Anti fungal Agents FUNGAL INFECTIONS • SYSTEMIC • LOCAL • HISTOPLASMOSIS • DERMATOPHYTO. • ASPERGILLOSIS • SPOROTRICHIOSI. • CRYPTOCOCCOSIS • ZYGOMYCOSIS • BLASTOMYCOSIS • CHROMOMYCOSI. • MUCORMYCOSIS • CANDIDIASIS AMPHOTERICIN B • Therapy is limited by toxicity, drug-induced renal impairment. • lipid-packaged drug binds to mammalian membrane less readily • lipid vehicle serves as an amphotericin reservoir • preferential binding allows for a reduction of toxicity Amphotericin B • some fungi contain lipases that liberate free amphotericin B • poorly absorbed from the GIT • Oral -effective only on fungi within the lumen of the tract and cannot be used for systemic disease. Mechanism of Action • It is selective in its fungicidal effect • Ergosterol, a cell membrane sterol, is found in the cell membrane of fungi • binds to ergosterol and alters the permeability of the cell by forming pores in the cell membrane • amphipathic characteristic -lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. • The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death. Antifungal Activity • It has activity against the clinically significant yeasts, including • Candida albicans • Cryptococcus neoformans; the organisms causing endemic mycoses • Histoplasma capsulatum • Blastomyces dermatitidis • Coccidioides immitis • the pathogenic molds, such as Aspergillus fumigatus Clinical Use • useful agent for all life-threatening mycotic infections • For treatment of systemic fungal disease, amphotericin B is given by slow I.V infusion • Local or topical administration of amphotericin B is used • Mycotic corneal ulcers and keratitis with topical drops and subconjunctival injection. • Fungal arthritis with adjunctive local injection directly into the joint. • Candiduria responds to bladder irrigation with amphotericin B, no significant systemic toxicity. Adverse Effects • The toxicity of amphotericin B can be divided into two broad categories: • immediate reactions, related to the infusion of the drug, and • occurring more slowly INFUSION-RELATED TOXICITY • fever, chills, muscle spasms, vomiting, headache, and hypotension. • Premedication with antipyretics, antihistamines, meperidine, or corticosteroids could help CUMULATIVE TOXICITY • Renal damage -most significant toxic reaction. • The degree of azotemia is variable • The irreversible form of amphotericin nephrotoxicity • Renal toxicity commonly manifests as renal tubular acidosis and severe potassium and magnesium wasting. • Abnormalities of liver function due to reduced erythropoietin production by damaged renal tubular cells. • After intrathecal therapy with amphotericin, seizures and arachnoiditis may develop FLUCYTOSINE • taken up by fungal cells via the enzyme cytosine permease. • It is converted intracellularly first to 5-FU and then to FdUMP and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis • Synergy with amphotericin B has been observed 5-flucytosine permease 5-flucytosine (outside) (inside) Cytosine deaminase 5dUMP& 5-fluorouracil FUTP (inhibits thymidylate Phosphoribosyl synthase) transferase RNA 5-FUMP • In vitro synergy with azole drugs has also been seen • Resistance is mediated through altered metabolism of flucytosine Clinical Use • The spectrum of activity of flucytosine is restricted to • C neoformans, • candida species, and • the dematiaceous molds that cause chromoblastomycosis. Combination therapy • Flucytosine is not used as a single agent combination therapy, • with amphotericin B for cryptococcal meningitis or • with itraconazole for chromoblastomycosis. Adverse Effects • metabolism to the toxic antineoplastic compound fluorouracil. • Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia • derangement of liver enzymes occurring less frequently. • A form of toxic enterocolitis can occur. AZOLES • Azoles are synthetic compounds that can be classified as either • imidazoles or triazoles • The imidazoles consist of ketoconazole, miconazole, and clotrimazole • The triazoles include itraconazole, fluconazole, voriconazole, and posaconazole. Mechanism of Action • the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes • Inhibit the synthesis of ergosterol by blocking demethylation (14-demethylase) of lanosterol - also inhibit cytochrome activity. • Imidazoles exhibit a lesser degree of selectivity than the triazoles Acetyl CoA Squalene Allylamine Squalene monooxygenase drugs Squalene-2,3 oxide Lanosterol 14- -demethylase Azoles (ergosterol) Resistance • Resistance to azoles occurs via multiple mechanisms. • altered demethylase • Increased production of 14-α-sterol demethylase • increasing use of these agents for prophylaxis and therapy –lead to resistance Clinical Use • The spectrum including many • candida species • C neoformans • the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis) • dermatophytes • itraconazole and voriconazole, even aspergillus infections. • amphotericin-resistant organisms such as P boydii. Adverse Effects • relatively nontoxic. • minor gastrointestinal upset • abnormalities in liver enzymes • very rarely, clinical hepatitis. Drug Interactions • All azole drugs affect the mammalian cytochrome P450 system of enzymes to some extent KETOCONAZOLE • Ketoconazole was the first oral azole introduced into clinical use. • greater propensity to inhibit mammalian than for fungal P450 • As a result, systemic ketoconazole has fallen out of clinical use in the USA Ketoconazole • Inhibits hepatic cytochrome P450 isozymes and increase plasma levels of other drugs, including anticoagulants, • cyclosporine, • oral hypoglycemics, and • phenytoin. • life-threatening cardiotoxicity when cisapride is used concomitantly with ketoconazole. • Inhibition of cytochrome P450 isoforms by ketoconazole interferes with the synthesis of adrenal and gonadal steroids and may lead • gynecomastia • menstrual irregularities, and • infertility. ITRACONAZOLE • available in oral and intravenous formulations • Drug absorption is increased by food and by low gastric pH. • interacts with hepatic microsomal enzymes • drug interaction -reduced bioavailability of itraconazole when taken with rifamycins (rifampin, rifabutin, rifapentine). • does not affect mammalian steroid synthesis • itraconazole displays potent antifungal activity, effectiveness reduced by bioavailability. Newer formulations • oral liquid and an I.V preparation, have utilized cyclodextran as a carrier molecule • enhance solubility and bioavailability. • penetrates poorly into the CSF • Itraconazole is the azole of choice for treatment of disease due to the dimorphic fungi histoplasma, Blastomyces and sporothrix • Itraconazole has activity against Aspergillus sp, but replaced by voriconazole as choice for aspergillosis. • Itraconazole is used extensively in the treatment of dermatophytoses and onychomycosis FLUCONAZOLE • Unlike ketoconazole and itraconazole, its oral bioavailability is high. • fluconazole has the least effect of all the azoles on hepatic microsomal enzymes. • few hepatic enzyme interactions and FLUCONAZOLE • better gastrointestinal tolerance • fluconazole has widest therapeutic index of the azoles • the azole of choice in the treatment and secondary prophylaxis of cryptococcal meningitis • I.V fluconazole - candidemia Fluconazole • commonly used for the treatment of mucocutaneous candidiasis • Coccidioidal disease, and in particular for meningitis • high doses of fluconazole / intrathecal amphotericin B. (only if not responding) • Fluconazole displays no activity against aspergillus • Prophylactic - reduce fungal disease in bone marrow transplant recipients and AIDS patients, • but the emergence of fluconazole-resistance seen Voriconazole • I.V and oral formulations. • Metabolism is predominantly hepatic. • clinically relevant inhibitor of mammalian CYP3A4. • dose reduction required when voriconazole is started, including cyclosporine, tacrolimus, and HMG-CoA reductase inhibitors. • toxicities include rash and elevated hepatic enzymes. • Visual disturbances • include blurring and changes in color vision or brightness. • Photosensitivity dermatitis is commonly observed in patients receiving chronic oral therapy. • excellent activity against Candida sp (including fluconazole-resistant species such as C krusei) • Voriconazole is less toxic than amphotericin B and is the treatment of choice for invasive aspergillosis. Posaconazole • Posaconazole is the newest triazole to be licensed in the USA. • It is available only in a liquid oral formulation • Absorption is improved when taken with meals high in fat. Posaconazole • Rapidly distributed to the tissues, resulting in high tissue levels • drug interactions with increased levels of CYP3A4 substrates such as tacrolimus and cyclosporine have been documented. Posaconazole • activity against most species of candida and aspergillus. • It is the only azole with activity against the agents of zygomycosis and mucormycosis. • prophylaxis of fungal infections ECHINOCANDINS • Caspofungin, micafungin, and anidulafungin are the only licensed agents in this category of antifungals • These agents are active against candida and aspergillus Pharmacokinetics • Echinocandins are available only in I.V formulations. • Caspofungin is administered as a single loading dose • Dosage adjustments are required in hepatic insufficiency. MOA • Echinocandins act at the level of the fungal cell wall by inhibiting the synthesis of (1–3) -glucan • This results in disruption of the fungal cell wall and cell death. Adverse Effects • minor gastrointestinal side effects • Elevated liver enzymes -in several patients receiving caspofungin in combination with cyclosporine • Micafungin has been shown to increase levels of nifedipine, cyclosporine, and sirolimus. • Anidulafungin no drug interactions, but histamine release may occur during intravenous infusion. Clinical Use • Caspofungin is currently licensed for disseminated and mucocutaneous candida infections, • empiric antifungal therapy during febrile neutropenia • Micafungin is licensed for mucocutaneous candidiasis, candidemia, and prophylaxis of candida infections • Anidulafungin is approved for use in esophageal candidiasis and invasive candidiasis, including candidemia. SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS • Griseofulvin fungistatic drug derived from a species of penicillium. • systemic treatment of dermatophytosis • Absorption is improved when it is given with fatty foods. Griseofulvin • it is deposited in newly forming skin - it binds to keratin • Nail infections may require therapy for months Adverse effects • include an allergic syndrome -serum sickness, hepatitis, and drug interactions with warfarin and phenobarbital. Terbinafine • used in the treatment of dermatophytoses, especially onychomycosis • terbinafine is a keratophilic medication it is fungicidal. • it interferes with ergosterol biosynthesis, inhibits the fungal enzyme squalene epoxidase • This leads to the accumulation of the sterol squalene, which is toxic to the organism. Acetyl CoA Squalene Allylamine Squalene monooxygenase drugs Squalene-2,3 oxide Lanosterol 14- -demethylase (ergosterol) Adverse effects • gastrointestinal upset and headache. • no significant drug interactions TOPICAL ANTIFUNGAL THERAPY • Nystatin is a polyene macrolide only used topically. • nystatin has little toxicity, - oral use is often limited by the unpleasant taste. • Nystatin is active against most Candida sp and is most commonly used for suppression of local candidal infections TOPICAL AZOLES • The two azoles most commonly used topically are clotrimazole and miconazole • used for vulvovaginal candidiasis. • Oral clotrimazole troches are available for treatment of oral thrush. • useful for dermatophytic infections, including tinea corporis, tinea pedis, and tinea cruris. • useful in the treatment of seborrheic dermatitis and pityriasis versicolor. Topical Allylamines • Terbinafine and naftifine are allylamines available as topical creams • Both are effective for treatment of tinea cruris and tinea corporis. • These are prescription drugs in the USA.