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Microbiology

Antifungal Classes

Understanding the different classes of antifungal agents, their mechanisms of action, and their spectrum of activity is essential for interpreting susceptibility testing results and guiding appropriate therapy. We’ll cover the major classes of antifungals, including azoles, polyenes, echinocandins, and others, highlighting their key characteristics

Classes of Antifungal Agents

Azoles

  • Mechanism of Action: Azoles inhibit the synthesis of ergosterol, a crucial component of the fungal cell membrane. They bind to and inhibit the enzyme lanosterol 14-alpha demethylase (CYP51), which is involved in the conversion of lanosterol to ergosterol. This leads to a depletion of ergosterol and an accumulation of toxic sterol intermediates, disrupting the cell membrane and inhibiting fungal growth
  • Spectrum of Activity: Azoles have a broad spectrum of activity against many yeasts and molds, but their activity varies depending on the specific azole and the fungal species
  • Types of Azoles
    • Imidazoles (e.g., clotrimazole, miconazole, ketoconazole): Primarily used for topical infections due to their limited systemic availability and potential for adverse effects
    • Triazoles (e.g., fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole): Used for both topical and systemic infections. They have better systemic availability and fewer adverse effects than imidazoles
      • Fluconazole: Good activity against many Candida species, but limited activity against molds. Does not cover Candida krusei or Aspergillus
      • Itraconazole: Broad spectrum of activity against yeasts and molds, including Aspergillus, Blastomyces, and Histoplasma. Available in oral and intravenous formulations
      • Voriconazole: Excellent activity against Aspergillus and other molds. Also active against many yeasts, including fluconazole-resistant Candida. Available in oral and intravenous formulations
      • Posaconazole: Broadest spectrum of activity among the azoles, including activity against Aspergillus, Fusarium, Mucorales, and many yeasts. Available in oral and intravenous formulations
      • Isavuconazole: Similar spectrum of activity to posaconazole, with good activity against Aspergillus and Mucorales. Available in oral and intravenous formulations
  • Advantages
    • Broad spectrum of activity
    • Available in oral and intravenous formulations (for many triazoles)
    • Relatively well-tolerated
  • Limitations
    • Drug interactions (azoles can inhibit or induce cytochrome P450 enzymes)
    • Development of resistance
    • Variable bioavailability (for some azoles)
    • QT prolongation (for some azoles)

Polyenes

  • Mechanism of Action: Polyenes bind to ergosterol in the fungal cell membrane, forming pores that disrupt the membrane’s integrity and lead to leakage of cellular contents, resulting in cell death
  • Spectrum of Activity: Polyenes have a broad spectrum of activity against most fungi, including yeasts and molds
  • Types of Polyenes
    • Amphotericin B: The most commonly used polyene. Available in several formulations:
      • Deoxycholate Amphotericin B (D-AmB): The conventional formulation, associated with significant toxicity
      • Lipid Formulations (e.g., liposomal amphotericin B, amphotericin B lipid complex, amphotericin B colloidal dispersion): Less toxic than D-AmB, allowing for higher doses to be administered
    • Nystatin: Primarily used for topical infections due to its poor systemic absorption
  • Advantages
    • Broad spectrum of activity
    • Effective against many resistant fungi
  • Limitations
    • Significant toxicity (especially D-AmB), including nephrotoxicity, infusion-related reactions, and electrolyte abnormalities
    • Poor oral absorption
    • Limited penetration into some tissues

Echinocandins

  • Mechanism of Action: Echinocandins inhibit the synthesis of beta-1,3-glucan, a crucial component of the fungal cell wall. This disrupts the cell wall and leads to cell death
  • Spectrum of Activity: Echinocandins are primarily active against Candida and Aspergillus species. They have limited activity against other molds and are not active against Cryptococcus
  • Types of Echinocandins
    • Caspofungin: Available in intravenous formulation
    • Micafungin: Available in intravenous formulation
    • Anidulafungin: Available in intravenous formulation
  • Advantages
    • Relatively well-tolerated
    • Good activity against Candida and Aspergillus
    • Fewer drug interactions compared to azoles
  • Limitations
    • Limited spectrum of activity
    • Only available in intravenous formulation
    • Resistance can develop, particularly in Candida glabrata

Allylamines

  • Mechanism of Action: Allylamines inhibit squalene epoxidase, an enzyme involved in the early steps of ergosterol synthesis. This leads to a depletion of ergosterol and an accumulation of squalene, disrupting the cell membrane
  • Spectrum of Activity: Allylamines are primarily active against dermatophytes
  • Types of Allylamines
    • Terbinafine: Available in oral and topical formulations
    • Naftifine: Available in topical formulation
  • Advantages
    • Effective against dermatophytes
    • Oral and topical formulations available
  • Limitations
    • Limited activity against yeasts and molds
    • Hepatotoxicity (rare)

Flucytosine (5-Fluorocytosine)

  • Mechanism of Action: Flucytosine is a pyrimidine analog that is converted to 5-fluorouracil (5-FU) inside the fungal cell. 5-FU inhibits DNA and RNA synthesis, disrupting cell growth
  • Spectrum of Activity: Flucytosine has activity against Cryptococcus, Candida, and some molds. It is often used in combination with amphotericin B to treat cryptococcal meningitis
  • Advantages
    • Good penetration into the central nervous system
  • Limitations
    • Rapid development of resistance when used as a single agent
    • Bone marrow suppression
    • Hepatotoxicity

Griseofulvin

  • Mechanism of Action: Griseofulvin disrupts microtubule function, inhibiting fungal cell mitosis
  • Spectrum of Activity: Griseofulvin is primarily active against dermatophytes
  • Advantages
    • Effective against dermatophytes
  • Limitations
    • Limited activity against yeasts and molds
    • Long duration of therapy required
    • Drug interactions
    • Hepatotoxicity

Key Takeaways

  • Understanding the classes of antifungal agents, their mechanisms of action, and their spectrum of activity is essential for interpreting susceptibility testing results and guiding appropriate therapy
  • Azoles inhibit ergosterol synthesis
  • Polyenes bind to ergosterol and disrupt the cell membrane
  • Echinocandins inhibit beta-1,3-glucan synthesis
  • Allylamines inhibit squalene epoxidase
  • Flucytosine inhibits DNA and RNA synthesis
  • Griseofulvin disrupts microtubule function

Key Terms

  • Antifungal Agent: A drug used to treat fungal infections
  • Ergosterol: A sterol found in the cell membrane of fungi
  • Cell Membrane: The outer boundary of a cell that controls the movement of substances in and out of the cell
  • Cell Wall: A rigid layer outside the cell membrane that provides support and protection
  • Drug Interaction: A situation in which one drug affects the activity of another drug
  • Bioavailability: The extent to which a drug is absorbed into the bloodstream and is available to reach its target site
  • QT Prolongation: A condition in which the QT interval on an electrocardiogram is prolonged, increasing the risk of arrhythmias
  • Nephrotoxicity: Toxicity to the kidneys
  • Infusion-Related Reaction: An adverse reaction that occurs during or shortly after the infusion of a drug
  • Electrolyte Abnormality: An imbalance in the levels of electrolytes (e.g., sodium, potassium, calcium) in the body
  • Hepatotoxicity: Toxicity to the liver
  • Bone Marrow Suppression: A condition in which the bone marrow produces fewer blood cells
  • Minimum Inhibitory Concentration (MIC): The lowest concentration of an antimicrobial agent that inhibits the visible growth of a microorganism
  • Broth Microdilution (BMD): A manual method for AFST that involves preparing two-fold dilutions of antifungal agents in a broth medium
  • Etest: A manual method for AFST that uses a plastic strip containing a gradient of antifungal concentrations
  • Automated System: A laboratory instrument that automates various steps of AFST
  • CLSI (Clinical and Laboratory Standards Institute): A non-profit organization that develops standards for laboratory testing
  • EUCAST (European Committee on Antimicrobial Susceptibility Testing): A European organization that develops standards for antimicrobial susceptibility testing
  • Mould-Specific Identification: Refers to laboratory techniques, including microscopic examination and molecular assays, used to accurately identify specific mold species in clinical samples, aiding in diagnosis and treatment of infections caused by these fungi
  • Panfungal PCR: is a molecular diagnostic technique that utilizes polymerase chain reaction (PCR) to amplify and detect conserved DNA sequences present in a wide range of fungi, allowing for the identification of fungal infections, even when traditional culture methods are negative or impractical