Vet Clin Exot Anim 6 (2003) 337–350

Antifungal drug therapy in avian species

Susan E. Orosz, PhD, DVM, Dipl. ABVP, ECAMS
AniMed Research Consulting LLC, 7830 Brown Road, Curtice, OH 43412, USA

Fungal infections can be broadly classified into three groups in people,

namely, superficial, subcutaneous, and systemic [1]. These classifications
appear to be similar in birds. Superficial infections in humans include
infections of the nails and hair. Their counterparts in birds would be
feathers, beak, claws, and often, the horny metatarsal skin [2]. These su-
perficial structures in people often are infected by dermatophytes, while
mucous membranes, also considered superficial, frequently are infected by
Candida species [1]. Subcutaneous infections usually are acquired by
traumatic inoculation, but the most serious and life-threatening are systemic
fungal infection in people [1] and in birds [3].
There has been a shift from gram-negative bacteria to gram-positive
bacteria and Candida species as the most common bloodstream pathogens
in US hospitals [4]. Candida species have accounted for the fourth most
commonly recovered isolate in blood cultures, with mortality rates from
candidemia ranging between 38% and 75% [5,6]. Additionally, the proportion
of infections caused by nonalbicans Candida species has increased [5]. This is
particularly alarming, as there is a decreased susceptibility of many of the
nonalbicans species with available antifungal agents. This may be a conse-
quence of nondiscriminate azole use [5]. Additionally, granulocytopenic
human patients or those receiving cytotoxic chemotherapy are highly sus-
ceptible to systemic disease from Aspergillus species Usually, inhalation of
the widely dispersed Candida from the environment precedes local invasion of
the lungs or sinuses before hematogenous dissemination. Therefore, clinicians
must be familiar with the pharmacology of various antifungal agents and their
appropriate use. The following discussion will focus on drugs in use in avian
species with caveats of their use and associated problems in people. New drugs
in the pipeline in human medicine also will be discussed.
There are five classes of antifungal agents: polyenes, fluoropyrimidines,
azoles, echinocandins, and allylamines [8].

E-mail address: drsusanorosz@aol.com

1094-9194/03/$ - see front matter Ó 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S1094-9194(03)00008-2
338 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350

Polyenes
Amphotericin B
Amphotericin B remains the only fungicidal drug available, although
some newer drugs in the pipeline may acquire that status. Since its com-
mercial availability in the 1950s, it continues to be the gold standard for
critically ill human patients with systemic fungal disease [9]. It is also the
treatment of choice for opportunistic mycoses other than mucosal candidal
infections that especially affect AIDS patients. Amphotericin B also has
been shown to provide effective therapy for antibiotic-resistant fever in
neutropenic patients [10]. Although fever is documented rarely in avian
patients, those not responding to antimicrobial therapy or neutropenic
avian patients of unknown origin or from chemotherapy may be considered
to be in a similar class.
As an amphoteric polyene macrolide, amphotericin B is insoluble in
saline at a neutral pH (pH 7) and is virtually insoluble in water. For this
reason, it is formulated as a suspension with sodium deoxycholate as its
dispersant [9,10]. When reconstituted with water, the dispersant forms
ribbon-like aggregates, producing a colloidal suspension. These aggregates
are relatively unstable and, when infused intravenously, dissociate rapidly
and release free amphotericin B [10].
The label for conventional amphotericin B, as described previously, states
that the drug is stable for 1 week as a 5 mg/mL suspension in water. When
diluted, 5% dextrose (pH greater than 4.2) should be used at 1:50 dilution
immediately before infusion. Conventional amphotericin B does not contain
a bacteriostatic agent, so it should be discarded after 24 hours of refrigera-
tion, when diluted as described. A 5% dextrose suspension of amphotericin
B is stable for 35 days when frozen [11] directly and for 6 months when
frozen in human serum [12].
For avian use, conventional amphotericin B can be diluted with sterile
water, divided into 10 mL aliquots using aseptic technique, and stored at
ÿ20°C [9]. The drug then is diluted further when thawed with dextrose for
intravenous (IV) use or with water for nebulization [9].
When it disassociates from its dispersant, the primary mechanism of action
for this free amphotericin B is its binding to sterols. In particular, it binds to
ergosterol found in the fungal cell membrane. This binding alters membrane
permeability by creating a barrel pore [13], directly causing leakage of sodium,
potassium, and hydrogen ions, thereby resulting in cell death [7,9,13]. Addi-
tionally, there are other biologic effects, including lipid peroxidation, inhi-
bition of membrane enzymes, and blockade of endocytosis.
Amphotericin B is fungicidal to a variety of organisms, including
Aspergillus species, Candida species, Blastomyces species, Coccidioides species,
Histoplasma species, Sporothrix species, and Mucor species [9]. Initial treatment
for mammals (dogs and cats) often divides a total cumulative dose of 4 to
 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350 339

11 mg/kg on an alternate day or basis until the total dose is reached, or until
clinically apparent toxicities develop. Penetration across some of the
physiologically privileged sites, such as the blood–brain barrier, joint spaces,
and ocular tissues, is poor [13].
In addition to binding to ergosterol, amphotericin B binds to mammalian
sterols, including cholesterol [7]. Renal toxicity is related directly to the
sterol rich cell membranes in kidney tubules. Conventional amphotericin B
alters the ionic permeability of the renal brush border cells and increases the
permeability of anions [7,13]. In response to this altered permeability, it has
been suggested that renal tissues may release mediators that cause an abrupt
decrease in renal blood flow [7]. Therefore, toxicity may be related to altered
permeability of renal tubular cells, causing nephrotoxicity directly or
indirectly by hypokalemia [7] as a consequence of ionic fluxes or by the
process of infusion, causing chills and fevers.
The overall response rate for systemic aspergillosis using conventional
amphotericin B has been reduced over time, with it reported recently at
55%, but only 5% to 10% for pulmonary infections [10]. This may result
from a reduced ability of amphotericin B to effectively change cell wall per-
meability [9].
Because of problems associated with conventional amphotericin B use,
new formulations have been developed with improved pharmacological
properties that have reduced toxicity, thereby increasing the therapeutic
fungicidal activity. Encapsulation of amphotericin B into liposomes or
complexing them with a lipid formulation has reduced toxicity successfully
[10,13]. There are three lipid formulations approved by the US Food and
Drug Administration: a unilamellar liposome (AmBisome), a colloidal
dispersion (Amphotecor amphotericin B colloidal dispersion, ABCD), and
a lipid complex (Abelcet) [13]. The primary mechanism for reduction of
toxicity is a decreased uptake of amphotericin B from the lipid formulation
to mammalian cell membranes. This occurs by two mechanisms. The first is
modulation of the rate of transfer of amphotericin B from its lipid carrier
to the cholesterol-containing membranes. All three formulations appear to
perform this function. This results in a reduced rate of drug transfer, which
would reduce the concentration of the drug at the fungal cell wall. Drug
concentration can be increased because of the reduced toxicity to offset
this problem, however. The second mechanism modulates clearance of the
complex. Two formulations, the lipid complex and colloid dispersion, are
phagocytized rapidly by the reticuloendothelial (RE) system [13], thereby
blunting peak plasma concentrations and reducing the concentration in the
blood reaching the vulnerable kidney tubular epithelium. The unilamellar
liposome amphotericin B is too large for phagocytes to ingest but still has
reduced toxicity because of its preferential transfer to fungal cells, as com-
pared with mammalian cells [13].
The preferential uptake of amphotericin B from two of these formulations
by macrophages can provide sustained release at the site of the fungal
340 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350

infection. It has been demonstrated in mice that the unilamellar liposome

formulation accumulates at the site of infection and penetrates the cell wall
of fungi with an extracellular or intracellular location [14]. This liposome
formulation, when compared with conventional amphotericin B, has sig-
nificantly greater efficacy in successfully treating pulmonary aspergillosis with
reduced toxicity [15]. It also has been shown to have enhanced success with
invasive or systemic candidiasis [16]. Based on its safety and efficacy, this
formulation is considered to be superior to conventional amphotericin B
and therefore should be designated as the first-line standard for systemic
fungal infections. Its price has kept it from acquiring that designation [17],
however.
The lipid complex formulation represents amphotericin B in a 2 l to 5 l
diameter lipid complex in a ribbon-like sheet. It is cleared rapidly by
phagocytosis of the RE cells and must be administered at a higher dose than
the conventional formulation to affect a cure [13]. Like the liposomal form,
when compared with conventional amphotericin B, it had greater efficacy
and safety with a variety of fungal infections experimentally induced [13] or
by clinical trial [18]. In the clinical trial [18], there was complete or partial
response in 57% of patients, including 42% with aspergillosis, 67% with
disseminated candidiasis, 71% with zygomycosis, and 82% with fusariosis.
Severe hypertension was associated with administration of the lipid for-
mulation in a person with multiple intraperitoneal and urinary fungal
pathogens, however [19].
The third formulation, the colloidal dispersion formulation, consists of
a disc-like lipid complex of approximately 115 nm [13]. It had superior
efficacy in experimental models of candidiasis, coccidiomycosis, cryptococ-
cosis, and aspergillosis when compared with conventional amphotericin B
[20]. Clinical studies [21,22] have demonstrated that the colloidal dispersion
is equally effective to the liposomal formulation, with both exceeding the
conventional formulation.
Conventional amphotericin B has been administered to avian patients by
a variety of methods. The IV formulation has been given intravenously or
injected into the trachea or intraosseous catheter or directly into an affected
air sac [9]. When flushed into the infraorbital sinus of an African gray parrot
(Psittacus erithacus), it resulted in a severe and fatal granulomatous reaction
[23]. Pharmacokinetic studies in turkeys, red-tailed hawks (Buteo jamai-
censis), broad-winged hawks (Buteo platypterus) and great-horned owls
(Bubo virginianu) reported a much shorter half-life for avian species ex-
amined when compared with mammals [24]. This reduced half-life is
probably responsible for the lack of any reported finding of nephrotoxicity
in avian species. The pharmacokinetics of the liposomal formulation should
be investigated in birds because of its ability to concentrate in the RE
cell line, including macrophages. This would have the potential to accu-
mulate drug at the site of the fungal granulomas, particularly in the air
sac system.
 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350 341

Nystatin
Nystatin is a polyene macrolide that has a similar mechanism of action
similar to amphotericin B, in that it alters membrane permeability by
binding to ergosterol [9]. Nystatin is not absorbed by an intact epithelium
such as the skin or gastrointestinal (GI) tract. If either surface is ulcerated,
however, it could be absorbed. Nystatin is considered to be even more toxic
when systemic than amphotericin B [9]. Therefore, it should be used only
when either epithelial surface is intact.
This macrolide is used commonly in avian species for GI candidiasis,
particularly ingluvial infections of psittacine chicks [9]. It should be avoided
when administered prophylactically during the hand feeding process because
of the potential for increasing drug resistance. This problem is particularly
prevalent with Candida species [9]. No pharmacokinetic studies have been
performed in any avian species. The empirical doses, however, appear to be
efficacious clinically [9]. This drug should be administered at least 30
minutes before feeding and not be given if there is ingluvial candidiasis [9],
because it has the potential to bypass the site of infection.
Nyotran [25] is a multilamellar liposomal formulation of nystatin
designed for use in systemic fungal infections. Liposomal encapsulation
has significantly reduced the toxicity of nystatin and has been shown to
protect erythrocytes from the toxicity associated with free nystatin. This
liposomal incorporation of drug allows for increased doses with a subse-
quent increase in survival from systemic fungal disease in experimental
settings. Nyotran appeared to possess fungistatic and fungicidal activities
against Aspergillus species, Candida species, and Cryptococcus neoformans.
Results [25] suggest it is as active as liposomal amphotericin B, but less
active than conventional amphotericin B or amphotericin B in the lipid
formulation. This drug is in clinical trials. It may prove extremely useful in
patients with Candida isolates that are nonresponsive to fluconazole and
may be an important therapeutic drug for C. neoformans in birds that were
considered untreatable with this fungal infection. No pharmacokinetic
studies or reports have been performed in birds.

Fluoropyrimidines
Flucytosine (5-fluorocytosine [5-FC]) is a fluorinated analog of cytosine.
There are two mechanisms of action of flucytosine: inhibition of DNA
synthesis and inhibition of RNA synthesis. The former is considered the
primary mechanism of action and results in disrupting protein formation,
while the latter alters the available pool of amino acids [9]. Flucytosine
is transported into susceptible fungi by cytosine permease, and then is
converted to 5 fluorouracil (5-FU) by deamination. Once inside the cell, it
cannot be transported across its cell membrane. There has been a rapid
emergence of secondary resistance to this drug with Candida species and
342 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350

Cryptococcus species, with 50% of Candida species and most Aspergillus

species showing resistance [8,9]. It should be used only in combination with
other antifungal agents, such as amphotericin B, or, in humans, with
fluconazole. Before the emergence of azoles, it was used prophylactically for
species prone to aspergillosis, such as swans, gyrfalcons, and other falcons
[9]. One study in a variety of raptors and turkeys, suggested dosing every 6
hours to maintain a blood concentration that meets or exceeds the minimum
inhibitory concentration (MIC) for Aspergillus species [23].
In mice, nonlinear regression analysis of data revealed that time above
the MIC and the area under the curve (AUC) MIC were important in
predicting efficacy, while the peak level MIC was least important [26].
Maximum efficacy was observed, however, when levels exceeded the MIC
for a minimum of 20% to 25% of the 24-hour dosing interval [26]. Its short
half life in mammals and birds is problematic, because it requires ad-
ministration three to four times per day [24,27], which is difficult to
accomplish in avian patients.

Azoles
The antifungal azoles are a class of synthetic compounds that contain one
or more five-membered azole rings. The imidazoles have two nitrogen atoms
in their five-membered rings. Imidazoles commonly used in avian medicine
include ketoconazole, clotrimazole, and miconazole. The triazoles have
three nitrogen atoms in their five-membered rings. The commonly used
triazoles in avian medicine include itraconazole and fluconazole. Compared
with imidazoles, triazoles are less susceptible to metabolic degradation, have
enhanced target specificity, increased potency, and a greater spectrum
of activity [9,27]. For this reason, new azole development has focused on
second-generation triazoles, including voriconazole and posaconazole.
Fluconazole and itraconazole, therefore, represent the first generation of
systemic triazoles. All azoles are considered fungistatic, and their mechanisms
of action center on the inhibition of cytochrome P450-dependent ergosterol
synthesis. The nitrogen atoms of the azole ring binds to the heme moiety of 14a
demethylase, which is the enzyme responsible for conversion of lanosterol to
ergosterol, the main sterol in the cell membrane of most fungi [9,27]. This leads
to the accumulation of 14-methylated ergosterols in the cell membrane,
leading to inhibition of cell growth and membrane disorganization [9]. Azoles
may have an additional function of inhibiting cytochrome C oxidative and
peroxidative enzymes [9,28–30].

Itraconazole
Itraconazole has species- and strain-dependent activity, which has been
reported to be fungicidal against filamentous fungi, including Aspergillus
species, and some strains of C. neoformans. It has been reported to be
 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350 343

generally fungistatic against yeast-like fungi [24]. Itraconazole is the only

triazole licensed for treatment of aspergillosis in people [17].
In vitro experiments demonstrated concentration-dependent, fungistatic
activity against Candida species and C. neoformans, with maximum effec-
tiveness at two and four to eight times the MIC, respectively [27]. This
suggests that itraconazole should not be the first drug selected for Candida
species in birds. In vitro studies of Aspergillus species, however, demon-
strated that itraconazole had time- and concentration-dependent fungicidal
activity, because there was greater than 87% to 97% killing of isolates
within 24 hours of drug exposure [27]. This indicates that itraconazole
should be considered primarily for treatment of aspergillosis in birds.
The relationship between drug concentrations and efficacy was assessed
in a model of invasive pulmonary aspergillosis using animals immunosup-
pressed with methylprednisolone and cyclosporine [31]. In that study, higher
plasma drug levels were associated with decreases in lung burden of A.
fumigatus. When peak concentrations were less than 5 lg/mL, there was
a precipitous decline in fungal activity. When levels were sustained above 5
lg/mL, there was a significant reduction in residual fungal activity in the
lungs [31]. This suggests that there is a critical threshold concentration that
can serve as the marker for predicting the blood concentration needed for
a fungicidal effect on the respiratory tract.
The concept of a critical threshold concentration does not take into
account the effect of bioactive metabolites, particularly hydroxyitracona-
zole. Bioassays incorporate these metabolites by including their activity to
provide a picture of total biologic activity and can lead to concentrations
three times higher than those measured by HPLC [32]. In contrast, in a study
measuring itraconazole and hydroxyitraconazole by HPLC in pigeons,
hydroxyitraconazole concentrations were consistently higher than those for
itraconazole in tissues [33], but they were not predictive at a quantifiable
level. Unlike the preceding study [32], however, hydroxyitraconazole levels
were lower in the plasma of pigeons than itraconazole levels [33]. These
results were similar to those from a study of red-tailed hawks. [34] If this
critical threshold concentration represents an accurate concentration, es-
pecially with less sensitive A. fumigatus isolates, a suggested dose of 5 to
10 mg/kg by mouth for oral itraconazole with food in pigeons [32], red-
tailed hawks [33], and possibly parrots [34] may be too low. These re-
commendations were based on data suggesting 0.25 lg/mL for a trough
plasma itraconazole concentration in people [36]. It may represent
a fungistatic level, but it is not effective for an appropriate kill effect sug-
gested by the fungicidal level, 5 lg/mL, for the plasma concentration of the
parent drug. In a study comparing ketoconazole, enilconazole, and
itraconazole in turkeys with experimentally induced aspergillosis, however,
6 mg/kg every 24 hours was an effective antifungal dosage for itraconazole
[36]. Aspergilloma lesions were reduced by greater than 90% in the lungs
and air sacs with this dose of itraconazole in these young growing birds [37].
344 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350

These experimental data from avian species [33–35] were derived from
preparing an oral formulation from the itraconazole capsule by mixing in
acid, then diluting it with orange juice and giving with food to enhance the
parent drug’s bioavailability. There are two new formulations of itracona-
zole developed using the solubilizing excipient hydroxypropyl B cyclodex-
trin [27], however. In people, it has reliable oral bioavailability in those
with superficial or systemic fungal infections. In clinical trials comparing
itraconazole oral solution with oral amphotericin B or fluconazole sus-
pension in neutropenic patients, there were fewer superficial and deep
fungal infections and fewer cases of aspergillosis and deaths from systemic
fungal infections in the group receiving the itraconazole oral solution
[38–40]. Several parrots receiving the oral itraconazole suspension at the
University of Tennessee achieved levels similar (Frazier DL, oral communi-
cation, 1999) to those previously reported [35] with the acid formulation
that was fed by gavage.
Comparison with the plasma concentration form suggested that the oral
itraconazole solution is at least equally effective in avian species.
A new IV formulation of itraconazole has been developed for those pa-
tients unable to take oral medications. An additional advantage is that this
formulation achieves therapeutic plasma concentrations in less than 48 hours
after initiating treatment [40]. In comparison, the steady state concentration
after oral administration of the capsule takes 10 to 14 days to achieve [9]. This
new IV formulation may be useful for acute debilitating aspergillosis in avian
species tolerant of azole therapy (non-African gray species).

Fluconazole
Based on in vitro studies, fluconazole is considered to be fungistatic
for many yeasts, including C. albicans, C. tropicalis, and C. glabrata [27,41,
42]. These studies also suggested that some of the C. albicans strains
were concentration-dependent and required doses greater than their MIC
for inhibiting fungal growth, however. Another time-kill study [43] with
C. albicans suggests that fluconazole might eliminate this yeast over ex-
tended periods of time without help from the host defense system. The
kidney has been designated as the endpoint for antifungal efficacy with dis-
seminated candidiasis [27]. The kill effect, however, in other organs may
differ, because fluconazole preferentially accumulates in the kidneys and is
excreted in the urine.
Fluconazole has very different pharmacokinetic properties when com-
pared with itraconazole. These differences are important to understand
when extrapolating their use for a variety of conditions in multiple species of
birds. Fluconazole is a water-soluble fluorine-substituted bis-triazole, while
itraconazole is poorly water soluble but lipophilic [9]. Fluconazole is ab-
sorbed rapidly and has high bioavailability in people, because dissolution
and absorption are not affected by gastric acidity or fasting in people.
 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350 345

Therefore, fluconazole most likely is absorbed rapidly in pediatric avian

patients and granivorous species with a higher pH of the stomach.
Itraconazole is essentially insoluble in aqueous solutions at a neutral pH,
but it is soluble in acidic solutions [9]. The oral and IV formulations have
a pH less than 5, and, if used directly on mucous membranes, they could
cause significant irritation. Fluconazole is water soluble with a near-neutral
pH, however, and it could be used directly on mucous membranes, but not
with the oral suspension. The spectrum of antifungal activity of fluconazole
is also very different than that for itraconazole. Itraconazole in an oral
capsule formulation (Sporonox) is erratic in its absorption; therefore an oral
solution formulation was developed that has greater bioavailability and
consequently greater efficacy [40]. Fluconazole, on the other hand, is readily
bioavailable and circulates in the plasma mostly as free drug. These factors
allow it to penetrate physiologically privileged sites such as the eye and
brain. It has negligible hepatic metabolism, while itraconazole has exten-
sive hepatic metabolism. Itraconazole is highly plasma protein-bound and
penetrates the brain poorly, but its active metabolite does concentrate in
brain tissue in birds [33,34]. Therefore, fluconazole would be ineffective in
treating an aspergilloma of the brain, even though it would accumulate
in brain tissue. A Candida infection of the infraorbital sinus should be
treated with fluconazole, however.
Only one study has investigated fluconazole use in birds. Fluconazole
was administered at 20 mg/kg every 48 hours or 10 mg/kg every 24 hours,
without problems noted in Goffin’s cockatoos, Timneh African gray
parrots, and orange-winged Amazon parrots for 14 days [44]. Detailed
pharmacokinetics have not been published, however. Even though no
adverse effects were noted in African greys in the study [44], clinical ex-
perience with its use suggests some African greys become partially to totally
anorexic.

Voriconazole and second-generation triazoles

Voriconazole is a second-generation triazole that can be administered
orally or intravenously. Its mechanism of action involves inhibiting fungal
P450-dependent 14-a demethylase in a dose-dependent manner. This drug
has had limited use in clinical patients and in vitro testing but appears to be
active against Aspergillus species, Candida species and C. neoformans [25,27].
In vitro testing with C. albicans, C. glabrata, and C. neoformans, however,
exhibited nonconcentration-dependent pharmacodynamics with voricona-
zole. Maximal fungistatic activity was approximately three times the MIC
[45]. If organisms were pretreated with voriconazole at the MIC, it resulted
in an increased kill by the polymorphonuclear leukocytes in the presence of
serum [17].
In general, this second-generation triazole has demonstrated an in vivo
efficacy in normal or immunocompromised animal models that was
346 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350

equivalent to or superior to itraconazole [46]. When used in clinical patients

that had failed previous treatment with amphotericin B or itraconazole, 9
out of 13 patients had a favorable response. Eleven patients experienced
mild-to-moderate visual disturbances of enhanced perception of light,
however [25]. Voriconazole appears to be absorbed well after oral ad-
ministration with peak serum levels at approximately 2 hours and steady-
state concentrations in the serum at 5 to 7 days with dosing every 12 hours.
Voriconazole, like itraconazole, is metabolized by the liver, and its
metabolites are excreted in the bile and urine. The drug is in phase II trials
[25].
Additional second-generation azoles include posaconazole and ravuco-
nazole [27]. These drugs work by similar mechanisms, which is a concern
with cross resistance between older and newer triazoles [5]. These drugs are
in clinical trials or pharmacokinetic evaluation in people only. They may
prove useful in birds, particularly those with Aspergillus species.

Echinocandins
Another group of compounds, the echinocandins, use a distinctly
different mode of action. They are semisynthetic derivatives of acrylated
cyclic hexapeptide antibiotics. These drugs result in osmotic fragility in the
fungal cell wall during synthesis that results in lysis, particularly at the tips
of emerging hyphae or buds. Lysis occurs because of inhibition of b1,3
glucan synthesis, a major structural component of the cell wall of asco-
mycetes and other fungi [45].
Drugs in the echinocandin category resulted from a search of the
biochemical metabolism of fungal metabolism that was distinctly different
from the enzymatic machinery for mammalian metabolism. This would
select for an antifungal action, while lowering mammalian toxicity.
A wide variety of clinically important Candida species and A. fumigatus
(both sensitive and resistant strains to amphotericin B) have been shown to
be sensitive to semisynthetic candins in vitro and in animal models of
disseminated infection [46]. It appears that Candida species that are insen-
sitive to the currently used azoles may be susceptible when exposed to the
echinocandins in vitro. When used initially in people, doses found to be
efficacious in animals were tolerated in people [47,48].
Elimination appears to be through biliary excretion. A 1-hour infusion
resulted in excretion over the next 27 days in human volunteers [49].
Semisynthetic drugs caspofungin and anidulafungin are being evaluated
further for clinical use. Caspofungin is being developed for once daily
parenteral use in those patients refractory to standard therapies for as-
pergillosis [49]. Further details on the pharmacology of these drugs may
suggest their safety and efficacy in avian species that are not tolerant of azole
therapy, particularly the African grey.
 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350 347

Allylamines
Allylamines represent a new class of antifungal agents that work by
inhibition of squalene epoxidase, which is a key enzyme in the biosynthesis
of ergosterol. This results in ergosterol depletion and the accumulation of
toxic sterols [8]. It is considered to be fungistatic [8] and fungicidal [50].
The formulation available of an allylamine is terbinafine (Lamisil). Oral
terbinafine, after absorption by the GI tract, first is metabolized and the
metabolites eliminated by excretion in the urine. It usually is prescribed
for dermatophyte infections in people at 250 mg per day. Although reports
suggest a broader use than just for dermatophytes and superficial mycoses,
it has been considered to have poor intrinsic activity against common
isolates of yeasts and molds, precluding its use for monotherapy [8]. Its
efficacy may be improved, however, when administered in combination with
azoles for treatment of azole resistant oral candidiasis and aspergillosis.
Further understanding of its pharmacology and its mechanism of action
may delineate appropriate dosing and frequency intervals for other fungal
infections.
In vitro, terbinafine is active against a broad spectrum of pathogenic
fungi. Additionally, clinical studies have determined it has been effective
in the treatment of cutaneous and lymphocutaneous sporotrichosis and
disseminated and refractory aspergillosis [50]. Doses for systemic infections
range between 5 to 15 mg/kg per day for a minimum of 84 days with lower
respiratory tract disease [51]. Higher doses of 250 to 2000 mg/70 kg day for
2 to 13 months were also used, however, for a clinical cure of 24 of 25
documented cases.
In vitro testing of terbinafine of C. albicans isolates from AIDS patients,
in combination with amphotericin B, fluconazole, and itraconazole, de-
monstrated synergistic activity [51]. There was synergy in 95% of isolates
at 24 hours, but that dropped to 30% by 48 hours. The two triazoles re-
tained synergy with 50% of the isolates at 24 and 48 hours, however. This
would suggest that terbinafine may be added to a treatment regimen when
monotherapy is not producing a clinical cure. In a series of three avian cases,
terbinafine was used successfully for upper and lower airway disease in a red-
lored Amazon, Congo African gray, and a harlequin macaw alone (two
of three) or in combination with IV conventional amphotericin B (one of
three) using an empirical dose of 10 mg/kg every 12 hours or once daily [52].
Two of three patients were nebulized with 500 mg terbinafine and 1 mL of
Mucomyst in 500 mL of water. Comparison of pharmacokinetic data in
people with empirical doses could be used to formulate a pharmacokinetic
study in avian species. Because systemic aspergillosis is very difficult to treat
in a variety of birds, higher dose pharmacokinetic studies designed for
refractory isolates would be extremely beneficial. Because terbinafine was
administered successfully in an African gray parrot at 15 mg/kg every 12
hours for 30 days without ill effect [52], it has great potential for use in
348 S.E. Orosz / Vet Clin Exot Anim 6 (2003) 337–350

systemic aspergillosis in these azole-sensitive species. Further studies are

needed to determine plasma levels and dosing intervals that could be
extrapolated to concentrations in people with clinical success. This drug
may provide a synergistic effect in some situations by addition to a treatment
regime. Caution should be used in avian patients with liver or renal disease,
however, because this drug is metabolized by these two organs. This could
be a particular problem if it is added to a treatment regimen using itra-
conazole in an avian patient with marginal liver function. Use of drugs
without appropriate pharmacokinetic data enhance fungal organism resis-
tance and should only be used when other, more established therapeutic
plans are not resulting in an improved clinical condition.

Acknowledgments
The author thanks the Lafeber Company for its support in producing this
manuscript.

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