Ch61 Antifungal Agents

1 Systemic Antifungal Agents: Drugs for Deeply Invasive Fungal Infections

全身性抗真菌药物：治疗深侵袭性真菌感染的药物

• Amphotericin B (两性霉素 B)
• Flucytosine (氟胞嘧啶)
• Imidazoles and Triazoles (咪唑类和三唑类)
  • Ketoconazole (酮康唑)
  • Itraconazole (伊曲康唑)
  • Fluconazole (氟康唑)
  • Voriconazole (伏立康唑)
  • Posaconazole (泊沙康唑)
  • Isavuconazole (艾沙康唑)
• Echinocandins (棘白菌素)
  • Caspofungin (卡泊芬净)
  • Micafungin (米卡芬净)
  • Anidulafungin (阿尼杜拉芬净)
• Other Systemic Antifungal Agents (其他全身性抗真菌药)
  • Griseofulvin (灰黄霉素)
  • Terbinafine (特比萘芬)
• Agents Active Against Microsporidia and Pneumocystis (对小孢子虫和肺孢子虫有活性的药物)
  • Albendazole (阿苯达唑)
  • Fumagillin (烟曲霉素)
  • Pentamidine (喷他脒)

1.2 Fluconazole (氟康唑)

Fluconazole is a fluorinated bis-triazole. (氟康唑是一种氟化双三唑)

ADME: Fluconazole is almost completely absorbed from the GI tract. Plasma concentrations are essentially the same whether the drug is given orally or intravenously, and its bioavailability is unaltered by food or gastric acidity. Peak plasma concentrations are 4 to 8 μg/mL after repetitive doses of 100 mg. Renal excretion accounts for more than 90% of elimination, and the elimination t1/2 is 25 to 30 h. Fluconazole diffuses readily into body fluids, including breast milk, sputum, and saliva; concentrations in CSF can reach 50% to 90% of the simultaneous values in plasma. The dosage interval should be increased from 24 to 48 h with a creatinine clearance of 21 to 40 mL/min and to 72 h at 10 to 20 mL/min. A dose of 100 to 200 mg should be given after hemodialysis. About 11% to 12% of drug in the plasma is protein bound.

ADME： 氟康唑几乎完全从胃肠道吸收。无论药物是口服还是静脉给药，血浆浓度基本相同，并且其生物利用度不受食物或胃酸度的影响。重复给药 100 mg 后，血浆峰浓度为 4 至 8 μg/mL。肾排泄占消除的 90% 以上，消除 t1/2 为 25 至 30 h。氟康唑很容易扩散到体液中，包括母乳、痰液和唾液;CSF 中的浓度可以达到血浆中同时值的 50% 至 90%。剂量间隔应从 24 至 48 小时（肌酐清除率为 21 至 40 mL/min）增加到 72 小时（10 至 20 mL/min）。血液透析后应给予 100 至 200 mg 的剂量。血浆中约 11% 至 12% 的药物与蛋白质结合。

Therapeutic Uses (治疗用途)

• Candidiasis: Fluconazole, 100 to 200 mg daily for 7 to 14 days, is effective in oropharyngeal candidiasis. A single dose of 150 mg is effective in uncomplicated vaginal candidiasis. A loading dose of 800 mg followed by 400 mg daily is useful in treating candidemia of nonimmunosuppressed patients (Pappas et al., 2007; Rex et al., 1994). Current treatment guidelines for candidemia indicate that fluconazole is an acceptable alternative to the first-line therapy of an echinocandin in select patients. Fluconazole is recommended as a step-down therapy provided the patient’s isolate is susceptible to the azole and follow-up blood cultures are negative (Pappas et al., 2016).

• 念珠菌病：氟康唑，每天 100 至 200 毫克，持续 7 至 14 天，对口咽念珠菌病有效。单剂量 150 毫克对无并发症的阴道念珠菌病有效。每天 800 毫克的负荷剂量，然后每天 400 毫克可用于治疗非免疫抑制患者的念珠菌血症（Pappas 等人，2007 年;Rex et al.， 1994）。目前的念珠菌血症治疗指南表明，氟康唑是特定患者一线棘白菌素一线治疗的可接受替代药物。如果患者的分离株对唑类药物敏感且后续血培养呈阴性，则建议使用氟康唑作为降级疗法（Pappas 等人，2016 年）。

• Cryptococcosis: Fluconazole, 400 mg daily, is used for the initial 8 weeks of the consolidation phase of the treatment of cryptococcal meningitis in patients with AIDS, after an induction course of at least 2 weeks of intravenous amphotericin B. If, after 8 weeks at 400 mg/day, the patient is no longer symptomatic, then the dose is decreased to 200 mg daily and continued indefinitely. If the patient has completed 12 months of treatment of cryptococcosis, responds to combination antiretroviral therapy, has a CD4 count maintained above 200/mm3 for at least 6 months, and is asymptomatic from cryptococcal meningitis, it is reasonable to discontinue maintenance fluconazole as long as the CD4 response is maintained. Fluconazole, 400 mg daily, has been recommended as continuation therapy in patients without AIDS with cryptococcal meningitis who have responded to an initial course of C-AMB or L-AMB and for patients with pulmonary cryptococcosis (Perfect et al., 2010). Recent clinical trials indicate that fluconazole can be combined with flucytosine for induction therapy with efficacy similar to amphotericin B combined with flucytosine (Molloy et al., 2018).

• 隐球菌病：氟康唑，每天 400 毫克，用于治疗艾滋病患者隐球菌性脑膜炎巩固阶段的最初 8 周，经过至少 2 周的静脉注射两性霉素 B 诱导疗程。如果以 400 毫克/天的速度 8 周后，患者不再有症状，则剂量减少至每天 200 毫克并无限期持续。如果患者已完成 12 个月的隐球菌病治疗，对联合抗逆转录病毒治疗有反应，CD4 计数维持在 200/mm3 以上至少 6 个月，并且隐球菌性脑膜炎无症状，只要 CD4 反应维持，停止氟康唑维持治疗是合理的。氟康唑，每天 400 毫克，已被推荐作为对 C-AMB 或 L-AMB 初始疗程有反应的无艾滋病隐球菌性脑膜炎患者以及肺隐球菌病患者的继续治疗（Perfect 等人，2010 年）。最近的临床试验表明，氟康唑可以与氟胞嘧啶联合用于诱导治疗，其疗效类似于两性霉素 B 联合氟胞嘧啶（Molloy et al.， 2018）。

• Other Mycoses: Fluconazole is the drug of choice for treatment of coccidioidal meningitis because of good penetration into the CSF and much lower morbidity compared to intrathecal amphotericin B (Galgiani et al., 2016). In other forms of coccidioidomycosis, fluconazole is comparable to itraconazole. Although itraconazole is the first-line therapy for blastomycosis, fluconazole is an alternative. Fluconazole has no useful activity against histoplasmosis or sporotrichosis, and is not effective in the prevention or treatment of aspergillosis. Fluconazole has no activity in mucormycosis.

• 其他真菌病：氟康唑是治疗球孢子菌脑膜炎的首选药物，因为与鞘内注射两性霉素 B 相比，氟康唑对 CSF 的渗透性好，发病率要低得多（Galgiani et al.， 2016）。在其他形式的球孢子菌病中，氟康唑与伊曲康唑相当。虽然伊曲康唑是芽生菌病的一线治疗，但氟康唑是一种替代疗法。氟康唑对组织胞浆菌病或孢子丝菌病没有有用的活性，对预防或治疗曲霉菌病无效。氟康唑在毛霉菌病中没有活性。

Dosage: Fluconazole is marketed in the U.S. as tablets of 50, 100, 150, and 200 mg for oral administration, powder for oral suspension providing 10 and 40 mg/mL, and intravenous solutions containing 2 mg/mL in saline and in dextrose solution. The daily dose of fluconazole should be based on the infecting organism and the patient’s response to therapy. Generally, recommended dosages are 50 to 400 mg once daily for either oral or intravenous administration. A loading dose of twice the daily maintenance dose is generally administered on the first day of therapy. Prolonged maintenance therapy may be required to prevent relapse. Children are treated with 12 mg/kg once daily (maximum 600 mg/day) without a loading dose. In adult patients, doses of up to 1200 mg have been safely administered in clinical trials for the treatment of cryptococcal meningitis.

剂量： 氟康唑在美国销售为 50、100、150 和 200 mg 口服片剂，口服混悬剂粉末提供 10 和 40 mg/mL，以及含有 2 mg/mL 的盐水和葡萄糖溶液的静脉注射溶液。氟康唑的每日剂量应基于感染微生物和患者对治疗的反应。通常，推荐剂量为 50 至 400 毫克，每天一次，口服或静脉给药。通常在治疗的第一天给予每日维持剂量 2 倍的负荷剂量。可能需要长期维持治疗以防止复发。儿童用 12 mg/kg 每天一次（最大 600 mg/天）治疗，无负荷剂量。在成年患者中，在治疗隐球菌性脑膜炎的临床试验中，已安全地施用高达 1200 毫克的剂量。

Adverse Effects: Side effects in patients receiving more than 7 days of drug, regardless of dose, include nausea, headache, skin rash, vomiting, abdominal pain, and diarrhea (all at 2%–4%). Reversible alopecia may occur with prolonged therapy at 400 mg daily. Rare cases of deaths due to hepatic failure or Stevens-Johnson syndrome have been reported. Fluconazole has been associated with skeletal and cardiac deformities in at least three infants born to two women taking high doses during pregnancy. Although a recent clinical study found no association between fluconazole receipt by mothers and most birth defects in their children, this study did find a statistically significant increase in tetralogy of Fallot in babies born to mothers who received fluconazole (Mølgaard-Nielsen et al., 2013). Fluconazole should be avoided during pregnancy.

不良反应： 接受超过 7 天药物的患者，无论剂量如何，副作用包括恶心、头痛、皮疹、呕吐、腹痛和腹泻（均为 2%-4%）。每天 400 毫克的长期治疗可能会发生可逆性脱发。已有罕见的肝功能衰竭或 Stevens-Johnson 综合征死亡病例报道。氟康唑与两名怀孕期间服用大剂量的妇女所生的至少 3 名婴儿的骨骼和心脏畸形有关。尽管最近的一项临床研究发现母亲接受氟康唑与其孩子的大多数出生缺陷之间没有关联，但这项研究确实发现接受氟康唑的母亲所生婴儿的法洛四联症在统计学上显着增加（Mølgaard-Nielsen 等人，2013 年）。怀孕期间应避免使用氟康唑。

Drug Interactions: Fluconazole is an inhibitor of CYP3A4 and CYP2C9. Fluconazole’s drug-drug interactions are shown in Tables 61–4, 61–5, and 61–6. Patients who receive more than 400 mg daily or azotemic patients who have elevated fluconazole blood levels may experience drug interactions not otherwise seen.

药物相互作用： 氟康唑是 CYP3A4 和 CYP2C9 的抑制剂。氟康唑的药物相互作用如表 61-4、61-5 和 61-6 所示。每天接受超过 400 毫克的患者或氟康唑血液水平升高的氮质血症患者可能会出现其他情况未见的药物相互作用。

1.3 特比萘芬 (Terbinafine)

Terbinafine is a synthetic allylamine, structurally similar to the topical agent naftifine (see discussion that follows). It inhibits fungal squalene epoxidase and thereby reduces ergosterol biosynthesis.

特比萘芬是一种合成烯丙胺，在结构上类似于外用剂萘替芬（见下面的讨论）。它抑制真菌角鲨烯环氧化酶，从而减少麦角甾醇的生物合成。

ADME: Terbinafine is well absorbed, but bioavailability is about 40% due to first-pass metabolism in the liver. The drug accumulates in skin, nails, and fat. The initial t1/2 is about 12 h but extends to 200 to 400 h at steady state. Terbinafine is not recommended in patients with marked azotemia or hepatic failure. Rifampin decreases and cimetidine increases plasma terbinafine concentrations.

ADME：特比萘芬吸收良好，但由于肝脏中的首过代谢，生物利用度约为 40%。该药物在皮肤、指甲和脂肪中积累。初始 t1/2 约为 12 小时，但在稳态下延长至 200 至 400 小时。不推荐将特比萘芬用于明显氮质血症或肝功能衰竭的患者。利福平降低血浆特比萘芬浓度，西咪替丁增加血浆特比萘芬浓度。

Therapeutic Uses: Terbinafine, given as one 250-mg tablet daily for adults, is somewhat more effective than itraconazole for nail onychomycosis. Duration of treatment varies with the site of infection but typically ranges between 6 and 12 weeks. The efficacy for the treatment of onychomycosis can be improved by the simultaneous use of amorolfine 5% nail lacquer (amorolfine is not approved for use in the U.S.). Terbinafine is also effective for the treatment of tinea capitis and has been used for the off-label treatment of ringworm elsewhere on the body.

治疗用途： 特比萘芬，成人每天一片 250 毫克片剂，比伊曲康唑对指甲甲真菌病更有效。治疗持续时间因感染部位而异，但通常在 6 至 12 周之间。同时使用 5% 阿莫罗芬指甲油可以提高治疗甲癣的疗效（阿莫罗芬在美国未获批使用）。特比萘芬对治疗头癣也有效，并已用于身体其他部位的癣的超说明书治疗。

Adverse Effects: The drug is well tolerated, with a low incidence of GI distress, headache, or rash. Very rarely, fatal hepatotoxicity, severe neutropenia, Stevens-Johnson syndrome, or toxic epidermal necrolysis may occur. Systemic terbinafine therapy for onychomycosis should be postponed until after pregnancy is complete.

不良反应：该药物耐受性良好，胃肠道不适、头痛或皮疹的发生率较低。极少数情况下，可能会发生致命的肝毒性、严重的中性粒细胞减少、Stevens-Johnson 综合征或中毒性表皮坏死松解症。甲癣的全身性特比萘芬治疗应推迟到妊娠完成后。

2 Topical Antifungal Agents (外用抗真菌药)

• Topical Imidazoles and Triazoles (外用咪唑类和三唑类)
  • Clotrimazole (克霉唑)
  • Econazole (益康唑)
  • Efinaconazole (艾氟康唑)
  • Miconazole (咪康唑)
  • Luliconazole (卢立康唑)
  • Terconazole and Butoconazole (特康唑和布托康唑)
  • Tioconazole (噻康唑)
  • Oxiconazole, Sulconazole, and Sertaconazole (奥昔康唑、磺康唑和舍他康唑)
  • Ketoconazole (酮康唑)
• Structurally Diverse Antifungal Agents (结构多样的抗真菌剂)
  • Ciclopirox Olamine (环吡酮乙醇胺)
  • Haloprogin （盐丙蛋白）
  • Tolnaftate (托萘酯)
  • Naftifine (萘替芬)
  • Terbinafine (特比萘芬)
  • Butenafine (布特萘芬)
  • Tavaborole (他伐硼罗)
  • Nystatin (制霉菌素)
  • Undecylenic Acid (十一烯酸)
  • Benzoic and Salicylic Acids (苯甲酸和水杨酸)