Ergosterol: fungal version of cholesterol in cell membrane

Polyenes

• Bind to ergosterol in the fungal cell membrane �?formation of pores in the fungal membrane �?disruption of electrolyte balance �?cell lysis �?cell death
  • It binds cholesterol to a degree, which explains a large number of its adverse effects.

Amphotericin B

Adverse effects

• Nephrotoxicity: Lipid-based formulations of the drug and IV hydration reduce nephrotoxicity.
• IV phlebitis
• Impaired renal tubule permeability �?hypokalemia and hypomagnesemia (restoring K⁺ and Mg2+ while administering the drug can counter this effect)
• Fever, chills (amphotericin B is sometimes referred to as “shake and bake�?
• Bone marrow suppression, anemia
• Arrhythmias

Nystatin

• Routes of administration (too toxic for intravenous use)
  • Topical
    • Vaginal candidiasis
    • Diaper rash
  • Oral (swish and swallow): oropharyngeal candidiasis

Azoles

• Mechanism of action
  • Inhibition of 14-alpha demethylase, a fungal cytochrome P450 �?�?fungal synthesis of ergosterol from lanosterol �?�?levels of ergosterol �?membrane instability �?cellular death.

Allylamine derivatives (terbinafine)

• Route of administration: oral
• Mechanism of action: inhibition fungal squalene epoxidase �?�?synthesis of ergosterol �?accumulation of squalene �?�?membrane permeability �?cell death
• Clinical use
  • Dermatophytosis (most commonly onychomycosis)
  • Tinea infections (e.g., tinea pedis)
• Adverse effects
  • Hepatotoxicity
  • Dysgeusia
  • Gastrointestinal upset
  • Headache

Echinocandins

• Drugs
  • Caspofungin
  • Anidulafungin
  • Micafungin
• Route of administration: IV
  • Mechanism of action: inhibition of β-glucan synthesis �?disruption of fungal cell wall synthesis �?�?resistance against osmotic forces �?cell death
• Clinical use
  • Invasive aspergillosis
  • Invasive candidiasis (particularly biofilm-embedded Candida )
• Adverse effects
  • Flushing (due to release of histamine)
  • Hepatotoxicity
  • Gastrointestinal upset

Benzofurans (griseofulvin)

• Route of administration: oral
• Mechanism of action: griseofulvin binds to keratin precursor cells �?accumulation in keratin-rich tissues (e.g., nails, hair) �?entry into the fungal cell �?interference with microtubule function �?disruption of fungal mitosis
• Clinical use: dermatophyte infections (e.g., tinea pedis)

Antimetabolites (flucytosine)

• Route of administration: oral
• Mechanism of action: converted to 5-fluorouracil by fungal cytosine deaminase, thereby inhibiting DNA and RNA synthesis