Antibiotic

Antifungal Drugs

Fungal infectious occur due to : 1- Abuse of broad spectrum antibiotics 2- Decrease in the patient immunity e.g DM, corticosteroid therapy, immunosuppressive therapy, severe burns.

Types of fungal infections

1. Superficial : Affect skin – mucous membrane.e.g.Tinea versicolorDermatophytes : Fungi that affect keratin layer of skin, hair, nail.e.g. tinea pedis ,ring worm infection(Tinea corporis)Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis , nail infections.

2- Deep infections

Affect internal organs as : lung ,heart , brain leading to pneumonia , endocarditis , meningitis.

Fungal Infection in Humans = Mycosis

Major Types of Mycoses superficial cutaneous subcutaneous systemic opportunistic Symptoms vary from cosmetic to life threatening

Classification of Antifungal Drugs

1- Antifungal Antibiotics : Griseofulvin Polyene macrolide : Amphotericin- B & Nystatin 2- Synthetic : Azoles : A) Imidazoles : Ketoconazole , Miconazole B) Triazoles : Fluconazole , Itraconazole


Synthetic Antifungal ( contin…) Flucytosine Squalene epoxidase inhibitors : e.g. Terbinafine & Naftifine.

CLASSIFICATION OF ANTIFUNGAL DRUGS

Drugs for systemic fungal infections Polyene antibiotics -Amphotericin B Pyrimidine antimetabolites -Flucytosine Antifungal azoles -Ketoconazole -Fluconazole -Itraconazole Echinocandins Caspofungin, micafungin, and anidulafungin
Drugs for superficial fungal infections Systemic drugs -Griseofulvin -Iodide Topical drugs -Nystatin -Haloprogin -Tolnaftate -Azoles (miconazole, econazole, clotrimazole, etc.)

Amphotericin-B Pharmacokinetics

Poorly absorbed orally , is effective for fungal infection of gastrointestinal tract. For systemic infections given as slow I.V.I. Highly bound to plasma protein . Poorly crossing BBB. Metabolized in liver Excreted slowly in urine over a period of several days. Half-life 15 days.

Mechanism of action

It is a selective fungicidal drug. Disrupt fungal cell membrane by binding to ergosterol , so alters the permeability of the cell membrane leading to leakage of intracellular ions & macromolecules (Allow K+ & Mg++ to leak out, altering fungal cell metabolism Causing cell death).

Mechanism of Action

Adverse Effects
1- Immediate reactions ( Infusion –related toxicity ).Fever, muscle spasm, vomiting ,headache, hypotension. Can be avoided by :A. Slowing the infusionB. Decreasing the daily dose C. Premedication with antipyretics, antihistamincs or corticosteroids.D. A test dose. A test dose of 1 mg per 20 mL 5% dextrose inwater infused over 30 minutes should be given.E.Use IV infusion pumps and the most distal veins possible.

2- Slower toxicity

Most serious is renal toxicity (nearly in all patients ). Hypokalemia Hypomagnesaemia Impaired liver functions Thrombocytopenia Anemia Normocytic anemia, likely due to decreased production of erythropoietin (frequent) -Thrombophlebitis -Delirium, seizures (after intrathecal injection)


Clinical uses
Has a broad spectrum of activity & fungicidal action. The drug of choice for life-threatening mycotic infections.

Routes of Administration

1- Slow I.V.I. For systemic fungal disease. 2- Intrathecal for fungal C.N.S. infections. Topical drops & direct subconjunctival injection for Mycotic corneal ulcers & keratitis. 3- Local injection into the joint in fungal arthritis. 4- Bladder irrigation in Candiduria.

Liposomal preparations of amphotericin B

Amphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane , so reducing : A. Nephrotoxicity B. Infusion toxicity Also, more effective More expensive

Nystatin

It is a polyene macrolide ,similar in structure & mechanism to amphotericin B. Too toxic for systemic use. Used only topically. It is available as creams, ointment , suppositories & other preparations. Not significantly absorbed from skin, mucous membrane, GIT .

Clinical uses

Prevent or treat superficial candidiasis of mouth, esophagus, intestinal tract. Vaginal candidiasis

Ketoconazole

Well absorbed orally . Bioavailability is decreased with antacids, H2 blockers , proton pump inhibitors & food . Half-life (7-8 hrs).

Ketoconazole (cont.)

Inactivated in liver & excreted in bile (feces ) & urine. Does not cross BBB.

Clinical uses

Used topically or systematic (oral route only ) to treat : 1- Oral & vaginal candidiasis. 2- Dermatophytosis. 3- Systemic mycoses & mucocutaneous candidiasis.

Adverse Effects

Nausea, vomiting ,anorexia Hepatotoxic Inhibits human P 450 enzymes Inhibits adrenal & gonadal steroids leading to : Menstrual irregularities Loss of libido Impotence Gynaecomastia in males

Triazoles

Fluconazole Itraconazole Voriconazole They are : Selective Causing less endocrine disturbance

Fluconazole

Completely absorbed from GIT Excellent bioavailability after oral administration Bioavailability is not affected by food or gastric PH Has the least effect on hepatic microsomal enzymes

Fluconazole (cont.)

Drug interactions are less common Penetrates well BBB so, it is the drug of choice of cryptococcal meningitis Excreted mainly through kidney Half-life 25-30 hours


Clinical uses
Candidiasis ( is effective in all forms of mucocutaneous candidiasis) Cryptococcus meningitis Histoplasmosis, blastomycosis, , ring worm. Not effective in aspergillosis

Side effects

Nausea, vomiting, headache, skin rash , diarrhea, abdominal pain , reversible alopecia. Hepatic failure may lead to death Highly teratogenic ( as other azoles) Inhibit P450 cytochrome. No endocrine side effects. Be careful with IV use for extravasation can cause tissue necrosis.

Flucytosine

Synthetic pyrimidine antimetabolite (cytotoxic drug ) often given in combination with amphotericin B & itraconazole. Systemic fungistatic


Mechanism of action Flucytosine is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively. Note:( Amphotericin B increases cell permeability , allowing more 5-FC to penetrate the cell, they are synergistic).

Human cells are unable to convert the parent drug to its active metabolites.

Pharmacokinetics
Rapidly & well absorbed orally Widely distributed including CSF. Mainly excreted unchanged through kidney Half-life 3-6 hours



Clinical uses
Severe deep fungal infections as in meningitis Generally given with amphotericin B For cryptococcal meningitis in AIDS patients

Adverse Effects

Nausea, vomiting , diarrhea, severe enterocolitis Reversible neutropenia, thrombocytopenia, bone marrow depression Alopecia Elevation in hepatic enzymes [toxicity may be due to the conversion of flucytosine to 5-fluorouracil by the intestinal flora of the host]

Griseofulvin

Fungistatic, has a narrow spectrum Given orally (Absorption increases with fatty meal ) Half-life 24 hours Taken selectively by newly formed skin & concentrated in the keratin. Induces cytochrome P450 enzymes Should be given for 2-6weeks for skin & hair infections to allow replacement of infected keratin by the resistant structure

Griseofulvin(cont.)

Inhibits fungal mitosis by interfering with microtubule function Used to treat dermatophyte infections ( ring worm of skin, hair, nails ). Highly effective in athlete,s foot. Ineffective topically. Not effective in subcutaneous or deep mycosis. Adverse effects ; Peripheral neuritis, mental confusion, fatigue, vertigo,GIT upset,enzyme inducer, blurred vision. Increases alcohol intoxication.

Antifungal Drugs Used For Topical Fungal Infections

1. Topical azole derivatives,clotrimazole,Itraconazole 2. Nystatin& Amphotericin 3. Terbinafine 4. Tolnaftate 5. Naftifine 6. Griseofulvin

Other group used systemically for systemic fungal infections Echinocandins which is the newest class, the first drug in this group approved in 2001 is*Caspofungin available only for IV infusion uses : Invasive candidiasis as first line therapy and invasive aspergillosis in patient refractory to/ or intolerant to Amphotericin –B or Itraconazole as a second line therapylater developed Micafungin and **anidulafunginDo not use dextrose as a diluent as the drug become unstable** can be used in patient with severe hepatic disease