Medical Pharmacology Chapter 37:  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:

    • Fever

    • Chills

    • Muscle spasms

    • Hypotension

    • Headache

    • Vomiting

•   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:

    • 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-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 with increasing 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-- drug interactions due to effects on cytochrome P450 enzyme systems

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