Antifungal Drugs

Fungal infections are a common cause of disease in both animals and man. Many of the fungi and yeasts that cause disease in the animal population are zoonotic and so owners and vets alike are also at risk of infection. As this group of organisms are eukaryotic cells, trying to combat them becomes a more complex and challenging prospect as they have the ability to be toxic to the animal's own cells. Therefore it is important to understand how these drugs work, their potential side effects and which species they are active against.

Polyene Antifungals

This group of drugs are fungicidal and act by forming bonds to ergosterol. Since ergosterol is an important component of the cytoplasmic membrane of the fungal cell, disruption of the permeability of the membrane results leading to cell death.

The three most commonly used drugs in this group are:

Natamycin

This is active against many filamentous and dimorphic fungi and against yeasts.
It is only available in topical form for application to the udder, skin, nose, eye and ear.

Nystatin

It is effective against Candida, Pityrosporum, Cryptococcus, dermatophytes and some filamentous and dimorphic fungi.
It is also only available in a topical application form.

Amphotericin B

This can be used topically and systemically and is the most important drug for systemic mycoses.
It is broad spectrum and is active against deep mycotic infective agents. Though Aspergillus is quite resistant and 50% of yeast causing bovine mastitis are susceptible.
It isn't absorbed after oral administration but following intravenous administration it binds to lipoproteins and so is slowly released systemically.
There is some synergy with flucytosine and rifampin but is antagonistic if given with ketaconazole.
Care must be used when given to dogs and cats as renal toxicity always follows after its use.

The Azoles

These are synthetic fungistatic agents that interfere with ergosterol formation, this results in the fungal cell being uncapable to divide. It is very broad spectrum, but unfortunately the formation of ergosterol is very similar to the synthesis of mammalian sterols and hence has a very narrow therapeutic range.

There are two groups of azoles; imidazoles and triazoles. They differ thanks to an addition of a triazole ring, this results in the triazoles having greater half-lives, lower toxicity and potentially increased anti-fungal activities.

Imidazoles

Enilconazole

It is not absorbed after oral dosing and so has a wide safety margin.
It is only licensed for topical ringworm treatment, but has been used off-license (following the cascade) for Malassezia pachydermatitis infections and nasal aspergillosis.

Ketaconazole

It has good oral bioavailability if given with food; it needs an acidic pH to be absorbed.
It is metabolised by the liver into inactive compounds that are then excreted in bile.
It has been used for deep mycoses therapy, treatment of ringworm and nasal aspergillosis.
Toxicity is low but can result in inappetance, pruritis, alopecia and lightening of hair.
It has been known to be tetragenic and embryotoxic and so shouldn't be used with pregnant animals.

Triazoles

Itraconazole

It is more potent than ketaconazole but likewise needs an acidic environment to be absorbed, and has a wider spectrum of activity.
It is eliminated by hepatic metabolism.
It is used mainly to treat systemic fungal infections.
Can cause anorexia and hepatic toxicity in dogs. If this occurs, stop therapy until appetite returns and then continue treatment at half the dose.

Fluconazole

Can enter the CNS, unlike other azoles and so is used to treat feline cryptococcosis infections.
It can give some mild levels of hepatotoxicity.

Griseofluvin

This drug is a natural antifungal produced by Penicillium griseofulvum, it works by interacting with fungal microtubules and halts mitosis and so is fungistatic.
It has a narrow spectrum of activity only really inhibiting the growth of dermatophytes.
It's oral bioavailability is variable depending on its formulation. It is deposited in new keratin in the hair, nails and skin, and moves from deep layers to superficial layers where it can then attack the ringworm.
It is eliminated by hepatic metabolism.
It is teratogenic, so should never be given to pregnant animals. It can exacerbate liver damage and so function should be monitored. There have been reports in cats of bone marrow toxicity.

Flucytosine

This drug is converted by fungal cells into 5-Fluorouracil, which inhibits DNA synthesis and so is fungistatic.
It is very narrow spectrum and only works against Candida species and Cryptococcus neoformans infections.
It has very good oral bioavailability and distrubutes widely throughout all tissue including the CSF.

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Fungal infections