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Section 15. Infection disease and Anti-infective drugs (感染性疾病与抗感染药 ). Charpter 2. Anti-infective drugs ( 抗感染药物)-3. Contents. Part 7. Antifungal agents Part 8. Antiviral agents Part 9. Antituberculous Drugs and Anti-lepric Drugs Part 10. Clinical Rational Uses of Antimicrobial Agents.

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Section 15.

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    1. Section 15. Infection disease andAnti-infective drugs(感染性疾病与抗感染药)

    2. Charpter 2. Anti-infective drugs(抗感染药物)-3

    3. Contents • Part 7. Antifungal agents • Part 8. Antiviral agents • Part 9.Antituberculous Drugs and Anti-lepric Drugs • Part 10.Clinical Rational Uses of Antimicrobial Agents

    4. Part 7. Antifungal agents (抗真菌药)

    5. Overview • Fungal infections traditionally have been divided totwo distinct classes: • Systemic infections(全身性感染) • Superficial infections(浅表真菌病) • So, the major antifungal agents are described with“systemic” and “topical”,although this distinction is becoming arbitrary.

    6. Classification Ⅰ. 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); Itraconazole(伊曲康唑), etc. Ⅱ. Topical antifungal agents: Nystatin(制霉菌素); Griseofulvin(灰黄霉素); Terbinafine(特比萘芬);

    7. Classification 1、Antibiotic (抗生素类): Amphotericin B(两性霉素B ); Nystatin(制霉菌素) Griseofulvin(灰黄霉素) 2、Azole (唑类) : imidazoles (咪唑类):ketoconazole(酮康唑), Triazoles(三唑类): Itraconazole(伊曲康唑), 3、Allylamine(丙烯胺类): Terbinafine (特比萘芬) 4、Pyrimidine (嘧啶类) : Flucytosine (氟胞嘧啶) 5、Echinocandins(棘白菌素类) Caspofungin(卡泊芬净)

    8. Mechanism of action 壳多糖 氟胞嘧啶 葡聚糖合成酶 特比萘芬 唑类 羊毛甾醇 角鲨烯环氧化酶 棘白菌素类

    9. Antibiotic 1、Antibiotic (抗生素类): • Amphotericin B(两性霉素B ); • Nystatin(制霉菌素) • Griseofulvin(灰黄霉素)

    10. Antibiotic Amphotercin B(两性霉素B) amphotercin B

    11. AmphotercinB Mechanism of Action • Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. • Ergosterol(麦角固醇),a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol(胆固醇). • Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin Bassociated pores in the cell membrane .

    12. Amphotercin B • Mechanism of antifungal action

    13. AmphotercinB Antifungal Activity • Broadest spectrum. • Candida albicans and Cryptococcus neoformans(白色念珠菌和新型隐球菌 ); • Endemic mycoses(地方性真菌病 ): Histoplasma capsulatum(组织胞浆菌), Blastomyces dermatitidis(皮炎芽生菌), and Coccidioides immitis(粗球孢子菌); • Pathogenic molds(致病霉菌), such as Aspergillus fumigatus ( 曲霉)and mucor(毛霉 ).

    14. AmphotercinB Pharmacokinetics • Poorly absorbed from the gastrointestinal tract. • Oral amphotericin B cannot be used for treatment of systemic disease. • >90% bound by serum proteins • Excreted slowly in the urine over a period of several days. • The serum t1/2 is approximately 15 days. • Hepatic impairment, renal impairment, and dialysis have little impact on drug concentrations, and therefore no dose adjustment is required. • The drug is widely distributed in most tissues, but only 2–3% of the blood level is reached in cerebrospinal fluid, thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis.

    15. AmphotercinB 2. Clinical Uses: Amphotericin Bremains the drug of first choice for all life-theatening mycotic infections(真菌感染). It is often as the initial regimen for serious fungal infections: eg. Cryptococcal meningitis(隐球菌脑膜炎).

    16. AmphotercinB Adverse Effects The toxicity of amphotericin B can be divided into two broad categories: • INFUSION-RELATED TOXICITY (输液相关性毒性) • Fever, chills, muscle spasms, vomiting, headache, and hypotension. • Prevention : • (1)They can be ameliorated by slowing the infusion rate or decreasing the daily dose. • (2)Pretreatment with oral acetami-nophen(醋氨酚), or use of intrave-nous hydrocortisone hemisuccinate (氢化可的松半琥酯) at the start of the infusion decreases reaction; • (3)Supplemental K+ is required; • CUMULATIVE TOXICITY(蓄积毒性) • Renal damage is the most significant toxic reaction. • Abnormalities of liver function tests are occasionally seen. • After intrathecal therapy (鞘内注射 )with amphotericin, seizures and a chemical arachnoiditis(蛛网膜炎) may develop, often with serious neurologic sequelae. • hematological toxicity: hypochromic(低血红蛋白性) and normocytic anemia, etc.

    17. Amphotercin B 5.NewformulationsofamphotercinB (1)Liposomal Amphotercin B(L-AMPH B, 两性霉素B脂质体); (2)Amphotercin B lipid complex(ABLC, 两性霉素B脂质复合体); (3)Amphotercin B collcodal dispersion (ABCD, 两性霉素B胶质分散体).

    18. Antibiotic Nystatin(制霉菌素) • Nystatin is a polyene macrolide much like amphotericin B. It is too toxic for parenteral administration(肠外给药 ) and is only used topically. • Nystatin is currently available in creams, ointments, suppositories, and other forms for application to skin and mucous membranes. • It is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract. As a result, nystatin has little toxicity, although oral use is often limited by the unpleasant taste. • Nystatin is active against most Candida spand is most commonly used for suppression of local candidal infections. • Common indications: oropharyngeal thrush(鹅口疮), vaginal candidiasis, and intertriginous candidal infections.

    19. Antibiotic Griseofulvin(灰黄霉素) (1) Mechanism of action :cellular level • Binds to microtubules and prevents mitosis in fungi. • it is deposited in newly forming skin where it binds to keratin(角质 ), protecting the skin from new infection. Because its action is to prevent infection of these new skin structures, griseofulvin must be administered for 2–6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. • Nail infections may require therapy for months to allow regrowth of the new protected nail and is often followed by relapse. (2) Clinical uses: Oral long-term therapy for dermatophyte, hair and nail infections (3)Adverse effects • An allergic syndrome much like serum sickness(血清病 ), hepatitis, • drug interactions with warfarin and phenobarbital.

    20. Azoles 2、Azoles(唑类) • Imidazoles (咪唑类): • ketoconazole(酮康唑), • Miconazole(咪康唑), • clotrimazole (克霉唑) • Triazoles(三唑类): • Itraconazole(伊曲康唑), • Fluconazole(氟康唑), • Voriconazole(伏立康唑), • Posaconazole(泊沙康唑).

    21. Azoles Mechanism of Action • Reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. • The selective toxicity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes. • Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their higher incidence of drug interactions and side effects. • Resistance to azoles occurs via multiple mechanisms. • The spectrum of action of azole medications is broad

    22. Azoles Pharmacokinetics

    23. Azoles Clinical Use • Many candida species(念珠菌 ), C neoformans(新型隐球菌), the endemic mycoses (地方性真菌病 ), blastomycosis(芽生菌 ), coccidioidomycosis(球孢子菌病 ), histoplasmosis(组织胞浆菌病 ), the dermatophytes(皮肤癣菌 ), and, in the case of itraconazole and voriconazole, even aspergillus infections(曲霉菌感染 ). • They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii(波氏假霉样真菌).

    24. Azoles Adverse Effects • The most common adverse reaction is relatively minor gastrointestinal upset. • All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis. • All azole drugs affect the mammalian cytochrome P450 system of enzymes to some extent, and consequently they are prone to drug interactions.

    25. - = no inhibition.

    26. Azoles Ketoconazole(酮康唑) • Ketoconazole was the first oral azole introduced into clinical use. • Less selective for fungal P450 than newer azoles. • Greater propensity to inhibit mammalian cytochrome P450 enzymes Clinical Uses: 1. Cutaneous candidiasis(皮肤念珠菌病): vaginal 2. Dermatophytosis(皮肤癣菌病 ) 3. Histoplasmosis(组织胞浆菌病)

    27. Azoles Fluconazole(氟康唑) • Fluconazole displays a high degree of water solubility and good cerebrospinal fluid penetration, its oral bioavailability is high. • The drug is available in oral and intravenous formulations. • Drug interactions are also less common because fluconazole has the least effect of all the azoles on hepatic microsomal enzymes. Because of fewer hepatic enzyme interactions and better gastrointestinal tolerance, fluconazole has the widest therapeutic index of the azoles, permitting more aggressive dosing in a variety of fungal infections. • Fluconazole displays no activity against aspergillus(曲霉菌 ) or other filamentous fungi(丝状真菌). • Clinical use • cryptococcal meningitis(隐球菌性脑膜炎). • Mucocutaneous candidiasis(皮肤粘膜念珠菌病). • Coccidioidal disease(球孢子菌病)

    28. Azoles Voriconazole(伏立康唑) • Voriconazole is available in intravenous and oral formulations. The drug is well absorbed orally, with a bioavailability exceeding 90%, and it exhibits less protein binding than itraconazole. • Metabolism is predominantly hepatic. Voriconazole is a clinically relevant inhibitor of mammalian CYP3A4. Adverse Effects • Observed toxicities include rash and elevated hepatic enzymes. • Visual disturbances are common, occurring in up to 30% of patients receiving intravenous voriconazole, and include blurring and changes in color vision or brightness. These visual changes usually occur immediately after a dose of voriconazole and resolve within 30 minutes. • Photosensitivity dermatitis is commonly observed in patients receiving chronic oral therapy. spectrum of action excellent activity against Candida sp(假丝菌)(including fluconazole-resistant species such as C krusei) and the dimorphic fungi(双相真菌)。

    29. Azoles Itraconazole(伊曲康唑) • Oral and intravenous formulations. Drug absorption is increased by food and by low gastric pH. • Penetrates poorly into the cerebrospinal fluid. • spectrum • Dermatophytoses(皮肤癣菌)and onychomycosis(甲癣). • Dimorphic fungi: histoplasma(组织胞浆菌), Blastomyces(芽生菌 ), and sporothrix(孢子丝菌). • Aspergillosis(曲霉菌病): but it has been replaced by voriconazole

    30. Azoles Posaconazole(泊沙康唑 ) • Posaconazole is the newest triazole to be licensed in the USA. It is available only in a liquid oral formulation. • Posaconazole is rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels. • Posaconazole is the broadest spectrum member of the azole family, with activity against most species of candida (念珠菌)and aspergillus(曲霉菌). • It is the only azole with significant activity against the agents of zygomycosis and mucormycosis(毛霉菌病). Clinical use • Prophylaxis of invasive aspergillosis(侵袭性曲霉病), • Prophylaxis offungal infections during induction chemotherapy for leukemia, allogeneic bone marrow transplant patients with graft-versus-host disease(异基因骨髓移植患者的移植物抗宿主病).

    31. Let’s take a rest !

    32. 3、Allylamine(丙胺类) Terbinafine (特比萘芬) • Terbinafine is a synthetic allylamine that is available in an oral formulation. • It is used in the treatment of dermatophytoses, especially onychomycosis (灰指甲). it is fungicidal. • It interferes with ergosterol biosynthesis, but rather than interacting with the P450 system, terbinafine inhibits the fungal enzyme squalene epoxidase (角鲨烯环氧化酶). This leads to the accumulation of the sterol squalene(甾醇角鲨烯),which is toxic to the organism. Adverse effects : rare • Primarily of gastrointestinal upset and headache. • Terbinafine does not seem to affect the P450 system and has demonstrated no significant drug interactions to date.

    33. Flucytosine 4、Flucytosine (氟胞嘧啶) Mechanism of Action Flucytosine is taken up by fungal cells viathe enzyme--cytosine permease(胞嘧啶渗透酶). 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.

    34. Flucytosine Mechanism of antifungal action: 胸腺嘧啶核苷合成酶

    35. Flucytosine Clinical uses: Flucytosineis anarrow-spectrumanti-fungal drug. Drug resistance occurs rapidly whenflucytosineis used alone. So,flucytosineisused predominantlyin combination with amphotericin Bfor thearpy of crypotococcal meningitis in AIDS patient, etc.

    36. Flucytosine Adverse reactions: Depressing the function of bone marrow(leading to leukopenia and thrombo-cytopenia, etc.). Plasma levels of hepatic transminase are elevated(reversible). Other reaction: including rash, nausea, vomiting, diarrhea, etc.

    37. Echinocandins 5、Echinocandins(棘白菌素类) • Caspofungin(卡泊芬净) • Micafungin(米卡芬净) • Anidulafungin(阿尼芬净) • Echinocandins are available only in intravenous formulations. • Mechanism of Action • Act at the level of the fungal cell wall by inhibiting the synthesis of (1–3)-glucan(葡聚糖).

    38. Spectrum of action • Active effect against candida (念珠菌)and aspergillus(曲霉菌), but not C neoformans (隐球菌) or the agents of zygomycosis and mucormycosis(毛霉菌病). • Adverse Effects • Echinocandin agents are extremely well tolerated, with minor gastrointestinal side effects and flushing reported infrequently.

    39. Echinocandins Caspofungin(卡泊芬净) • water-soluble and highly protein-bound. • t1/2: 9–11 hours • metabolites are excreted by the kidneys and gastrointestinal tract. • Dosage adjustments are required only in the presence of severe hepatic insufficiency. • Clinical Use • Caspofungin is currently licensed for disseminated and mucocutaneous candida infections(侵袭性和皮肤粘膜念珠菌病) • Note:caspofungin is licensed for use in invasive aspergillosis(侵袭性曲霉病) only as salvage therapy(抢救治疗)in patients who have failed to respond to amphotericin B, and not as primary therapy.

    40. Echinocandins Micafungin (米卡芬净) • similar properties with Caspofungin • t1/2: 11–15 hours • Clinical use: • Micafungin is licensed for mucocutaneous candidiasis, candidemia, and prophylaxis of candida infections in bone marrow transplant patients.

    41. Anidulafungin (阿尼芬净) • t1/2: 24–48 hours. • Clinical use: • esophageal candidiasis and invasive candidiasis, including candidemia. • For esophageal candidiasis, it is administered intravenously at 100 mg on the first day and 50 mg/d thereafter for 14 days. • For candidemia, a loading dose of 200 mg is recommended with 100 mg/d thereafter for at least 14 days after the last positive blood culture.

    42. Part 2 Antiviral drugs Anti-influenza virus agent Antiherpes agents

    43. Anti-HIV agents • Entry inhibitors(入胞抑制药) • Reverse transcriptase inhibitor(逆转录酶抑制剂) • Nonnucleoside reverse transcriptase inhibitor(非核苷逆转录酶抑制剂, NNRTI); • Nucleoside reverse transcriptase inhibitor(核苷逆转录酶抑制剂, NRTI); • Protease inhibitor(蛋白酶抑制剂,PI) • Integrase Inhibitors (整合酶抑制药)

    44. Antiviral drugs2 Antiviral therapy 流感病毒 疱疹病毒 • Influenza—RNA virus • herpesviruses (HSV)—DNA virus • human immunodeficiency virus (HIV)- RNA Reverse transcript virus 艾滋病毒 肝炎病毒

    45. 病毒吸附侵入(attachment & penetration) 合成病毒 核酸\蛋白质 病毒颗粒 装配成熟(assembly) 从细胞内 释放(release) 合成 核酸多聚酶 病毒脱壳(uncoating)

    46. Antiviral drugs1 1 Anti-influenza virus agents • M2蛋白抑制剂: • Amantadine(金刚烷胺)--influenza A • Neuraminidase(神经氨酸酶,NA) inhibitors • Oseltamivir(奥司他韦);zanamivir(扎那米韦)--influenza A &B • 广谱抗病毒药 • Ribavirin(利巴韦林, virazole病毒唑)--DNA &RNA viurs

    47. Mechanism of Antiviral drug action 病毒侵入 病毒吸附 病毒脱壳 合成病毒 核酸\蛋白质 病毒颗粒 装配成熟 释放