Antifungal agents

Fungus Enkaryotic microorganism Larger than bacteria Have cell walls that contain chitin, unlike the cell walls of bacteria, which contain murein. Yeast and mold Hypha and spore 芽生分生孢子(Blastoconidia),壁孢子 Chlamydoconidia

Overview Fungal infections classification: Superficial infections: Ringworm (tinea) → skin and mucous membrane. Incidence rate is high. Systemic infections: Candida albicans (白色念珠菌）, Cuyitococcus Neofonmans（新型隐球菌） → opportunist infections. Fatality rate is high.

Overview Fungal infections classification: Superficial infections: Ringworm (tinea) → skin and mucous membrane. Incidence rate is high. Systemic infections: Candida albicans (白色念珠菌）, Cuyitococcus Neofonmans（新型隐球菌） → opportunist infections. Fatality rate is high.

Candida albicans Skin, mucous (浅表) Organ: lung, esophagus, bladder, intestinal tract CNS

Antifungal agents classification: Antibiotics: Amphotericin B（两性霉素B） Azole: Ketoconazole （酮康唑） Allylamine: Terbinafine （特比萘芬） Pyrimidine: Flucytosine （氟胞嘧啶）

Antifungal agents classification: Systemic antifungal agents Amphotercin B（两性霉素B） Flucytosine（氟胞嘧啶） Azoles antifungal agents Ketoconazole（酮康唑） Fluconazol（氟康唑） Superficial antifungal agents Nystatin（制霉菌素） Griseofulvin（灰黄霉素） Terbinafine（特比萘芬）

Systemic antifungal agents Amphotercin B（两性霉素B） Flucytosine（氟胞嘧啶）

Amphotericin B Produced by Streptomyces nodosus. Polyene macrolide antibiotics Pharmacokinetics: Poorly absorbed from the gastrointestinal tract . More than 90% bound by serum proteins. Excreted slowly in the urine.

Amphotericin B Pharmacological Effect: broad-spectrum Effective: Cryptococcus neoformans, canidia, Histoplasma capsulatum, Blastomyces dermatitidis, coccidioides, Sporothrix Resistance: ringworm fungus, some aspergillus Uneffective: bacteria, virus, Rickettsia

Amphotercin B 1. Mechanism of action: Amphotercin B binds to ergosterol (麦角固醇) and alter the permeability of the fungal cell membrane by forming pore, and the pore allows the leakage of intracelluar ions and macromolecules, eventually leading to cell death.

Amphotercin B Mechanism of action 疏水 亲水

Amphotercin B 2. Clinical Uses: It is often as the initial regimen for serious fungal infections. Cryptococcal meningitis （隐球菌脑膜炎） Candidiasis （念珠菌病） Coccidioidomycosis （球孢子菌病） Histoplasmosis （组织胞浆菌病） Blastomycosis dermatitidis （皮炎芽生菌病） Invasive Aspergillosis （侵袭性曲霉菌病） Sporotrichosis（孢子丝菌病）

Amphotercin B 3. Adverse reactions: (1) fever, chill, dizziness, and hypotension（低血压）, etc. (2) nephrotoxic (3) renal tubular acidosis（肾小管酸化） and renal wasting K+ and Mg 2+ (4) hematological toxicity: hypochromic （低血红蛋白性）and normocytic（正常色素性） anemia, etc.

Amphotercin B 3. Adverse reactions: (5) hepatotoxicity (6) cardiac toxicity (7) CNS side effects (8) hypersensitive reaction

Amphotercin B 4. Prevention of adverse reaction: (1) Fresh prepare. Administration in advance of NSAIDs or antihistamine drug, and Glucocorticoid simultaneously . (2) Supplemental K+ is required. (3) Periodic Monitoring. (4) Drugs interaction.

Amphotercin B 5. New formulations of Amphotercin B : (1) Amphotercin B lipid complex, ABLC(脂质复合体) (2) Amphotercin B collcodal dispersion, ABCD(胶质分散体) (3) Liposomal Amphotercin B, L-AMPH B(脂质体)

Liposomal Amphotericin B Lipid preparations reduce toxicity without sacrificing efficacy. Lipid formulations distributes mostly in reticular endothelial tissue (liver, spleen, lung), but less in kidney.

Flucytosine（氟胞嘧啶） Chemical structure

Flucytosine Mechanism of action Poorly protein-bound and penetrates well into all body fluid compartments, including the cerebrospinal fluid.

Flucytosine Clinical Uses: Flucytosine is a norrow-spectrum antifungal drug. Spectrum of action: Cryptococcus neoformans, some candida species, etc. Drug resistance occurs rapidly when flucytosine is used alone. So, flucytosine is used predominantly in combination with amphotericin B for therapy of crypotococcal meningitis.

Flucytosine Adverse reactions: Depressing the function of bone marrow (leading to leukopenia and thrombocytopenia, etc.). Plasma levels of hepatic enzymes are elevated (reversible). Other effect, including rash, nausea, vomiting, diarrhea.

Azoles antifungal agents Classification : Imidazoles (咪唑类) Ketoconazle （酮康唑） Miconazole（咪康唑） Clotrimazole（克霉唑） Triazoles(三唑类) → systemic treatment Fluconazole （氟康唑） itraconazole（伊曲康唑）

Azoles antifungal agents Mechanism of action: The antifungal activity of azole drugs results from the reduction of ergosterol (麦角固醇) synthesis by inhibition of fungal cytochrome P450 enzyme 14α-demethylase and subsequent accumulation of 14α-methyl sterols. Imidazoles exhibit a lesser degree of specificity than the triazoles, accounting for their higher incidence of drug interactions and side effects.

Azoles antifungal agents Pharmacological Effect: broad-spectrum Effective: Cryptococcus neoformans, canidia, Histoplasma capsulatum (组织胞浆菌病), Chromatiales(着色真菌), Coccidioides (球孢子菌), Sporothrix(孢子丝菌), Aspergillus (曲霉菌) Uneffective: trichophyton (毛霉菌)

Azoles antifungal agents Clotrimazole（克酶唑）miconazole（咪康唑） Only used topically (局部) now. Commonly used for dermatophytosis or local candidal infections.

Azoles antifungal agents Ketoconazle （酮康唑） : Ketoconazle was the first oral azloes introduced into clinical use （ 浅表、深部）. Less selective for fungal P450 Inhibition of human P450 interferes with biosynthesis of adrenal and gonadal steroid hormones; Alter the metabolism of other drugs. For all of the above indications, itraconazole （伊曲康唑）or fluconazole （氟康唑） has replaced ketoconazle for patients who can afford the more expensive, newer product.

Itraconazole （伊曲康唑） Azoles antifungal agents Itraconazole （伊曲康唑） is a broad-spectrum newer antifungal azoles. Its antifungal spectrum is broader than ketoconazole, and its side effects is less than ketoconazole.

Itraconazole （伊曲康唑） Its absorption is increased by food and by low gastric pH. High concentration in fat rich tissue, but low in CSF. Treatment of dermatophytosis (皮真菌病) and onychomycosis (甲真菌病). Dematiacious(暗色孢科真菌), Sporothrix (孢子丝菌), Histoplasma capsulatum (组织胞浆菌), Blastomyce(芽生菌), Cryptococcus neoformans (less active than fluconazole and amphotercin B), Canidia (but not UTIs) only agent with significant activity against aspergillus (曲霉菌) species.

Azoles antifungal agents Fluconazole （氟康唑） Fluconazole （氟康唑） has high bioavailability, good CSF penetration. Its absorption is not affected by food and by low gastric pH. Less drug interaction and side effects (least effect on hepatic enzyme of all the azoles). The widest therapeutic index (治疗指数) of the azoles. Be used in: (1) Candidiasis（念珠菌病）, (2) Cryptococcosis（隐球菌病）, (3) other fungal infection.

大扶康全球上市20年来，在全球已有超过1亿的受益者 大扶康®光辉史 1992年9月大扶康®获准在中国上市 国家卫生部遴选为抗真菌基本药物 1993年 1992年 英国女王授予 “1991年女王科技成就大奖” WHO列为抗真菌基本药物 1991年 FDA准许大扶康®在美国上市 横空出世获准在英国和法国上市 1990年 大扶康全球上市20年来，在全球已有超过1亿的受益者 1988年 Charlier C et al. J Antimicrob Chemother. 2006;57:384-410.

Topical antifungal agents Nystatin（制霉菌素） Griseofulvin（灰黄霉素） Terbinafine（特比萘芬）

Nystatin（制霉菌素） Like Amphotericin B and has same action. Only used topically (局部), commonly used for suppression of local candidal infections (念珠菌病). Not absorbed from skin, mucous membranes, or the gastrointestinal tract, so not effective for systemic infections and little significant toxicity.

Griseofulvin（灰黄霉素） Derived from a species of penicillium. Insoluble Interfere DNA synthesis and spindle formation during reduction division Active to superficial fungal infection (小孢子菌、毛发癣菌、表皮癣菌）, but not systemic infections or bacteria.

Griseofulvin（灰黄霉素） Administered in a microcrystalline form only using in the systemic treatment of dermatophytosis (皮癣). Deposited in skin or newly forming fair and nail, where it binds to keratin (角蛋白), protecting from new infection.

Griseofulvin（灰黄霉素） It has been largely replaced by newer antifungal medications such as itraconazle and terbinafine（特比萘芬）.

Terbinafine （特比萘芬） Inhibits the fungal enzyme squalene epoxidase. Dermatophytosis, especially onychomycosis . More effective than griseofulvin or itraconazole. Adverse effects are rare: gastrointestinal upset.

Antifungal agents: Superficial anti-fungus Systemic anti-fungus Amphotercin B （两性霉素B） Flucytosine（氟胞嘧啶) Ketoconazole（酮康唑） Fluconazol（氟康唑） Itraconazole（伊曲康唑） Nystatin（制霉菌素） Griseofulvin（灰黄霉素） Terbinafine（特比萘芬） Miconazole（咪康唑） Clotrimazole（克霉唑） Ketoconazole（酮康唑） Fluconazol（氟康唑） Itraconazole (伊曲康唑）