Antifungal Drugs

• Ketoconazole: (Nizoral)

  •  Less selective (than itraconazole (Sporanox) or fluconazole (Diflucan)) for fungal cytochrome P450 enzymes. Accordingly:

    1.  Detoconazole (Nizoral)-- by inhibiting human cytochrome P450 inhibits adrenal and gonadal steroid hormone biosynthesis. Endocrine effects:

       •  Gynecomastia

       •  Infertility

       •  Menstrual irregularities

    2. Ketoconazole (Nizoral) administration may altere metabolism of other drugs thus increasing their toxicity. Some examples:

       •  Increased cyclosporine levels

       •  Increased arrhythmias associated with:

         • Some nonsedating antihistamines

           • Astemizole

           • Terfenadine

  • Drugs influence ketoconazole (Nizoral) levels:

    • Cimetidine (Tagamet), by increasing gastric pH,  interferes with ketoconazole absorption.

    • Rifamycins (rifampin (Rimactane), rifabutin (Mycobutin))  increase azole hepatic metabolism

  • Clinical Use:  ketoconazole (Nizoral)

    • Limited, due to endocrine side effects and drug-drug interactions and because of narrow therapeutic range. However may be used for low dose, effective treatment of:

      • Mucocutaneous candidiasis

      • Non-meningeal Coccidiodomycosis

• Itraconazole (Sporanox)

  • Oral administration

  • Some interaction with hepatic microsomal P450 enzymes

    • No effect on steroid synthesis

    • Compared to ketoconazole (Nizoral), much less effect on metabolism of other drugs. Major drug-drug interaction: reduced itraconazole bioavailability when coadministered with rifamycins (rifampin (Rimactane), rifabutin (Mycobutin))

  • Most potent of azoles (efficacy may be limited by bioavailability)

  • Poor penetration into cerebral spinal fluid

  • Clinical Use-Itraconazole (Sporanox): Agent of choice-

    • Treatment of dermatophytes.

    • Treatment of onychomycosis

    • Only agent with substantial activity against Aspergillus species.

    • Preferred azole for treatment of diseases caused by dimorphic fungi:

      • Histoplasma

      • Blastomyces

      • Sporothrix

• Fluconazole (Diflucan)

  • Distinguishing feature: water solubility and good cerebral spinal fluid penetration

  • Excellent oral bioavailability

  • Limited drug-drug interactions; among azoles, least effect on cytochrome P450 hepatic microsomal enzyme system

  • Clinical Use-Fluconazole (Diflucan):

    • Wide therapeutic window

    • Azole of choice:

      • Treatment and secondary prophylaxis -- cryptococcal meningitis

      • IV fluconazole -- equivalent amphotericin B (Fungizone, Amphotec)in treating candidemia in ICU patients (patients with normal white blood cell counts)

    • Effective in treating:

      • Mucocutaneous candidiasis

      • Coccidioidal disease -- high-dose fluconazole debuts in place of intrathecal amphotericin B

• Griseofulvin:

  • Very insoluble; fungiostatic (derived from Penicillium)

  • Largely replaced in clinical use by itraconazole and terbinafine.

  • Single Clinical Use: systemic treatment of dermatophytosis

  • Mechanism of action-Griseofulvin:

    • Binds to new skin keratin -- preventing news skin infection

    • Long-term therapy may be required

  •  Adverse Effects-Griseofulvin:

    1. Allergic syndrome (like serum sickness)

    2. Hepatitis

    3. Drug-drug interactions:

       • With warfarin

       • With phenobarbital

• Terbinafine: (Lamisil)

  • Oral formulation

  • Karatophilic (like griseofulvin); fungicidal

  • Mechanism of Action:-- terbinafine inhibits fungal squalene epoxidase

    • Squalene accumulates to toxic levels

  • Clinical Use: Terbinafine (Brethine)

    • Treatment of dermatophytoses

    • Up to 90% cure rate for onychomycosis-- or effective than griseofulvin or itraconazole

  •  Adverse Effects:Terbinafine (Lamisil)

    • Rare -- gastrointestinal upset, headache

    • No effect on cytochrome P450 microsomal enzyme metabolizing system

• Nystatin (Mycostatin):  topical use

  • Polyene macrolide -- like amphotericin B

  • Mechanism of Action: promotes membrane pore formation

  • Topical use only -- due to systemic toxicity

  • Clinical Use-Nystatin (Mycostatin):

    • Active against most Candida organisms

    • Most often used for treating local candidal infections

      • Oropharyngeal thrush

      • Vaginal candidiasis

      • Intertriginous (chaffed skin) candidal infections

• Common Topical Azoles:  Clotrimazole (Mycelex), Miconazole (Monistat)

  • Clinical Uses of Topical Azoles:

    • Vulvovaginal candidiasis

    • Oral thrush (clotrimazole troches)

    • Dermatophytic infections

      • Tinea corporis

      • Tinea pedis

      • Tinea cruris

    • Topical/shampoo ketoconazole:

      • Seborrheic dermatitis

      • Pityriasis versicolor

• Topical Allylamines (terbinafine (Lamisil), naftifine)

  • Creams for tinea cruris; tinea corporis

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