By Dr.Mohamed Abd AlMoneim Attia Antifungal drugs By Dr.Mohamed Abd AlMoneim Attia

Fungal Infections Develop due to a loss of mechanical barriers (i.e. burns, major surgery) or immunodeficiency (chemotherapy, organ transplant, AIDS) fungal infections may be superficial or systemic Fungi possess different ribosomes, cell wall components, and discrete nuclear membrane

Bacteria Fungi Nucleus no yes Ribosomes 70S 80S Cell Wall Peptidoglycan Chitin Membrane No sterols Ergosterol

Fungal Pathogens Systemic Infections Opportunistic pathogens Candida albicans Cryptococcus neoformans Aspergillus Pneumocystis carinii

Fungal Pathogens Systemic Infections Blastomyces dermatitidis Histoplasma capsulatum Parracoccidiodes brasiliensis

Fungal Pathogens Superficial Infections Dermatophytes Candida albicans

Antifungal drugs Drugs for systemic infections Polyene Antibiotics Imidazole Antifungal Drugs Flucytosine Drugs for superficial infections Polyenes, Imidazoles and Griseofulvin Naftifine

Polyene Antibiotics Polyenes bind to sterols - selectivity is poor. Clinical Uses Amphotericin B: systemic fungal infections Nystatin: topical treatment of skin, oral and intestinal Candida infections Candicidin: topical treatment of vaginal candidiasis. Adverse Reactions (systemic use) Fever, gastrointestinal distress, cardiotoxicity, hemolytic anemia, leukopenia, hepatotoxicity, nephrotoxicity.

Ketoconazole Mechanisms of action (we think) blocks synthesis of ergosterol

Ketoconazole Clinical Uses - Adverse Reactions Systemic and mucocutaneous infections. Prevention of Candida infection in immune suppressed patients. Adverse Reactions Mild side effects: GI distress and pruritus Serious side effects: Hepatic toxicity - The drug must be discontinued if hepatitis occurs. Gynecomastia - inhibition of testosterone synthesis

Other Imidazole Antifungals Miconazole- topical treatment of dermatophyte infections and treatment of vaginal candidiasis. Clotrimazole - topical treatment of cutaneous and vaginal infections. Triazole Antifungals Itraconazole - wider spectrum of activity than ketoconazole and fewer adverse effects. Drug of choice for several systemic infections. Fluconazole - Cryptococcus (HIV+)

Flucytosine Clinical Uses (limited): Adverse Reactions: Combined with amphotericin B - systemic Cryptococcus and Candida infections. Adverse Reactions: Bone marrow depression - leukopenia and thrombocytopenia Gastrointestinal distress Reversible hepatotoxicity

Griseofulvin G G G G Centrosome Microtubules Nucleus

Griseofulvin Binds to keratin and reaches high concentrations in the keratinized cells of the skin and the hair. Clinical Uses: Dermatophytes - Trichophyton, Epidermophyton and Microsporum. Adverse Reactions: Temporary headache is common. Nervous system - mental confusion, fatigue, visual impairment. Gastrointestinal distress

Mucocutaneous Antifungals Griseofulvin enters fungal cells by an energy-dependent process interacts with the microtubules within the fungus to disrupt the mitotic spindle and inhibit mitosis resistance due to lack of energy-dependent uptake system toxicities include allergic syndrome and hepatitis

Naftifine Broad spectrum, fungicidal Clinical Uses: inhibits squalene epoxidase causes buildup of intracellular squalene decreases ergosterol synthesis Clinical Uses: Dermatophytes (tinea cruris & tinea corporis), Candida. Can cause local irritation.

Thank you