4 – Antifungals

Question 1

What are the 2 categories of drugs for antifungal therapy?

Answer 1

• Systemic
• Topical
  o Can’t give systemically: toxic or not absorbed well

Question 2

What are the main systemic antifungals?

Answer 2

• Azole antifungals
  o Ketonconazole
  o Itraconazole
  o (fluconazole)
• (Amphotericin B)

Question 3

What are the types of fungal infections?

Answer 3

1. Superficial mycoses
   a. Affect the skin, hair and nails
2. Systemic (invasive) mycoses
   a. Involve internal organs
   b. Primary vs. opportunistic
   c. Prolonged duration of therapy typically required (months)

Question 4

What are the targets for antifungal therapy?

Answer 4

1. Ergosterol in cell membrane instead of cholesterol
2. Not many go after fungal DNA synthesis
3. CHITIN in cell wall

Question 5

(Amphotericin B)

Answer 5

• Only used in clinicals (IV)
• *severe, systemic fungal infections
• Binds to sterols in fungal cell membrane
• Broad range, no effect on bacteria or rickettsia
• Toxic (but not completely acting on ergosterol)
• *monitor renal parameters

Question 6

(Amphotericin B) toxicity

Answer 6

• ESPECIALLY IN CATS
• NEPHROTEOXIC (decreased GFR)
  o Reversible at first, but irreversible with prolonged use
• Anorexia, vomiting
• Anemia

Question 7

What is (Amphotericin B) used for?

Answer 7

• Used for invasive fungal infections in dogs, cats, horses
  o Aspergillosis
  o Blastomycosis
  o Cryptococcous
  o Candida

Question 8

Systemic azoles (oral/injectable) and vet use

Answer 8

• Most NOT currently licensed for vet use
  o Human formulations are used
  o **Exception: Itrafungol (cats) (Itraconazole): use extra label in dogs

Question 9

What are the ‘azole’ mechanism of action?

Answer 9

• Bind to cytochrome P450 enzyme complex
  o Can impact mammalian CYP450 enzymes
• Inhibits synthesis of ERGOSTEROL
  o End result=damage fungal cell membrane

Question 10

What is a CYP450 function normally?

Answer 10

• Converts lanosterol to cholesterol
• Required for synthesis of steroid hormones, including cortisol and reproductive steroids
  o *ketoconazole used to treat hyperadrenocorticism (BUT better options available)
• Significant drug interactions (ex. cyclosporine mixed with ketoconazole=not a good idea)

Question 11

What are the general PK/PD of ‘azoles’?

Answer 11

• Possible concentration-INDEPENDENT fungistatic agents

Question 12

What is the goal of dosing with ‘azoles’?

Answer 12

• MAINTAIN 1-2x minimum inhibitory concentration (MIC) of fungal species for entire dose interval
  o Frequent dosing and a LONG time (2-3 months)

Question 13

‘azole’ antifungal resistance

Answer 13

• Develop resistance oer time
• Failure of drug accumulation in the pathogen
  o DECREASED drug INFLUX
  o INCREASE drug EFFLUX
• *changes in drug interaction with target enzymes in ergosterol synthesis pathway

Question 14

*What are the formulations of ketoconazole?

Answer 14

• oral tables and suspensions
• topical creams/shampoos
• *all human products
• **TOPICAL OR SYSTEMIC

Question 15

*What is ketoconazole used for in vet med?

Answer 15

• Treat mycotic infections due to
  o Yeast
  o Systemic fungi (Blastomycosis, Cryptococcosis, etc.)
  o Dermatophytes

Question 16

*What are the adverse effects of Ketoconazole?

Answer 16

• Hepatic toxicity (especially in CATS)
  o Dose-dependent
  o Monitor liver enzymes
  o Watch for drug interactions
• GI: nausea, vomiting, anorexia (not as serious)
  o Dose-dependent
  o Decrease AE if administered with food
• *less toxic than Amphotericin B

Question 17

**Itraconazole formulations

Answer 17

• Itrafungol oral solution licensed for use in cats (labeled only for dermatophytosis, but can be used systemically)
• Human products: oral capsules or solutions (Ex. Sporanox)
• *typically expensive but safer and more effective than most antifungals
• *compounded is very SKETCH- *FORMULATION matters to get adequate oral bioavailability

Question 18

**What are the PK of Itraconazole?

Answer 18

• Increased oral bioavailability when given with food
• High volume of distribution
  o Accumulates in hair/skin

Question 19

**Itraconazole compared to ketoconazole

Answer 19

• More potent antifungal activity
• Similar AE but generally SAFER (may be able to go longer with a higher dose)
• Similar hepatic CYP45- metabolism and potential drug interactions

Question 20

What are the clinical uses of Itraconazole?

Answer 20

• Itrafungol label
  o Dermatophytes
  o Yeasts
  o Various dimorphic fungi, zygomycetes and eumycetes

Question 21

What are some extra-label uses of Itraconazole?

Answer 21

• Systemic fungal diseases: blastomycosis (dogs), cryptococcus (cats)
• Horses: guttural pouch mycosis, nasal aspergillosis, fungal keratitis

Question 22

(fluconazole)

Answer 22

• No vet formulations
• Penetrates well into tissues and CROSSES BBB
• Limited hepatic metabolism, mostly EXCRETED IN URINE
• Expensive
• Narrower antifungal spectrum
• *fungal CNS infections (fungal meningitis) OR animals with severe hepatic disease

Question 23

What examples of topical antifungals?

Answer 23

• Azoles
  o (miconazole)
  o (clotrimazole)
• (terbinafine): *do NOT need to be administered every day (once and then a week later)

Question 24

What is important to know about topical azoles?

Answer 24

• Use them way more than the systemic antifungals
• *3 active ingredients (antifungal + antibiotic + steroid)
• *used against SUPERFICIAL skin/ear mycotic infections

Question 25

Why do we not use topical azoles systemically?

Answer 25

• NOT SAFE
• Rapid hepatic enzyme induction (increase drug clearance)
• Serious AE
• *not a problem as there are no formulations for systemic use