Antifungal Agents

• Factors increasing incidence and severity of human fungal infections:

• increase use of broad spectrum antibiotics

• HIV epidemic

• cancer chemotherapy protocols

• Examples of increased incidence: Candida albicans -- fourth most common organism isolated from blood (USA)

•  Most fungi: completely resistant to conventional antibacterial agents

• Significant Development: availability of relatively non-toxic, orally administered, azole drugs.

•  Concern: evolution of azole-resistant fungi

  • Promising new drug classes (inhibitors of fungal cell wall synthesi, but not yet available -- in clinical trials 1998):

    • nikkomycins

    • echinocandin analogues

• Three Antifungal Drug Categories:

  1. systemic drugs: systemic infection (oral or parenteral route of administration)

  2. mucocutaneous infections: oral route of administration

  3. mucocutaneous infections: topical

Systemic Infections

• Amphotericin B: (Fungizone, Amphotec)

  • produced by Streptomyces nodosus

  • Antifungal Activity:

    1. Broadest spectrum of antifungal action

    2. activity against yeasts:

       • Candida albicans

       • Candida neoformans

    3. activity against endemic mycoses:

       • Histoplasma capsulatum

       • Blastomyces dermatitidis

       • Coccidiodes immitis

    4. pathogenic molds

       • Aspergillus fumigatus

       • Mucor

• Pharmacokinetics: Amphotericin B (Fungizone, Amphotec)

  1. poorly absorbed from the GI tract

     • oral administration: useful for gastrointestinal luminal fungal infections (non-systemic)

  2. intravenous administration -- to treat systemic infection

     • > 90% protein-bound

     • mainly metabolized -- some excreted by the kidney

     • poor cerebral spinal fluid levels following IV administration:

       • intrathecal drug administration may be required in some cases of fungal meningitis

• Mechanism of Action: Amphotericin B (Fungizone, Amphotec)

  • in fungi the major sterol: ergosterol (mammalian cell membrane: major sterol-- cholesterol

  • amphotericin B binds to ergosterol -- changing cell permeability

    • Amphotericin B induced pores resulted in fungal cell death through:

      1. ion leakage

      2. loss of macromolecules

    •  Amphotericin B binding to human membrane sterols occurs:

      • possible basis for drug toxicity

•  Adverse Effects: Amphotericin B (Fungizone, Amphotec)

  • Common Reactions Associated with intravenous Route of Administration:

•  Delayed Toxicity:Amphotericin B

  1.  Renal damage -- most significant toxic effect; Frequency -- nearly all patients

     • may require dialysis

     • reversible component: pre-renal kidney failure (reversible)

     • irreversible component: renal tubular necrosis

     • Renal toxicity associated with:

       1. renal tubular acidosis

       2. potassium loss

       3. magnesium loss

       4. Less renal damage with concurrent sodium (saline infusion) administration with amphotericin B

  2. Abnormal liver function tests:(occasional)

  3. Reduced erythropoietin production: (associated with renal tubular cell damage)

  4. Convulsions: associated with intrathecal amphotericin B administration.

• Clinical Use: amphotericin B (Fungizone, Amphotec)

  • Drug of choice for nearly all life-threatening fungal infections.

  • Initial induction treatment -- then one of the newer azole drugs (ketoconazole (Nizoral), itraconazole (Sporanox), fluconazole (Diflucan))

  • Amphotericin B treatment induction:

    • important in:

      • immunosuppressed patients

      • severe fungal pneumonia

      • cryptococcal meningitis (altered mental status present)

      • long-term antifungal treatment may beer acquired (azole maintenance therapy)

      • may be used in neutropenic cancer patients remaining febrile despite management using broad-spectrum antibiotics.

  •   Intrathecal treatment: fungal meningitis (other therapies preferred, in part due to difficulty maintaining CSF access and poor patients tolerance)

  • Local Administration:

    • mycotic corneal ulcers (topical or subconjuctival injection)

    • kerititis (topical or subconjuctival injection)

    • fungal arthritis (joint injection)

    • Candiduria: bladder irrigation (no systemic toxicity)

• Flucytosine (Ancobon)

  • Introduction:

    • water-soluble pyrimidine analog (related to flurouracil)

    • narrower spectrum infection compared amphotericin B

  • Pharmacokinetics: Flucytosine (Ancobon)

  • penetrates well into body fluid compartments -- including the CSF

  • eliminated by glomerular filtration (may be removed by hemodialysis)

    •  toxicity may occur with reduced renal function

    •  toxicity more likely to occur in AIDS patients

  • Mechanism of Action: Flucytosine (Ancobon)

    • Uptake by fungal cells mediated by cytosine permease

      • converted intracellularly to:

        1. 5-fluorouracil (5-FU)

        2. 5-fluorodeoxyuridine monophosphate (FdUMP)-- DNA synthesis inhibitor

        3. fluorouridine triphosphate (FUTP) -- RNA synthesis inhibitor

    • Synergism with amphotericin B

      • possible mechanism: increased flucytosine penetration through amphotericin B-damaged fungal cell membranes

    • Synergism with azoles (undefined mechanism)

    • Resistance: rapidly develops and monotherapy

      • probable mechanism: altered flucytosine metabolism

  •  Adverse Effects: Flucytosine (Ancobon)

    •  Probably due to toxic, antineoplastic metabolites (5-FU)

    • Most common toxicities:

      1. anemia

      2. leukopenia

      3. thrombocytopenia

    •  Narrow therapeutic window (toxicity of higher levels; rapid development of resistance at lower, sub-therapeutic levels

  • Clinical Use: Flucytosine (Ancobon)

    • not used in monotherapy (rationale: synergism with other drugs; avoidance of resistance)

    • Effective against:

      1. Cryptococcus neoformans

      2. some Candida species

      3. chromoblastomycosis

    • In combination with amphotericin B for: cryptococcal meningitis

    • in combination with a terconazole for: chromoblastomycosis

• Azoles-- introduction

  • Major advantage-Azoles: oral Route of Administration, relatively nontoxic

  • Synthetic compounds-- classification depending on the number of nitrogen atoms in the five-membered azole ring

    • imidazoles

      1. ketoconazole (Nizoral)

      2. miconazole (topical) (Monistat)

      3. clotrimazole (topical) (Mycelex)

    • triazoles

      1. itraconazole (Sporanox)-- systemic treatment

      2. fluconazole (Diflucan)-- systemic treatment

  • Mechanism of Action: Azoles

    • decreased ergosterol synthesis due to inhibition of fungal cytochrome P450 enzymes

      • Specificity: -- these drugs have higher affinity for fungal compared to human cytochrome P450 enzymes

        • triazoles -- higher specificity (fewer side effects)

        • imidazoles -- lower specificity (more side effects)

    • Resistance: -- multiple mechanisms; increased incidence of resistance

  • Clinical Use: Azoles

    1. many Candida species

    2. Cryptococcus neoformans

    3. endemic mycoses:

       • blastomycoses

       • Coccidiodomycosis

       • histoplasmosis

    4. dermatophytes

    5. Aspergillus:itraconazole

    6. Pseudallesceria boydii (amphotericin-resistant organism)

  •  Adverse Effects: Azoles

    • relatively nontoxic

    • Most common: minor gastrointestinal upset

    • Very rare: hepatitis

  •  Drug Interactions: Azoles-- drug interactions due to effects on cytochrome P450 enzyme systems