Nursing Pharmacology:  Antifungal Drugs

Antifungal Agents

• Factors increasing incidence and severity of human fungal infections:

  • Increased 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 are completely resistant to conventional antibacterial agents

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

  • Concern: evolution of azole-resistant fungi

• 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. Rhrombocytopenia

    •  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 with azoles is the availability of the oral Route of Administration and that these agents are relatively nontoxic.

  • Synthetic compounds:

    • 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

       • Hstoplasmosis

    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 administration may cause drug interactions secondary to alterations in the cytochrome P450 enzyme drug metabolizing system.

Sheppard,D. and Lampiris, H.W., Antifungal Agents, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 780-786

Bennett, J.E. Fungal Infections (Section 15: Infectious Diseases), In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., andBraunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 1148-1163