Anti-Fungal Therapy Flashcards
3 Types of Fungal Infections
1) SUPERFICIAL - skin/hair/nails
2) SUBCUTANEOUS - dermis/subcutaneous tissue/adjacent structures
3) SYSTEMIC - internal organs
What is the difference between superficial/subcutaneous and systemic fungal infections?
Superficial/subcutaneous - Can occur in healthy individuals
Systemic - Opportunistic fungal infections that occur in diseased/immunocompromised conditions
[HIV epidemic, cancer chemotherapy usage, organ Tx immunosuppressive therapy, autoimmune, widespread usage of antibiotics]
3 Anti-fungal Drug Classifications
1) SYSTEMIC (oral/IV)
2) SYSTEMIC drugs for MUCOCUTANEOUS infections
3) TOPICAL drugs
Anti-fungal Drug Targets (unique to fungi and absent in humans)
1) CELL WALL
2) CELL MEMBRANE (fungi use ERGOSTEROL instead of cholesterol in human cells)
3) DNA SYNTHESIS
Anti-fungal cell membrane targeting drugs:
Amphotericin B (used for systemic fungal infections)
Azoles (Imidazoles [K,C,M] + Triazoles [I,F,V,P])
Allylamines
Nystatin (NOT used for systemic fungal infections)
Anti-fungal cell wall targeting drug
Echinocandins (C,A,M)
Anti-fungal DNA synthesis targeting drug
Flucytosine
What is the structure of amphotericin B (most commonly used anti-fungal drug) AND nystatin?
Macrolide with an AMPHIPATHIC ring structure (hydrophilic + hydrophobic components)
What is the difference in medication usage between amphotericin B and nystatin?
Amphotericin B - used for systemic (opportunistic) infections
Nystatin - NOT used for systemic (opportunistic) infections
Mechanism of AMPHOTERICIN B + NYSTATIN
Amphipathic molecule:
NONPOLAR side: Binds SELECTIVELY to ergosterol (fungal cell membrane) and not cholesterol
POLAR side: Forms pores for ion efflux leakage -> Kills fungi
Which fungal species display intrinsic amphotericin B resistance?
Candida lusitaniae
Pseudallescheria boydii
What is the drug of choice for nearly ALL life-threatening systemic fungal infections?
Amphotericin B
Amphotericin B Clinical Usages
1) Life-threatening systemic infections - Often used as INITIAL treatment in critical cases -> TRIAZOLES (CHRONIC therapy/Relapse preventions)
2) Topical drops for mycotic corneal ulcer/keratitis
3) Local injection for fungal arthritis
Amphotericin B Administration
1) Suspension by IV (in deoxycholate lipophilic soln) - Since amphotericin B is INSOLUBLE in water
2) Oral - Only if it is a GI infection (poor drug absorption)
Preparation for reducing amphotericin B’s high toxicity
LIPOSOMAL PREPARATION - drug formulated in a lipid package
Enables higher doses with reduced nephrotoxicity
Most common problematic toxicity of Amphotericin B
RENAL DAMAGE (slower toxicity)
Acute (infusion-related) Toxicity of Amphotericin B __
How can this be managed?
Fever/chills/vomiting/headache/hypotension
Managed by:
1) Decreasing dose
2) Premedication with antipyretics (oral acetaminophen), antihistamins, meperidine, hydrocortisone
Slower toxicity of Amphotericin B
Renal Damage
Anemia
Occasional impaired liver function
Main precautionary element of drug interactions regarding Amphotericin B
Avoid administration if other nephrotoxic drugs are being administered as well (cyclosporine + aminoglycosides)
Mechanism of FLUCYTOSINE
1) Uptake by fungal cytosine permease
2) Conversion to 5-FU by cytosine deaminase
3) INHIBIT RNA synthesis: 5-FU converted to 5-FUTP
4) INHIBIT DNA synthesis: 5-FU converted to 5-FdUMP -> Inhibits thymidylate synthase
Selectivity of flucytosine: What can flucytosine target that human cells do not have?
CYTOSINE DEAMINASE: 5-flucytosine (5-FC)’s conversion to 5-FU by this enzyme
Mammalian cells poorly convert 5-FC to 5-FU