Five main groups of Antifungals

• Allylamines - Terbinafine, Naftifine
• Azoles-Miconazole, Clotrimazole, Ketoconazole, Itraconazole, Fluconazole, Enilconazole
• Polyenes-Amphotericin B, Nystatin, Natamycin
• Flucytosine (5-FC)
• Griseofulvin

Consistently Fungistatic Drugs

Azoles

Griseofulvin

Fungistatic/fungicidal Drugs

• Depends on organisms involved and concentration of drug present

Flucytosine (5-FC)

Allylamines

Consistently fungicidal drug

Polyenes

Administration time of Antifungals

• With exception of polyenes, anti-fungals only fxn vs. replicating fungi (which replicate slowly). So must be administered for a prolonged period of time

Antifungals that inhibit/disrupt cell membrane function/synthesis

Allylamines

Azoles

Polyenes

Antifungals that inhibit nucleic acid synthesis

Flucytosine (5-FC)

Griseofulvin

Criteria for Selection of Antifungals

1. Determining which drug or drug class has activity vs. organism of interest (dermatophytes, moles, and/or yeast)
2. Availability of particular drug in desired dosage form
3. Relative toxicity of selected drug

Examples of allylamines

Naftifine (Naftin)

Terbinafine (Lamisil)

Mechanism of Allylamine Action 

• Following either topical or oral admin, concentrates in nail and skin
• Binds to enzyme that converts squalene to lanosterol (precursor of ergosterol synthesis) --> cell membrane synthesis/function disrupted --> increased permeability such that contents leak out of cell
• ONLY VS REPLICATING FUNGI

Spectrum of Allylamines activity

Fungicidal vs. dermatophytes

Terbinafine can sometimes be used as fungistatic drug vs. cryptococcus

Use for Allylamines

• Following topical/oral admin, concentrates in nails/skin so great for dermatophyte infections (Metabo in liver so if PO, must be monitered by blood)
• Terbinafine occasionally used for crypto infections

Adverse effects of Allylamines

Since allylamines target fungal-specific enzyme, neither topical/oral admin results in significant adverse effects. However, liver metabolism, so must check blood for liver function if given PO

Examples of Azoles

• Miconazole (Monistat): Topical
• Clotrimazole: Topical
  
• Enilconazole: Topical
  
• Ketoconazole (Nizoral): Topical/Oral - Mod distribution - hepatic metabolism
• Itraconazole (Sporanox): Topical/Oral - Mod distribution - hepatic metabolism
• Fuconazole (Diflucan): Oral/IV - Excellent distribution Excreted Unchanged in urine

Mechanism of Azole Activity

• Azole binds to enzyme that converts lanosterol to ergosterol --> disruption of cell membrane synthesis/function --> Increased cell permeability and leaking of cell contents
• FUNGISTATIC only effective vs. REPLICATING cells

Spectrum of Azoles Activity

• Dermatophytes
• Yeasts (Blastomyces dermatitidis, Histoplasma capsulatum, Cryptococcus neoformans, Candida, Coccidioides immitis, Sporothrix schenkii, Malassezia)
• Molds (Aspergillus)

**Broad Spectrum**

Uses for Azoles

• Topically for treatment of eye, skin, and vaginal fungal infections
• Dermatophyte infections, Mycotic otitis externa (Malassezia), Equine fungal keratitis (Aspergillus), Guttural pouch mycosis (Aspergillus), Vaginitis (Candida)
• PO for systemic fungal infections (Cryptococcosis, histoplasmosis, coccidiomycosis, blastomycosis, aspergillosis)

Adverse Effects of Azoles

• Clotrimazole, miconazole, and enilconazole very toxic so only use topically (No adverse effects if topical)
• Systemic admin of ketoconazole and itraconazole = hepatotoxis, teratogenic/carcinogenic. Only PO
• Fluconazole excreted unchanged in urine, so few if any adverse effects. Therefore, IV and PO.

Examples of Polyenes

Amphotericin B (Fungizone)
Natamycin
Nystatin (Panalog)

Mechanism of Polyene Activity

• Do not penetrate tissues well, so must administerdirectly to site of infection (IV or intrathecal for systemic fungal infections)
• Polyenes bind ergosterol and interact with the fungal cell membrane to form a pore in the cell membrane --> Intracellular potassium, nutrients, etc... leak out and the internal osmotic pressure is not maintained. Damage is irreversible so the cell dies.

**FUNGICIDAL and affects both Growing and Stationary phase fungi**

Spectrum of Activity for Polyenes

• Molds: Aspergillus
• Dermatophytes
• Yeasts: Blastomyces dermatitidis, Histoplasma capsulatum, Cryptococcus neoformans, Candida, Coccidioides immitis, Sporothrix schenkii, Malassezia
• Algae: Prototheca spp
• Protozoa: Leishmania sp, Naegleria fowleri

Uses for Polyenes

• Primarily topical applications
• IN for guttural pouch mycosis (Aspergillus)
• Oral for thrush
• Topically for mycotic keratitis (Aspergillus)
• Topically for otitis externa in dogs (Malassezia sp)
• Topically for dermatophyte infections (Microsporum, Tichophyton)
  
• Rarely systemic fungal infections
• IV/intrathecal: cryptococcosis, histoplasmosis, coccidiomycosis, blastomycosis, aspergillosis
• Nystatin used topically and orally (for GI fungal infections). Natamycin only topically (Equine fungal keratitis) Very insoluble and can be used topically without systemic adverse effects.
  
• Amphotericin B is used topically and only one to be used IV. In human med, used to treat systemic fungal infections and Naegleriosis. Rarely in vet med due to side effects
  

Amphotericin B is often combined with ____ b/c _____

Fluconazole or Flucytosine (5-FC)

Synergistic activity as well as ability to reduce dose and minimize adverse effects

Adverse effects of Polyenes

• None if given topically
• Systemic admin of amphotericin B due to cross-reactivity with cholesterol:
• Nephrotoxicity: associated with binding of distal renal tubular cells and vascular sm mm cells. Must monitor patient renal function
• Hepatotoxicity
• Neurotoxicity: During IV infusion, may exhibit fever, vomiting, depression, and severe shaking
• Thrombophelbitis

Brand name for Flucytosine (5-FC)

Ancobon

Mechanism of flucytosine (5-FC) Action

• Flucytosine (5-FC) is structural analogue of cytosine (which can be converted to uracil as well)
• Taken up by fungal cells via cytosine permease, which normally works to scavange cytosine. Upon uptake 5-FC deaminated to 5-fluorouracil by cytosine deaminase. 5-fluorouracil is converted to 50fluorouridine monophosphate (F-dUMP) and fluorouridine triphosphate (F-UTP)
• F-dUMP cannot be converted by thymidylate synthetase into dTMP, so DNA synthesis blocked
• F-UTP competes with uracil for incorporation into RNA. mRNA containing fluorouracil instead of uracil cannot be translated for protein synthesis

**ONLY WORKS with fungi that have cytosine permease and cytosine deaminase (Cryptococcus, Aspergillus, and Candida). AND ONLY WORKS vs. replicating fungi**

***Usually fungistatic, but can be fungicidal***

Spectrum of Flucytosine (5-FC) Activity

• Yeasts - Cryptococcus and Candida
• Molds: Aspergillus

**ONLY replicating/growing fungi that have cytosine permease and cytosine deaminase**

Use for Flucytosine (5-FC)

• Orally for treatment of systemic cryptococcosis, candidiasis, or aspergillosis (rarely used due to expense).
• Admin in combo with azole (fluconazole, itraconazole) or Amphotericin B
• So expensive rarely used

Pharmacokinetics and Adverse Effects of Flucytosine (5-FC)

• Only administered PO: well-absorbed and distributed and penetrates virtulaly all tissues
• Excreted unchanged in the urine
• Targets fungal enzymes, so few, if any adverse effects: nausea, vomiting, rashes common

Resistance to Flucytosine (5-FC)

• Readily occurs: Loss or decreased activity of cytosine permease, cytosine deaminase, and/or uridine pyrophosphorylase
• Due to easy resistance developments, ususaly used wtih amphotericin B or one of the azoles (itraconazole, fluconazole).
• Combo with amphotericin B synergistic b/c amphotericin B increases fungal permeability. Also allows for lowering of amphotericin B dosage

Brand Name for Griseofulvin

Fulvicin

Spectrum of activity for Griseofulvin

ONLY DERMATOPHYTES

Mechanism of Griseofulvin Action

• MUST be given PO because topical application does not penetrate to deeper layers of skin
• Absorption from GIT enhanced by using smaller particle sizes and administering with a fatty meal. Will concentrate in keratinized tissue
  
• Binds microtubules
• Inhibits mitotic spindle formation during cell division such that DNA replication and cell division during metaphase are blocked
• May also damage DNA such that it is unable to replicate (fungicidial)
• Results in inhibition of hyphae formation (fungistatic)
• Concentrates in basal cells of epidermis and carried with them as they mature and form barrier to further hyphal penetration.
  

**ONLY vs. growing/replicating cells --> Infection eradicated only after keratinized structures are shed and replaced by uninfected tissue. Treatment is very slow process. Clip hair/nail to speed up **

Adverse Effects of Griseofulvin

• Teratogenicity (cleft palate, skeletal and brain malformation in kittens). DO NOT GIVE to pregnant animals
• Carcinogenicity (Cross-reacts with mammalian microtubules). DO NOT GIVE to food animals
• GI upset (Nausea, vomiting, diarrhea). GIVE WITH FOOD.
• Inhibits spermatogenesis