Antifungal drugsAntifungal drugs

ByDr.Mohamed Abd AlMoneim

Attia

Fungal InfectionsFungal 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 FungiBacteria FungiNucleus no yesRibosomes 70S 80SCell Wall Peptidoglycan

ChitinMembrane No sterols

Ergosterol

Fungal PathogensFungal Pathogens

Systemic Infections–Opportunistic pathogens

» Candida albicans» Cryptococcus neoformans» Aspergillus»Pneumocystis carinii

Fungal PathogensFungal Pathogens

Systemic Infections– – Blastomyces dermatitidis – Histoplasma capsulatum– Parracoccidiodes

brasiliensis

Fungal PathogensFungal Pathogens

Superficial Infections– Dermatophytes– Candida albicans

Antifungal drugsAntifungal drugs

Drugs for systemic infections– Polyene Antibiotics– Imidazole Antifungal Drugs– Flucytosine

Drugs for superficial infections– Polyenes, Imidazoles and – Griseofulvin– Naftifine

Polyene AntibioticsPolyene 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,Fever, gastrointestinal distress, cardiotoxicity, hemolytic anemia, leukopenia, hepatotoxicity, nephrotoxicitynephrotoxicity.

KetoconazoleKetoconazole

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

Clinical Uses - – 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 The drug must be discontinued if hepatitis occurs.hepatitis occurs.

»Gynecomastia - inhibition of testosterone synthesis

KetoconazoleKetoconazole

Other Imidazole AntifungalsOther Imidazole Antifungals Miconazole- topical treatment of dermatophyte

infections and treatment of vaginal candidiasis. Clotrimazole - topical treatment of cutaneous

and vaginal infections.

Itraconazole - wider spectrum of activity than ketoconazole and fewer adverse effects. Drug of choice for several systemic infections.

Fluconazole - Cryptococcus (HIV+)

Triazole AntifungalsTriazole Antifungals

Clinical Uses (limited): – Combined with amphotericin B - systemic

Cryptococcus and Candida infections. Adverse Reactions:

– Bone marrow depression - leukopenia and thrombocytopenia

– Gastrointestinal distress– Reversible hepatotoxicity

FlucytosineFlucytosine

GriseofulvinGriseofulvin

Nucleus

Centrosome

GG GG

GG

GG

Microtubules

GriseofulvinGriseofulvin 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

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 Naftifine

Broad spectrum, fungicidal– inhibits squalene epoxidase– causes buildup of intracellular squalene – decreases ergosterol synthesis

Clinical Uses: – Dermatophytes (tinea cruris & tinea

corporis), Candida. Can cause local irritation.