Chapter 48 Antifungal Agents

Fungal infections Superficial Skin Hair Nails Mucous membrane

Deep Tissues (muscle & connective tissue) Organs

Oral infection with Candida (Thrush)

Antifungal drugs • Work by exploiting differences between mammalian and fungal cells to kill the fungal organism without dangerous effects on the host. • Both fungi and humans are eukaryots. • Difficult to find or design drugs that target fungi without affecting human cells. (side effects)

What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol

DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis.

Cell Wall Unlike mammalian cells, fungi have a cell wall

Antifungal agents Systemic/systemic

Amphotericin B Flucytosine Azoles Echinocandins Criseofulvin

Systemic/mucocutaneous

Terbinafine Nystatine Topical

Topical Azoles Topical Allylamines

Sites of Action of Antifungal Agents Terbinafine

Fig. 1

Amphotericin B, Nystatin

Mode action of antifungal drugs

I. SYSTEMIC ANTIFUNGAL DRUGS FOR SYSTEMIC INFECTIONS

Amphotericin B Amphotericin B is a polyene antibiotic isolated from Streptomyces nodosus. • Broad-spectrum polyene macrolide antibiotic is the most potent antifungal agent for systemic mycosis, in clinical use since 1960 • Fungicidal drug at higher concentrations & static at lower levels.

Structure and chemical characteristics

• poorly water soluble • administered by IV infusion (0.1 mg/ml) or (0.3 mg/ml) in 5% dextrose • extremely unstable in solution, particularly in normal saline

Mechanism of action It has affinity for ergosterol present in the cell membrane and forms a micropore thus disrupt the membrane function and cell death. •resistance is rare and slow to develop

Pharmacokinetics    

Insoluble in water Poorly absorbed from GIT Cannot cross BBB Highly bound to plasma proteins

For treatment of meningitis, it must be given intrathecally. Given only via IV injection or intrathecally.

Clinical uses • Broad spectrum antifungal • Useful for 1. Candida that causes – oral – vaginal – cutaneous candidiasis

2. 3. 4. 5.

Cryptococcus Histoplasma Aspergillosis Also effective for Leishmaniasis (Reserve drug for resistant cases of Kala Azar)

Adverse effects A. INFUSION-RELATED TOXICITY Acute reactions (immediate reactions)– related to the infusion of the drug: Fever and chills, muscle spasms, vomiting, headache, and hypotension B. CUMULATIVE TOXICITY Long term - Nephrotoxicity, anemia, CNS toxicity

Flucytosine (5-FC) • Narrow-spectrum antifungal drug • Drug resistance occurs rapidly when flucytosine is used alone • •

Blockade of fungal DNA synthesis Well absorbed orally and penetrates into CSF

Therapeutic uses  Candida infections ( in combination with amphotericin B)  Cryptococcal meningitis ( in combination with amphotericin B)  Chromoblastomycocis ( in combination with Itraconazole ) Adverse effects  Reversible bone marrow depression (leukopenia, thrombocytopenia)  Liver dysfunction  Enterocolitis - rare

Azoles antifungal agents • Imidazoles: – Topical: Clotrimazole, miconazole – Systemic: Ketoconazole

• Triazoles: Fluconazole, itraconazole and voriconazole—Systemic Mechanism of action: Reduce ergosterol synthesis by inhibition of fungal cytochrome P450 enzyme

Clinical uses BROAD SPECTRUM OF ACTIVITY – Candida, Cryptococcus, Blastomyces, Histoplasma, Coccidiodes , Dermatophytes

Adverse effects Relatively nontoxic. Minor GI upset Abnormalities in liver enzymes (inhibit cytochrome P450 enzymes) Very rarely, clinical hepatitis

Ketoconazle: • The first oral azoles introduced into clinical use (systemically or topically) • Less selective for fungal P450 • Out of clinical use Itraconazole: • Antifungal spectrum: broader than ketoconazole • Fungistatic action but very effective in immunocompromizrd patients • Steroid hormone synthesis inhibition is absent and no serious hepatotoxicity • Penetration of drug in brain & CSF is poor • Much more selective than ketoconazole

Fluconazole: Broad-spectrum Fungicidal drug It is also somewhat effective against some Gram-positive & anaerobic bacteria • good water solubility and good CSF penetration (high bioavailability). • drug interactions and side effects are also less because of its least effect on hepatic enzyme of all the azoles. • Be used in: (1) Candidiasis, (2) cryptococcal meningitis. Voriconazole:  The newest triazole to be licensed  less mammalian P450 inhibition  Visual disturbance are common (30%)  Be used in: (1) Candidiasis (2) Invasive aspergillosis

ECHINOCANDINS Caspofungin, micafungin & anidulafungin The newest class of antifungal. Active against candida and aspergillus, but not Cryptococcus neoformans.

MOA: Inhibit beta glucan synthesis in the fungal cell wall, thus disrupt fungal cell wall and cause cell death. ADEs: • Extremely well tolerated • Minor GI side effects • Flushing • Elevated liver enzymes (caspofungin + cyclosporine) • Histamine release during IV infusion

II. SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS

GRISEOFULVIN • Very insoluble, fungistatic ,and derived from a species of penicillium • Better absorption when given with fatty foods • Only use in the systemic treatment of dermatophytosis • Largerly replaced by itraconazole and terbinafine ADEs:  Allergic reaction  Photosensitivity  Hepatitis  Teratogenesis

TERBINAFINE • • • •

Synthetic allylamine Orally active Dermatophytoses, especially onychomycosis Keratophilic medication , fungicidal

ADEs:  Rare, mild, self-limiting, GI upset, Headache

III. TOPICAL ANTIFUNGAL THERAPY

NYSTATIN • Only used topically: creams, ointments, suppositories, and other • Acts as amphotericin B • It is not absorbed , unpleasant taste. • Local candidal infections, oropharyngeal thrush, vaginal candidiasis. • Adverse effects are rare.

TOPICAL AZOLES • Clotrimazole • Miconazole

TOPICAL ALLYLAMINES  Terbinafine  Naftifine