Antifungals

▪ Have been developed to treat the many fungal

organism that cause superficial mycoses such as
ringworm (skin infections) and deep and systemic
infections
▪ Number of agents expanding- increasing number of
fungal infections in humans
▪ Limited number only specifically licensed for vet med
▪ Most have severe adverse effects as drugs targeting
eucaryotic cells
▪ Most antifungal agents are fungistatic, require host
response
 Fungal infections

Ringworm in cattle

Ringworm in cat

Aspergillosis/
Rhinitis in a dog
 Fungal infections

Sporotrichosis in a dog

MRI Cryptococcus in
in cat

Blastomycosis- dog
 Canine
pythiosis

Worldwide distribution

Malasazzia spp
 Antifungals
Reasons for therapeutic failure:

▪ Host inflammatory response- fungal infections

particularly difficult in immunocompromised
▪ Location in protected areas- ie brain, eye, sinuses
▪ Rigid structure of some fungi
▪ Infection within host cells

▪ Discontinuation before resolution- long therapy

normally required
 The Fungal Cell Wall
mannoproteins

β1,3
β1,6
glucans

Cell β1,3 glucan chitin

membrane synthase
ergosterol

Atlas of fungal Infections, Richard Diamond Ed. 1999

Introduction to Medical Mycology. Merck and Co. 2001
 Antifungals
Anti-fungal antibiotics used in veterinary species
include:
• Amphotericin B – aspergillosis, histoplasmosis and
blastomycosis, cryptococcal infections
• Flucytosine- Cryptococcal and Candida infection
• Griseofulvin – “ringworm” infections
• Azole antifungals- internal and external fungal
infections, ringworm, yeasts
• Terbinafine- ringworm, Sporothrix
 Amphotericin B
“Fungizone”
“AmBisome”

• A polyene antibiotic
• Acts by binding to ergosterol on the fungal cell
membrane, disrupting cell membrane stability→ cell
death
• Effective against a broad range of filamentous fungi
• Also has an immunomodulatory effect
 Amphotericin B
Clinical applications
• Initial treatment of choice for rapidly progressing
systemic mycoses
• Initial treatment for cryptococcal meningitis but
diffuses poorly into CSF
• Animals with mycotic gastrointestinal disease where
vomiting prevents oral drug use
 Amphotericin B
Pharmacokinetics
• Poorly absorbed from GIT- primarily given
parenterally- IV
• Highly bound to plasma proteins
• Rapidly cleared from plasma, binds to
cholesterol-containing membranes in tissues
• High concs. in liver, kidney-
• Will cross inflamed pleura and synovium
• Low concs. in CSF, bone, eye and urine
• Metabolic fate unknown- very little metabolised
product found in bile or urine
 Amphotericin B
Adverse Effects
• Cumulative dose- related nephrotoxicity in
companion animals
• Up to 80% of dogs show some degree of
nephrotoxicity
• Due to strong vasoconstrictor effect on renal blood
flow
• Other AEs include fever, nausea, anorexia
 Flucytosine

“Ancotil”

• initially developed as an antineoplastic agent

• Infrequently used in vet med as an antifungal
• used in combination with other drugs
• achieves satisfactory concentrations in the CSF
 Flucytosine

• penetrates fungal cells where it is deaminated by

cytosine deaminase to fluorouracil. Fluorouracil acts as
an antimetabolite by competing with uracil ⇨
DNA synthesis is halted.
• principally active against strains of Cryptococcus and
Candida.
• Synergistic with amphotericin B, combined therapy in
cryptococcal meningitis
 Flucytosine

Adverse Effects:
• GI disturbances;
• Potentially-dose dependent bone marrow
depression, cutaneous eruption & rash, oral
ulceration, increased hepatic enzymes, CNS effects in
cats.
Use with caution:
• Patients with renal impairment, hepatic disease,
pre-existing bone marrow depression, hematologic
diseases
 Azole antifungals
Two groups
• Imadazoles
– Miconazole
– Enilconazole Miconazole
– Clotrimazole
– Ketoconazole
• Triazoles
– Fluconazole
– Itraconazole
– Voriconazole
Fluconazole
 Azole antifungals
• Now the initial treatment of choice for all but the most
rapidly progressing systemic fungal infections
• Can treat mycoses on an outpatient basis with oral
medication
• Work more slowly than Amphotericin B (4-10 days)
• are potent inhibitors of mammalian cell cytochrome P450
• Decreased synthesis of testosterone, cortisol,
cholesterol, and androgens may occur during azole
administration
• Some are immunosuppressant- inhibit T-lymphocyte
proliferation
 Acetyl CoA

Squalene

Terbinafin Squalene epoxidase

e
Lanosterol

Azoles 14-demethylase

Ergosterol
Sites of enzyme inhibition by antifungal drugs in ergosterol
pathway
 Ketoconazole
“Nisoral”
• used regularly in veterinary medicine, but its use is
being supplanted by newer antifungal agents.
• lower efficacy against many fungal organisms
compared with itraconazole and voriconazole,
• greater potential for adverse effects.
 Ketoconazole
Potential indications
• systemic treatment of otitis and dermatitis caused by
Malassezia spp
• infections caused by Candida species and
Microsporum canis.
• has also been used to treat serious systemic
mycoses- supplanted by newer drugs
 Ketoconazole
Pharmacokinetics
• Ketoconazole is variably absorbed when
administered orally in dogs. No studies in dogs have
examined the effect of feeding but is recommended
to be given with food
• Ketoconazole is highly protein-bound (> 98%) and
penetrates poorly into protected (CNS, eye, prostate)
• eliminated primarily by hepatic metabolism
• T ½ very short (data from dogs)
• No data are available on ketoconazole in cats.
 Ketoconazole
Adverse effects
• nausea, anorexia, and vomiting; more frequently at
higher dosages.
• Pruritus, alopecia, lightening of the coat, & weight loss -
long-term therapy.
• Hepatic demage- cats may be more sensitive
• Ketoconazole is teratogenic and not recommended for
use in pregnant or lactating animals.
• Inhibition of testosterone has resulted in gynecomastia,
impotence, and azoospermia in humans
• Cortisol production is also inhibited by ketoconazole,
more so in dogs than in cats *
• is a Pgp efflux pump inhibitor.
 Itraconazole

“Itranox” “Intraconazole” “Sporanox”

• preferred to ketoconazole for most fungal infections in
humans
• It is available as 100-mg capsules and as a suspension (10
mg/ml). The capsules contain beads coated with
itraconazole, which facilitates drug absorption from the
intestines.
 Itraconazole
Potential indications
• Clinical uses for itraconazole include treating all of the
fungal infections listed for ketoconazole, but itraconazole
is preferred because of its increased activity and
decreased adverse effects.
 Itraconazole
Pharmacokinetics
• highly protein-bound (> 99%) but is well-distributed
throughout the body.
• accumulates in skin, liver, fat, and the adrenal
medulla.
• does not reach MIC in CSF
• Itraconazole is variably absorbed after oral
administration in dogs and cats
• Primarily eliminated by hepatic metabolism and
biliary secretion
• T ½ long (28- 30 hrs) dogs and cats
 Itraconazole
Adverse effects

• better tolerated than ketoconazole in dogs and cats.

• can result in nausea, vomiting, and anorexia,
• Hepatotoxicosis may occur in as many as 10% of dogs
receiving long-term treatment with itraconazole
• has minimal effects on cortisol testosterone
concentrations.
• is also a Pgp efflux pump inhibitor.
 Enilconazole
“Imaverol”
• Available as topical preparation UK, ROI

Indications
• For the treatment of dermatomycoses in cattle, horses
and dogs induced by the following pathogenic fungi:
Trichophyton verrucosum
Trichophyton mentagrophytes
Trichophyton equinum
Microsporum canis
Microsporum gypseum
 Enilconazole
Pharmacokinetics
• Systemic availability after topical administration of
enilconazole in animals is very low.
• extensive first-pass metabolism after oral
administration. Tissue residues are almost
non-existent.
• extensively metabolised, main excretion routes are
urine and faeces.
• Excretion in the milk from cattle is very limited.
“Dermatophytes will extend
into the hair follicles. Possible
crusts must therefore be
removed with a hard brush
which has been
soaked in the diluted Imaverol
emulsion.
It is highly recommended that
the animal is sprayed entirely
at the first treatment so as to
reach the subclinical lesions
as well.
Treatment 4 times at 3 day
intervals”
 Enilconazole

Adverse effects
• hypersalivation, idiopathic muscle weakness and
slightly elevated serum alanine aminotransferase
(ALT) concentrations has been reported in cats
• Emesis when used as an intranasal infusion in dogs
• Considered potentially carcinogenic in humans
 Other Azoles
Clotrimazole (ie “Canesten”) and miconazole
(“Daktarin”) are recommended for use in topical
yeast infections, superficial dermatophytes, and for
use as intranasal infusion in nasal aspergillosis
 Other Azoles
• Fluconazole (“Diflucan”)- treatment of choice for
cryptococcus CNS infections as can penetrate CNS-
poor activity against dermatophytes
• Voriconazole (“Vfend”) and posaconazole
(“Noxafil”)= newest azoles- available in USA- limited
information available for dog and cat, and are costly
 Griseofulvin
“Grisol- V” “Fulvicin” “Grysio” “Gryfungal”
• Fungistatic drug
• Derived from Pennicillium griseofulvum
Indications and spectrum
• Indicated and approved in many countries for treatment
of dermatophtic infections of hair, skin (and claws) of
dogs, cats, horses
• not active against Candida albicans, Aspergillus
fumigatus and other systemic fungal infections.
 Griseofulvin
Mechanism of action
• Binds to tubulin, interfering with microtubule
function, thus inhibiting fungal mitosis.
 Griseofulvin
Pharmacokinetics
• irregularly absorbed from the GIT - absorption
enhanced by fatty meal
• is deposited in keratin precursor cells and is
concentrated in the stratum corneum of the skin and
in the nails and hairs, thus preventing fungal invasion
of newly formed cells.
• metabolised in the liver mainly to
demethylgriseofulvin → excreted in the urine.
• A large amount appears unchanged in the faeces:
• Less than 1% is excreted unchanged in the urine:
some is excreted in the sweat
 Griseofulvin
Adverse effects
• Long-term administration
reported to be hepatotoxic in
cats and to induce hepatomas in
mice and thyroid tumours in rats
- but not in hamsters.
• Griseofulvin may be teratogenic -
handler precautions
 Griseofulvin

Adverse effects
• Vomiting, diarrhoea, and anorexia- more often cats
than dogs
• Bone marrow suppression in kittens- should not be
used in kittens under 8 weeks of age
• In general adverse reactions more common in
Himalayan, Abyssinians, Persian and Siamese cats
 Terbinafine
“Lamisil”
• Orally and topical antifungal
• Good efficacy against dermatophytes
and yeasts
• Inhibits squaline epoxide
• does not affect steroid synthesis as do
the imidazoles
• Fungicidal
• Shows great promise for future use in
treatment of dermatophytes in cats
• has activity against Aspergillus,
Blastomyces, Histoplasma, Sporothrix
and Cryptococcus.
• not very effective for pythiosis
Recommended further reading

Moriello KA, Coyner K, Paterson S, Mignon B (2017) Diagnosis

and treatment of dermatophytosis in dogs and cats.: Clinical
Consensus Guidelines of the World Association for Veterinary
Dermatology. Vet Dermatol. Jun;28(3):266-e68. doi:
10.1111/vde.12440.
 Case study

Abstract
This report describes the clinical findings, clinicopathology and treatment
of otomycosis caused by Aspergillus spp. in an atopic dog affected by
chronic unilateral purulent otitis externa unresponsive to topical and oral
antibiotics and antifungal treatments.
Cytology of otic exudate revealed neutrophils and septate fungal hyphae,
and otic culture grew Aspergillus spp. and no bacteria. Treatments
included allergen-specific immunotherapy, topical and oral antifungal
therapy and anti-inflammatory steroid therapy.