Antifungals Lecture Notes PDF

ANTIFUNGAL AGENTS Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Many fungal infections are self-limiting and require no chemotherapy. Superficial mycoses are often treated, but topical therapy can be used, thus limiting toxi...

ANTIFUNGAL AGENTS Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Many fungal infections are self-limiting and require no chemotherapy. Superficial mycoses are often treated, but topical therapy can be used, thus limiting toxicity to the host. Invasive or systemic fungal infections that are not controlled by the host’s immune system require the prolonged Fungal use of antifungals. Given that most of the patients with Infections these infections also have underlying immunosuppression, invasive mycosis can be among the most difficult of all infectious diseases to treat successfully. https://accessmedicine-mhmedical- com.ezproxylocal.library.nova.edu/book.aspx?boo kid=2268 Ref: Sherris Medical Microbiology  Pathogenic Fungi The Superficial and Subcutaneous Fungi: Dermatophytes, Malassezia, Sporo thrix, and Pigmented Molds The Opportunistic Fungi: Candida, Aspergillus, the zygomycetes, and Pneumocystis The Systemic Fungal Pathogens: Cryptococcus, Histoplasma, Blastomyces, Coccidioides, Paracoccidioides  Prototype Drugs: Polyenes: Amphotericin B (Fungizone, Abelcet, AmBisome, Amphotec), Nystatin (Mycostatin) Flucytosine (5-FC, Ancobon), Griseofulvin (Grifulvin, Grisactin, Fulvicin) Imidazoles: Clotrimazole (Lotrimin, Mycelex), Fluconazole (Diflucan), Itraconazole (Sporanox), Ketoconazole (Nizoral), Miconazole (Monistat, Micatin) and many more.. Echinocandins: Anidulafungin (Eraxis), Micafungin (Mycamine), Caspofungin Terbinafine (Lamisil) Butenafine (Mentax), Haloprogin (Halotex), Naftifine (Naftin), Natamycin (Natacyn), Tolnaftate (Aftate, Tinactin) are additional agents Targets of antifungal drugs. Most antifungals target the fungal cell membrane or cell wall (Flucytosine & Griseofulvin are exceptions).  They are polyene antibiotics from the soil actinomycete Streptomyces. Mechanism of action: Polyenes are amphipathic molecules (hydrophilic and lipophilic). Forms pores or channels by Amphotericin B interacting with ergosterol (the sterol of fungal membrane, a major fungal lipid), thus rendering the cell membrane (Ablecet, permeable to Na+, K+ and H+ ions causing leakage. Ambisome, Amphocin, Clinical uses: Any severe fungal infection against Candida, Histoplasma, Cryptococcus neoformans, Blastomyces Fungizone, dermatitidis, Histoplasma capsulatum, Coccidiodes immitis, Amphotec, as Paracoccidioides, Aspergillus, Penicillium and the agents of mucormycosis (fungi Mucorales) etc. parenteral, Used intravenously in fungal meningitis and systemic conventional and infections. Used intrathecal in patients with meningitis lipid formulations. caused by coccidioides. Used for bladder irrigation for Candida cystitis. 3% cream is used in superficial candida Lipid formulations infections. are given Adverse: Flushing, chills, fever, phlebitis, headache, anemia, respiratory stridor (whistling respiration), reversible intravenously) decreased renal function (nephrotoxicity). Azotemia (increase of urea in blood) in patients receiving drug for deep mycoses. Lipid formulations (costly) bind to mammalian membranes less readily therefore they reduce drug-induce renal impairment.  A fluorinated pyrimidine related to fluorouracil. Mechanism: Flucytosine gets deaminated to 5- fluorouracil (5-FU) a potent antimetabolite, by cytosine deaminase, and 5-FU inhibits thymidylate synthase enzyme. Human cells are unable to convert the parent drug to its active metabolites. Flucytosine is fungistatic Flucytosine (mammalian cell does not convert flucytosine to fluorouracil and 5-FU is an anticancer agent). (Ancobon Clinical Use: As oral capsules, in systemic candidiasis and cryptococcal infections and the oral agents of chromomycosis (chronic mycoses with skin lesions resembling cauliflower like capsule) appearance caused by fungi resembling copper pennies of different species). In cryptococcal meningitis in combination with amphotericin B. Adverse: Reversible bone marrow suppression and dose dependent GI effects. Toxicity may be seen due to the conversion to 5-fluoruracil by the intestinal microflora.  The azole antifungals are Imidazoles and Triazoles. Both classes have similar spectra and mechanism of action. Mechanism of action: In fungal ergosterol biosynthesis there is a step involving sterol 14-alpha demethylase enzyme. Azoles inhibit Imidazoles this enzyme and causes accumulation of 14- aplpha methyl sterols. This disrupts the and packing of phospholipids thus inhibiting growth of fungi. Triazoles Drugs: Ketoconazole, Miconazole, Clotrimazole, Butoconazole, Tioconazole, Oxiconazole, Sulconazole, Itraconazole, Fluconazole, Posaconazole, Terconazole and many.  Itraconazole (Sporanox, oral and parenteral for deep mycoses) is a water-soluble triazole Itraconazole is used in the suppressive therapy of histoplasmosis in HIV seropositive patients. Its effects are similar to ketoconazole but with more fungal specificity. Fluconazole (Diflucan, oral, parenteral) is water- Imidazoles soluble imidazole with effective antifungal activity in immunocompetent and immunocompromised patients. Fluconazole is used in suppressive therapy and and primary treatment of cryptococcal meningitis as in AIDS patients. It is effective in the treatment of Triazoles mucosal candidiasis including oropharyngeal and esophageal candidiasis. It is also used in the primary treatment of coccidioidal meningitis as well as blastomycosis and histoplasmosis. Nausea, vomiting, gastric pain, headache, rashes etc. are adverse effects of imidazoles and triazoles. Seizures, anaphylaxis, exfoliative dermatitis are rare adverse effects.  Ketoconazole is the imidazole antifungal that is routinely used systemically. It was the first oral antifungal agent available for deep systemic mycoses. Ketoconazole is also effective against deep-seated candidiasis (need many months for cure). Also effective against oral and pharyngeal candidiasis in patients with advanced AIDS. Ketoconazole is metabolized extensively and the Ketoconazole metabolites appear in the feces. (Nizoral, oral, Endocrinological abnormalities due to inhibition of steroid biosynthesis (decrease in libido, topical) gynecomastia etc.), and hepatitis in some patients after prolonged treatment are other adverse effects. Not recommended in pregnancy and in nursing mothers. Most imidazoles are active against broad- spectrum fungi including dermatophytes, yeasts, dimorphic fungi, eumycetes, actinomycetes. Also used in tinea infections (fungi that are dermatophytes)  Structure and mechanism similar to Amphotericin B. Nystatin Active against Cryptococcus, Candida, Histoplasma, Blastomyces and dermatophytes (Mycostatin, Epidermophyton, Trichophyton and Microsporum. Biostatin, Given oral, never given parenterally. Used Nyamyc, primarily for Candida infections of the mucosa, skin, intestinal tract and vagina. Nystat, tablet Topical nystatin is the choice for oral moniliasis and troche, (candidiasis), thrush and denture stomatitis. Clinical use: Topical for oral candidiasis (oral topical, moniliasis, thrush, denture stomatitis), and for intestinal & pharyngeal candidiasis (esophageal vaginal) and gastric treatment of candida). Adverse: Too toxic parenterally, terrible foul taste. Mild and transient GI disturbances, nausea, vomiting, diarrhea etc.  Griseofulvin is a fungistatic, insoluble in water. Griseofulvin Mechanism: Inhibits mitosis at metaphase by disrupting (Fulvicin, spindle formation (microtubule function), fungistatic. Grifulvin, Griseofulvin binds avidly with newly synthesized keratin and deposits in keratin Grisactin, precursor cells. Fulvin P/G Clinical Use: Systemic drug in diseases of skin, hair and nails due to Microsporum, Oral Epidermophyton and Trichophyton. No effect on other fungi. preparations Adverse: Rare, may be severe neurological only) disturbances, mostly headache, induction of hepatic microsomal enzymes, hematological disorders (leukopenia, neutropenia), and is a direct vasodilator. Oral systemic antifungal for mucocutaneous infections  Anidulafungin (Eraxis): Anidulafungin is an echinocandin (i.v. use) antifungal agent derived from Aspergillus. Anidulafungin is fungicidal with low possibilities of developing resistance. Anidulafungin is active against candida and aspergillus. Anidulafungin has the unique mechanism of inhibiting the fungal-specific enzyme glucan synthase, which is required for the synthesis of the fungal cell wall component namely Beta 1- 3 D glucan. Micafungin (Mycamine): Micagungin is an echinocandin antifungal agent and is used ECHINOCANDINS intravenously. Micafungin is approved for esophageal candidiasis, candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses, and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. Caspofungin (Cancidas): Effective for the treatment of mucosal and invasive candidiasis and invasive aspergillosis and Pneumocystis carinii infection. Caspofungin has acceptable safety profile.  Terbinafine inhibits fungal squalene allylamine monooxygenase (squalene epoxidase). An oral form has efficacy comparable to itraconazole for onychomycosis with decreased risk of hepatotoxicity. Terbinafine Oral administration for aspergillosis (Lamisil) and onychomycosis. Recently terbinafine has been approved for tinea capitis (ringworm of the scalp, fungal infection). Oral systemic antifungal for mucocutaneous infections  Other Antifungals Ciclopirox (Loprox): Haloprogin (Halotex) : Broad spectrum antimycotic Topical 1% solution (available as cream and lotion) (discontinued) with site of action cell membrane. Tolnaftate (Aftate, Naftifine (Naftin): Tinactin, Ting): An allylamine active against Available topically as cream dermatophytes that inhibits powder and powder aerosol for squalene epoxidase. Available as dermatophyte infections. 1% cream (topical drug) Undecylenic acid (un-deh- Butenafine (Mentax): sil-EN-ik, Cruex, Desenex) A Benzylamine related to Fatty acid with fungistatic allylamines. 1% cream is used activity for topical skin for superficial dermatophytosis. infections  https://accessmedicine- mhmedical- com.ezproxylocal.library.nova.ed u/book.aspx?bookid=2268 Ref: Sherris Medical Microbiology References https://accessmedicine- mhmedical- com.ezproxylocal.library.nova.ed u/Book.aspx?bookid=2988#2506 05694 Basic & Clinical Pharmacology: Katzung