includes reduced drug uptake, drug export through efflux pumps, or reduced affinity of target enzymes. Unlike bacterial cells, intact fungal cells do not readily take up exogenous DNA. As a result, transferable drug resistance (e.g., horizontal gene transfer) has not been described among widely divergent fungal taxa. Prevention of emergence and spread of resistant fungi depends on hygienic precautions and taking maximal advantage of the pharmacodynamic properties of the particular drug class, as well as using local rather than systemic treatment (thus reducing general exposure of the animal’s fungal flora to antifungal agents). Additionally, combination antifungal therapy is a well‐recognized strategy to prevent emergence of flucytosine resistance. In vitro and laboratory animal model studies have elicited many pharmacodynamic characteristics for antifungal agents. Analysis of clinical data in humans also suggests that pharmacodynamic targets identified in animal models are predictive of outcomes in humans (Andes, 2004). The activity of antifungal agents may be concentration dependent, time dependent, or both. The polyenes and echinocandins exert a long postantifungal effect and are concentration dependent. The best predictor of efficacy for these drugs is a maximum serum concentration (Cmax) to MIC ratio of 3–10/1, with high ratios conferring better activity. In contrast, flucytosine has a short postantifungal effect and the best predictor of efficacy is the time period for which serum concentrations exceed the MIC of a given pathogen. The triazoles exert characteristics of both time‐ and concentration‐dependent activity. The best predictor of efficacy for these drugs is a 24‐hour area under the serum concentration versus time curve (AUC)/MIC ratio of 25/1. Terbinafine is mainly used in dogs and cats for the systemic treatment of persistent or intractable dermatophyte infections, in which it is more effective than ketoconazole, itraconazole, or griseofulvin. It is also used in the treatment of other systemic fungal infections. Allylamines are synthetic drugs that inhibit squalene epoxidase, a critical enzyme in the biosynthesis of ergosterol, the principal sterol in the cell membrane of susceptible fungi. This causes fungal cell death primarily due to the increase in membrane permeability mediated by the accumulation of high concentrations of squalene. High levels of squalene cause release of lytic enzymes which are lethal to the fungal cell. Isolates with an MIC ≤1 μg/ml are considered susceptible, 2–4 μg/ml represent intermediate susceptibility, and isolates with an MIC ≥8 μg/ml are resistant. The MIC of terbinafine is low in vitro for dermatophytes species as well as nondermatophyte organisms including Aspergillus spp., Blastomyces dermatitidis, Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Malassezia spp., Scopulariopsis brevicaulis, Sporothrix schenckii, and certain Candida spp. No effect can be expected against Nakaseomyces (Candida) glabrata, C. tropicalis, and Pichia kudriavzeveii (Candida krusei). Mechanisms of resistance to allylamines include efflux out of the fungal cell via ABC transporters, mutations in the ERG1P gene encoding squalene epoxidase (SQLE), stress tolerance induction, and detoxification (Martinez‐Rossi et al., 2018). Resistance has been described in Trichophyton rubrum and T. interdigitale due to mutations in the SQLE gene affecting the allylamine binding site on the enzyme (Saunte et al., 2019). Terbinafine resistance in Microsporum canis has been reported due to overexpression of the genes encoding ABC transporter proteins (Kano et al., 2018). Production of melanins by Sporothrix brasiliensis and S. schenkii has also been shown in vitro to be protective against terbinafine (Almeida‐Paes et al., 2016). Terbinafine is a lipophilic allylamine compound that is well absorbed (>70% in people) after oral administration and binds strongly to plasma proteins. Oral absorption is not affected by food. The drug is rapidly absorbed after oral administration in dogs (Sakai et al., 2011). In horses, relative oral bioavailability of terbinafine is less than 20% of that observed in dogs (Williams et al., 2011). The excretion of terbinafine is primarily in urine and to a lesser extent in feces. Terbinafine penetrates keratinized tissues, and enters the stratum corneum and sebum by direct diffusion through the dermis and living epidermis. Plasma terbinafine concentrations are not particularly good indicators of concentrations in the target organs, since the drug persists in the skin for prolonged periods. In a study in cats, there was no difference in plasma concentrations between low‐ (10–20 mg/kg q24 h) versus high‐dose (30–40 mg/kg q24 h) terbinafine, but concentrations in hair were significantly greater with the high dose (Kotnik et al., 2001). Therapeutic concentrations of terbinafine in cat hair persist for over five weeks after 14 days of oral therapy (Foust et al., 2007). In vivo studies have shown that terbinafine is an inhibitor of the CYP450 enzymes. Co‐administration of terbinafine with drugs predominantly metabolized by the CYP450 2D6 isozyme should be done with careful monitoring and may require a reduction in dose of the 2D6‐metabolized drug. Terbinafine clearance is increased 100% by rifampin, a CYP450 enzyme inducer. In horses, cimetidine, a CYP450 enzyme inhibitor, increased plasma concentrations and oral bioavailablity (Younkin et al., 2017). Terbinafine clearance is unaffected by cyclosporine. Theoretically, combinations of azoles and terbinafine should be synergistic since they target different points of the same fungal metabolic pathway. This has been corroborated in several studies in vitro. Combinations of terbinafine with fluconazole, itraconazole, or voriconazole have shown synergy in vitro against species of Aspergillus, Candida, and Mucor and even against fluconazole‐resistant Candida isolates and itraconazole‐resistant Aspergillus strains (Cuenta‐Estrella, 2004). The combination of terbinafine with caspofungin or fluconazole is synergistic in vitro against many strains of Pythium insidiosum (Cavalheiro et al., 2009). The interaction of terbinafine with amphotericin B or flucytosine has also been assessed. In vitro studies have indicated that these combinations exhibit neither interactions nor antagonistic effects against Aspergillus and other fungi. Terbinafine is well tolerated with a low incidence of adverse reactions in dogs and cats. Adverse effects involve the gastrointestinal system and the skin. Abnormalities in liver enzymes and hematological parameters are rarely observed. Terbinafine is available as oral tablets and topical cream for use in human medicine. Due to its high rate of efficacy and low incidence of adverse reactions, terbinafine is often given for various dermatomycoses infections. Terbinafine therapy has also been efficacious in some patients with sporotrichosis, aspergillosis, chromoblastomycosis, and leishmaniasis. There is also evidence that resistant Candida infections may respond to a combination of terbinafine and a triazole. Terbinafine is more active in vitro than griseofulvin against Microsporum canis, M. gypseum, and Trichophyton mentagrophytes (Hofbauer et al., 2002). In dogs and cats, terbinafine has been shown to be effective for the treatment of both experimental and naturally acquired dermatophytosis. The length of therapy for mycological cure ranges between 33 and 63 days (Kotnik et al., 2002; Moriello, 2004). Terbinafine has also been shown as effective as ketokonazole in reducing yeast counts in dogs with Malassezia dermatitis (Rosales et al., 2005). There are individual reports of successful treatment of canine pythiosis using a combination of terbinafine and itraconazole. Terbinafine is included in the World Small Animal Veterinary Association’s List of Essential Medicines for Cats and Dogs (2020) as a topical agent for treatment of superficial yeast, principally Malassezia, and dermatophyte infections (Core List), and as an oral preparation for systemic activity against superficial and deep fungal infections (Complementary List). The polyene group of naturally occurring antifungal agents includes amphotericin B, nystatin, and natamycin. Toxicity limits the use of most polyenes to topical treatment only, except for amphotericin B which is administered systemically. Amphotericin B was the mainstay of systemic antifungal treatment for many years, until the authorization of the azole antifungal drugs. Amphotericin B is still the drug of choice for systemic treatment of filamentous fungal infections. A major advantage of this drug is its fungicidal activity, so that it is often used in treatment of life‐threatening yeast or dimorphic fungal infections. Lipid formulations of amphotericin B are generally used to reduce nephrotoxicity and include a liposomal preparation and a lipid complex. Amphotericin B usefulness is limited by its toxicity and inability to distribute to many tissues; however, penetration into CSF is increased in the presence of meningitis and with use of the liposomal formulation. Amphotericin is a conjugated heptene product of Streptomyces nodosus (Figure 19.2). It is an amphoteric polyene macrolide that is poorly soluble in water and unstable at 37 °C. Antifungal effects of this antibiotic are optimal between pH 6.0 and 7.5 and decrease at lower pHs. Figure 19.2 Structural formula of amphotericin B. Polyenes bind with ergosterol within the fungal cell membrane, increasing its permeability and causing leakage of potassium ions and essential small organic molecules from the fungal cell. The oxidation of amphotericin B also destabilizes the fungal membrane by generating free radicals. This induces oxidative stress, causing fungal cell death. Amphotericin B binds cholesterol in mammalian cell membranes less avidly, but this still makes it the most toxic of the clinically useful systemic antifungal drugs. Amphotericin B is a broad‐spectrum, antifungal agent with the advantage of fungicidal activity against most pathogenic fungi. Isolates with an MIC ≤1 μg/ml are considered susceptible. Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, and Sporothrix schenckii are typically susceptible, in decreasing order. Most Aspergillus spp. are susceptible. Prototheca, an alga associated with cutaneous, subcutaneous and systemic infections in several animals species as well as bovine intramammary infection, is also susceptible. Intrinsic resistance to amphotericin B is common in Aspergillus terreus, A. lentulus, A. flavus, Scedosporium spp., Trichosporon, Candida auris, and C. lusitaniae (Mandell et al., 2019). The underlying mechanism is not known (Posch et al., 2018). Dermatophytes and strains of Pseudoallescheria boydii are often intrinsically resistant to amphotericin B. Acquired resistance can occur due to reductions of ergosterol content of the fungal cell membrane, resulting from mutations in ergosterol biosynthesis genes or increased production of reactive‐oxidant scavengers. For Candida spp., resistance results from alterations in ERG2 and ERG6 genes encoding for enzymes involved in the ergosterol biosynthetic pathway causing a reduction in ergosterol within the fungal cell membrane and hence resistance to amphotericin B (Jensen et al., 2015). However, in C. albicans, mutations are described in ERG2, ERG3, and ERG11 genes. Amphotericin B resistance may also arise in C. albicans strains that produce increased amounts of catalase, which helps to protect from oxidative cell damage (O’Shaughnessy et al., 2009). Resistance during treatment of susceptible fungi such as Candida spp. and C. neoformans has been rarely documented. Amphotericin B is poorly absorbed orally (<5%), so parenteral (IV) administration is required. The plasma elimination half‐life in dogs, after IV injection of conventional amphotericin B, is approximately 26 hours (Kukui et al., 2003). Its distribution is limited to extracellular fluid compartments. The metabolic pathways are unknown but it exhibits biphasic elimination. The drug is thought to bind to plasma or cellular lipoproteins and be released slowly from these sites. Approximately 5% of the injected dose is excreted by the kidneys, and continues to be excreted in the urine of humans for several weeks after cessation of therapy. Penetration into cerebrospinal fluid (CSF) is poor (5%) but increases with meningitis. Systemic absorption from the lungs following aerosol administration is poor so this route has been used successfully in the treatment of pulmonary aspergillosis. Experiences in human medicine reveal that the pharmacokinetics of amphotericin B differ according to the formulation. Peak plasma concentrations after administration of the liposomal formulation are higher than those achieved with conventional amphotericin B. In contrast, peak plasma concentrations after administration of the lipid complex or colloidal formulations are lower due to more rapid distribution of the drug to tissues. Lipid‐based formulations appear to be taken up extensively by the reticuloendothelial system, which may give them considerable therapeutic advantage. The lipid complexes, but not the liposomal or conventional amphotericin B, are concentrated and accumulate in lung tissue (Matot and Pizov, 2000). This affinity for the lung may have implications in the treatment of fungal pneumonia. Due to both the serious nature of systemic fungal infections and the toxicity of amphotericin B, synergistic combinations of drugs have been investigated to enable reduction of dosage and expedite clinical cure. Flucytosine and amphotericin B show additive or synergistic effects in vitro against Candida spp., Cryptococcus, and Aspergillus. The combination is synergistic in cryptococcal meningitis in humans, producing faster cure, fewer relapses, more rapid sterilization of CSF, and less nephrotoxicity. There is a theoretical concern that co‐administration of amphotericin B and azole agents will lead to antagonism because of azole inhibition of ergosterol synthesis, resulting in less ergosterol in the cell membrane available for the binding of polyenes. Amphotericin B can also interfere with the influx of the azole agents by damaging the membrane structure. Combination therapy with various imidazoles or triazoles against Candida spp., C. neoformans, and Aspergillus spp. has produced complex interactions in vitro that are hard to interpret. Results of animal models with candidiasis have been contradictory, with most studies showing either indifference or antagonism. Results in animal models of invasive aspergillosis and cryptococcal infection have given equivocal results, with some studies showing synergism, some showing antagonism, and most studies showing indifference (Cuenta‐Estrella, 2004). Renal toxicity inevitably accompanies treatment with micellar (conventional) amphotericin B. Toxicity is attributed to renal vasoconstriction and subsequent reduction in glomerular filtration rate. The drug may also have a direct toxic effect. Early reversible nephrotoxicosis occurs with each daily dose, but permanent nephrotoxicosis is related to the total cumulative dose. Dosing every other day reduces nephrotoxic effects compared to administering the same dose daily. Other adverse effects include thrombophlebitis at the injection site and hypokalemia with resulting cardiac arrhythmias, sweating, nausea, malaise, and depression. In dogs and cats, signs of nephrotoxicity develop within 3–4 weeks of starting treatment, associated with blood urea nitrogen (BUN) levels of 3.3–3.9 mmol/l (60–70 mg/dl). The effect may be reversible and the drug should be discontinued until BUN falls below 2.2 mmol/l (40 mg/dl). BUN or other sensitive kidney parameters such as symmetric dimethylarginine should be monitored twice weekly during treatment. In addition, serum potassium should be monitored and hypokalemia corrected by oral supplementation. Hypokalemia does not seem to be as common in dogs and cats as in humans. Lipid‐based formulations of amphotericin B lessen the infusion‐related toxicities (e.g., nausea, fever, chills) and reduce nephrotoxicity. This reduced toxicity means that higher daily doses of the lipid‐based formulations may be used. Amphotericin B lipid complexes are selectively taken up by mononuclear phagocytes rather than by protein binding, thus tissues rich in mononuclear cells develop high concentrations of the drug. Doses >5 mg/kg of conventional amphotericin B in dogs caused death as a result of cardiac abnormalities. Doses of 2–5 mg/kg occasionally caused cardiac arrhythmias in dogs, but doses <1 mg/kg had no effect on the heart. Administration of the liposomal amphotericin B formulation to dogs at daily dosages of 8 and 16 mg/kg resulted in weight loss, vomiting, and tubular necrosis. A daily dose of 4 mg/kg for 30 days was associated with occasional vomiting, a moderate increase in BUN and creatinine concentrations, and histopathological changes consistent with moderate tubular nephrosis. In contrast, a daily dose of 1 mg/kg was well tolerated and only associated with an increased urine volume and lower specific gravity (Bekerski et al., 1999). Renal and clinicopathological changes observed with administration of the liposomal formulation at a daily dose of 4 mg/kg were similar to those reported after administration of the colloidal formulation at a dose of 5 mg/kg, or to the conventional amphotericin B formulation administered at a daily dose of 0.6 mg/kg. The amphotericin B sodium deoxycholate compound with phosphate buffer is water soluble and used for IV administration. Lipid‐based formulations (liposomal [AmBisome®], colloidal [Amphocil® or Amphotec®], or lipid complex [Abelcet]®) are less toxic than the micellar suspension, which is the conventional formulation (Fungizone®). Concurrent use of flucytosine decreases the dosage of amphotericin B required to treat cryptococcal infection. There is no general agreement as to the optimum dosage, total dose, or duration of treatment required for amphotericin B in veterinary patients. The dosage used for the conventional formulation ranges between 0.25 and 1.0 mg/kg/day. For otherwise healthy dogs, an initial IV dosage of 0.5 mg/kg q48 hours is often used; BUN or other sensitive kidney parameters are monitored for evidence of kidney damage. If BUN exceeds 3.3 mmol/l (60 mg/dl), the dose is discontinued or reduced by 25–50% until BUN falls below 2.2 mmol/l (40 mg/dl). Administration by slow IV infusion and with intravenous fluids reduces the risk or severity of systemic toxicity (e.g., vomiting, diarrhea, weight loss) and results in less renal damage. In severely debilitated dogs an initial dosage of 0.2 mg/kg IV has been proposed, increasing by 0.1 mg/kg daily until day 4 (0.5 mg/kg), then using this maintenance dosage. In cats with cryptococcal infection, combining amphotericin B with flucytosine reduces the length of treatment course required for successful therapy. Subcutaneous administration of amphotericin in 0.45% saline with 2.5% dextrose in dogs (0.5–0.8 mg/kg in 500 ml) and cats (same dose, in 400 ml) 2–3 times weekly was described as a way of administering large quantities of amphotericin without producing the marked azotemia associated with IV injection (Malik et al., 1996a). These amounts were given subcutaneously 2–3 times weekly over several months, to a total cumulative dose of 8–26 mg/kg body weight. In the aforementioned study, the drug was administered in combination with a triazole drug for the treatment of cryptococcal infection. Treatment duration with conventional amphotericin B varies with clinical response but may be up to 12 weeks. For blastomycosis, the total cumulative dose used is about 12 mg/kg. Clinical experience with lipid‐based formulations in animals is limited but dosages of 1–3 mg/kg three times weekly for a total of 9–12 treatments (cumulative dose of 24–27 mg/kg) have been used in dogs. In cats, a lower dose of 1 mg/kg three times weekly for a total of 12 treatments (cumulative dose of 12 mg/kg) has been recommended (Grooters et al., 2003). In veterinary medicine, the advantages of lipid‐based formulations may be negated by their high cost. Amphotericin B is the most toxic antimicrobial in clinical use but its fungicidal action makes it clinically useful for most systemic fungal infections (e.g., Blastomyces, Histoplasma, Cryptococcus, Coccidioides, Candida, and Aspergillus) in immunocompromised hosts. In nonimmunocompromised hosts, the less toxic, though fungistatic, triazole drugs may be equally valuable for yeast infections. For systemic infections caused by dimorphic fungi in nonimmunocompromised hosts, amphotericin B may be preceded by or replaced with ketoconazole or itraconazole treatment. In a retrospective study of 115 dogs with blastomycosis, treatment with itraconazole was as effective as treatment with a combination of amphotericin B and ketoconazole (Arceneaux et al., 1998). Amphotericin B lipid complex has been used to treat dogs with blastomycosis at 1 mg/kg q48 hours, for a total cumulative dose of 8–12 mg/kg. Most dogs given a cumulative dose of 12 mg/kg became clinically free of blastomycosis; the two dogs in the study receiving a total dose of 8 mg/kg relapsed with blastomycosis. No dogs developed evidence of renal damage (Krawiec et al., 1996). Historically, amphotericin B was the only reliable antifungal drug for systemic aspergillosis and zygomycosis (Mucor, Rhizopus); however, the newer triazoles itraconazole and voriconazole are alternatives for this purpose. Aerosol treatment of pulmonary aspergillosis with amphotericin B may be one way to assure high lung concentrations and low toxicity due to low systemic absorption from the lungs. Amphotericin B has not always been effective in nasal or disseminated Aspergillus infections in animals, possibly because of the lack of susceptibility of the causative fungal species to the drug. Amphotericin B may be a drug of choice in the treatment of Prototheca infections alone or in combination with itraconazole (Stenner et al., 2007
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Antifungal Chemotherapy
General Considerations
Class
Agent
Formulations
Spectrum
Allylamine
Terbinafine
O, T
Broad spectruma
Pyrimidine synthesis inhibitors
Flucytosine
O, IVe
Yeasts,b some Aspergillus
Azole (Imidazole)
Ketoconazole
O, T
Dermatophytes, yeasts, dimorphic fungic
Miconazole
T
Broad spectrum
Enilconazole
T
Broad spectrum
Clotrimazole
T
Broad spectrum
Othersd
T
Azole (Triazole)
Fluconazole
O, IV, T
Yeasts, dimorphic fungi
Itraconazole
O, IV
Broad spectrum
Voriconazole
O, IV
Broad spectrum
Posaconazole
O, T
Broad spectrum
Echinocandin
Caspofungin
IV
Candida spp., Aspergillus
Anidulafungin
IV
Candida spp., Aspergillus
Micafungin
IV
Candida spp., Aspergillus
Polyene
Amphotericin B
IV, T
Broad spectrum
Nystatin
T
Yeasts
Natamycin
T
Broad spectrum
Other
Griseofulvin
O
Dermatophytes
Amorolfine
T
Dermatophytes, Candida spp.
Butenafine
T
Dermatophytes
Ciclopirox
T
Dermatophytes, yeasts
Haloprogin
T
Dermatophytes, Candida spp.
Tolnaftate
T
Dermatophytes
Undecylenic acid
T
Dermatophytes
Antifungal Susceptibility Testing
Antifungal Drug Resistance
Pharmacodynamic Properties
Antifungal Drugs for Systemic Administration
Allylamines: Terbinafine
Mechanism of Action
Antifungal Activity
Pharmacokinetic Properties
Drug Interactions
Toxicity and Adverse Effects
Clincal Use
Polyenes: Amphotericin B
Mechanism of Action
Antifungal Activity
Resistance
Pharmacokinetic Properties
Drug Interactions
Toxicity and Adverse Effects
Dosage Considerations
Clinical Use
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