Antifungal drugs Lec 18 30 -1-2017 Dr. Naza M. Ali

Antifungal Drugs Fungal infections are generally resistant to Unlike bacteria, fungi are eukaryotic. Fungal infections are generally resistant to antibiotics used in the treatment of bacterial infections, and conversely, bacteria are resistant to antifungal agents. Infectious diseases caused by fungi are called mycoses, they are often chronic in nature.

Mycoses divided into: Cutaneous mycoses: Infection are superficial and only involve the (skin, hair, nails). Subcutaneous mycoses: Fungi that grow in soil and on vegetation and are introduced into subcutaneous tissue through trauma.

Systemic mycoses: Infections result from inhalation of the spores of dimorphic fungi that have their saprophytic mold forms in the soil. are most difficult to treat which are often life threatening.

Mechanism of drug acting on fungi Alter cell membrane permeability 2. Block nucleic acid synthesis 3. Disrupt microtubule functions

Drugs for subcutaneous and systemic fungal infections 1. Amphoteracin B 2. Flucytosine 5-FC 3. Azole antifungal agents: -Ketoconazole -Fluconazole -Itraconazole -Voriconazole -Posaconazole (new)

4. Echinocandins -Caspofungin - Micafungin

Amphoteracin B Is a naturally occurring polyene macrolide antibiotic produced by Streptomyces nodosus. Is the drug of choice for the treatment of life-threatening systemic mycoses. Conventional amphotericin (amphotericin B deoxycholate, the nonlipid formulation) has undergone several formulation improvements to reduce the incidence of side effects( nephrotoxicity).

The drug is used in combination with flucytosine to achieve more rapid sterilization of the CSF. Amphotericin B is either fungicidal or fungistatic, depending on organism and concentration of the drug. It is often used for initial induction regiments before follow up treatment with an azole.

It has widest antifungal agents spectrum than any agents and the drug of choice for systemic most infections caused by Aspergillus, Blastomyces, Candida albicans, Cryptococcus, Histoplasma and Mucor. it is usually given by slow IV infusion. In case of fungal meningitis( by intrathecal route). Local administration in treatment of mycotic corneal ulcer

Mechansim of action of Amphoteracin B Is a polyene macrolide related to nystatin polyenes are molecules with both hydrophilic & lipophilic characteristics. Several amphotericin B molecules bind to ergosterol in the plasma membranes of fungal cells, and cause the formation of artificial pores (channels). The pores disrupt membrane function, allowing electrolytes and small molecules to leak from the cell, resulting in cell death.

Resistance: Fungal resistance, is associated with decreased ergosterol content of the fungal membrane.

Pharmacokinetics: Amphotericin B is used by slow, (IV) infusion Is insoluble in water, and injectable preparations require the addition of sodium deoxycholate, which produces a soluble colloidal dispersion. The more dangerous intrathecal route is chosen for the treatment of meningitis.

Amphotericin B has also been formulated with a variety of artificial lipids that form liposomes. Amphotericin B is extensively bound to plasma protein. Inflammation favors penetration into various body fluids.

Adverse effects Amphotericin B has a low therapeutic index A total adult daily dose should not exceed 1.5 mg/kg Small test doses are usually administered to avoid anaphylaxis or convulsions

Fever & chills: These occur most commonly 1-3 hours after starting IV, but they usually subside with repeated administration of the drug. Premedication with an antipyretic or a corticosteroid helps to prevent problem.

Azotemia (elevated blood urea) 2. Renal impairment: Azotemia (elevated blood urea) adequate hydration can decrease its severity. 3. Hypotension: A shock-like fall in blood pressure 4. Anemia 5. Neurologic effects