Antifungal Agents

What are Therapeutic challenges in animals?

Fungal cell walls

Cell membranes - ergosterol

Slime layers

Intracellular

What two drugs are the only ones that can get into the fungal cell?

Griseofulvin

Flucytosine

What are pharmacodynamics of Polyene (Amphotericin B, Nystatin, Natamycin)?

Poor formation in fungal cells via interactions w/ ergosterol

What is the spectrum of Amphotericin B?

Broad anti fungal spectrum - Fungalcidal

What are the indications of Amphotericin B?

- Severe systemic fungal infection

-Fungal keratitis

What drugs will Amphotericin B be combined w/ to reduced toxicity?

Ketoconazole

Fluconazole

Itraconazole

What drug will we combine Amphotericin B to get into the CNS, Bone or ocular infections?

Flucytosine

What are pharmacokinetics of Amphotericin B?

IV/SQ (not absorbed orally)

Doesn't get to eye, bone, BBB

Slow excreation in the kidney - unchanged

What are AE of Amphotericin B?

Renal toxicity - renal vaso constriction - monitor frequently

What animals do you not have to worry about nephrotoxicity in w/ Amphotericin B?

Birds - shorter 1/2 life

What are the indications for Nystatin and Natamycin?

Funglicidal to yeast infections caused by Candida and Malassezia

What is the DOC for Equine fungal keratitis caused by Fusarium?

Natamycin

Why are AE rare w/ Nystatin and Natamycin?

Not well absorbed orally/ systemically - usually a topical administration

What are pharmacodynamics of Azoles?

Fungal static - Inhibits synthesis of ergosterol and leads to toxic intermediate sterols accumulation

What are pharmacokinetics of Azoles?

Wildly distributed

Liver metabolism

Bile excretion

Which two Azoles can get into the CNS? Which do we use more and why?

Fluconazole - cheeper - used more

Voriconazole

What are indications for ketoconazole?

Systemic mycoses, severe yeast infections

Topicals of ketoconazole are used for ___

oral uses of ketoconazole are used for?

Dermatophytes

Systemic mycotic infections

What are indications for Voriconazole?

Equine fungal keratitis - ophthalmic compounded

Blastomyces, Cryptococcus, Asperggillus

What are indications for Itraconazole?

Ophthalmic ointment for fungal keratitis in horses

What are indications for fluconazole?

Cryptococcal meningitis

Fungal UTIs- accumulates in urine

Coccidioides

What animal is clotrimazole and miconazole not effective in for tx dermatophyte infections?

Cats

What are indications for Clotrimazole?

Combined w/ betamethasone and gentamicin for otic use in dogs

What are indications for miconazole?

Equine fungal keratitis

Malassezia dermatitis - topical

When would we used Posaconazole?

For itraconazole or fluconazole resistant infections in cats and small dogs - very expensive

What are AE of all Azoles?

Worst in cats

P450 inhibitor

General GI issues

Which Azole has the worst AE?

Ketoconazole

-GI,

-Hepatotox

-Drug interactions - (used w/ cyclosporin to make last longer)

Which Azole has the least AE and is best tolerated?

Fluconazole

What are Pharmacodynamics of Terbinafine?

Fungicidal

Interferes w/ sterol biosynthesis

toxic build of of squalene

What are Indications for Terbinafine?

Dermatophyte skin infections - Cats and dogs

Oral tx in birds of Aspergillosis

What are pharmacokinetics of Terbinafine?

Oral

High PPB

Metabolized in liver

Urine excretion

What are AE of Terbinafine?

Well tolerated - few AE - no drug interactions

What are pharmacodynamics of Griseofulvin?

Fungistatic

Binds microtubules and destroys the mitotic spindle

What are Indications for Griseofulvin?

dermatophyte infections

Ring worm in horses

What are phamacokinetics of Griseofulvin?

Distributes to keratin precursor cells of skin, hair shafts and nails - prevents spread of infection

What are the AE of Griseofulvin?

Leukopenia and Anemia - cats

Photosensitivity,

Anorexia

Hepatooxicity

Teratogenic - cat/ horse

What are pharmacodynamics in Flucytosine?

Metabolic antagonism of fungal DNA/ RNA

-5-fluorouracil (prodrug)

What does Flucytosine require to function?

Cytosine deaminase - seen in bacteria and fungus

What are indications for Flucytosine?

Fungicidal - cryptococcus, Candida, Aspergillus

Meningeal Cryptococcus - (combine w/ Amphotericin)

What are pharmacokinetics of Flucytosine?

PO

BBB

Urine unchanged

What are AE of Flucytosine?

Mild GI

poss bone marrow suppression