Fungal Skin Infections

  • Fungal Skin Infections (真菌性皮膚感染)

  • Introduction (介紹)

    • This lecture discusses fungal skin infections, their transmission, symptoms, and treatment options. (本講座討論了真菌性皮膚感染、它們的傳播、癥狀和治療方案。)

    • The significance of antimicrobial resistance (AMR) in the treatment of fungal infections is also covered. (還涵蓋了抗菌素耐藥性 （AMR） 在治療真菌感染中的重要性。)

  • Learning Outcomes (學習成果)

    • Understand fungal infections and their transmission (瞭解真菌感染及其傳播)

    • Recognize common fungal skin infections (also hair/scalp & nails) and their symptoms (識別常見的真菌皮膚感染（包括頭髮/頭皮和指甲）及其癥狀)

    • Know the common anti-fungal treatments (瞭解常見的抗真菌治療)

    • Be able to explain the mechanism of action of anti-fungal drugs (能夠解釋抗真菌藥物的作用機制)

    • Be able to make decisions about the most suitable treatment options as well as other self- care measures (能夠決定最合適的治療方案以及其他自我護理措施)

    • Appreciate the significance of AMR for treatment of fungal infections (瞭解AMR治療真菌感染的重要性)

  • Main Types of Fungal Infections (真菌感染的主要類型)

    • Superficial: Limited to the stratum corneum (outermost layer of the skin), not typically associated with inflammation. (淺表： 局限於角質層（皮膚的最外層），通常與炎症無關。)

    • Cutaneous: Involves the integument, including nails and hair, affecting deeper layers of the epidermis; induces an inflammatory response, causing redness and itching. (皮膚： 涉及外皮，包括指甲和頭髮，影響表皮的更深層;誘發炎症反應，引起發紅和瘙癢。)

    • Subcutaneous: Penetrates the epidermis, infecting deeper tissues, often resulting from cuts or wounds. (皮下： 穿透表皮，感染更深的組織，通常由割傷或傷口引起。)

    • Systemic/deep: Spread throughout the body or deeper into organs such as the lungs and central nervous system; more common in immunocompromised individuals. (全身性/深部： 擴散到全身或更深處進入器官，例如肺和中樞神經系統;在免疫功能低下的個體中更常見。)

    • Superficial skin infections are mainly caused by dermatophytes or Candida species. (淺表皮膚感染主要由皮膚癬菌或 念珠菌 引起。)

    • Skin and nail infections are common, especially toenail infections and athlete’s foot. (皮膚和指甲感染很常見，尤其是腳趾甲感染和腳癬。)

  • Candidiasis (念珠菌病)

    • Most common fungal infection in the UK. (英國最常見的真菌感染。)

    • Candida species are widely distributed in the environment. (念珠菌 屬廣泛分佈在環境中。)

    • They are part of the normal commensal population of the skin. (它們是皮膚正常共生種群的一部分。)

    • Types include C. albicans, C. tropicalis, C. glabrata, C. pseudotropicalis, etc. (類型包括白色念珠菌、熱帶念珠菌、光滑念珠菌、假熱帶念珠菌等。)

    • Infection can be due to broad-spectrum antibiotics or immunodeficiency. (感染可能是由於廣譜抗生素或免疫缺陷引起的。)

    • Candida has a modest capacity to invade, using adhesins and extracellular lipases and proteases. (念珠菌 具有適度的侵入能力，使用粘附素和細胞外脂肪酶和蛋白酶。)

  • Candidiasis Symptoms (念珠菌病癥狀)

    • Usually localized (skin, mucosae (e.g. vaginal, oral thrush), nail (onychomycosis)). (通常局部（皮膚、粘膜（例如陰道、鵝口瘡）、指甲（甲癣））。)

    • Symptoms include pain, itching, and creamy curd-like plaques on mucosal surfaces which may bleed when removed. (癥狀包括疼痛、瘙癢和粘膜表面的奶油狀凝乳狀斑塊，去除后可能會出血。)

    • In immunocompromised patients, it can become systemic. (在免疫功能低下患者中，它可以變成全身性。)

    • Systemic symptoms: pharyngitis, esophagitis, dysphagia with weight loss, disseminated disease, and sepsis. (全身癥狀：咽炎、食管炎、吞咽困難伴體重減輕、播散性疾病和膿毒症。)

  • Candidiasis Diagnosis (念珠菌病診斷)

    • Clinical features. (臨床特徵。)

    • KOH (potassium hydroxide) testing. (KOH（氫氧化鉀）檢測。)

    • Laboratory culture. (實驗室培養。)

  • Candidiasis Treatment (念珠菌病治療)

    • Azoles: (唑類：)

      • Imidazoles: e.g., clotrimazole (Canesten, topical). (咪唑類藥物：例如克黴唑（Canesten，外用）。)

      • Triazoles: e.g., fluconazole (Canesten, oral). (三唑類藥物：例如氟康唑（Canesten，口服）。)

    • Polyenes: (Polyenes：)

      • Nystatin (for oral-related infections, skin; local application). (制黴菌素（用於口腔相關感染，皮膚;局部應用）。)

      • Amphotericin (systemic, IV). (兩性黴素（內吸性，IV）。)

    • Caspofungin (IV) if systemic. (卡泊芬淨 （IV） 如果是全身性的。)

    • Flucytosine with amphotericin for some indications. (氟胞嘧啶聯合兩性黴素用於某些適應症。)

  • Polyenes: Mechanism of Action (多烯：作用機制)

    • Bind to ergosterol in the fungal cell membrane. (與真菌細胞膜中的麥角甾醇結合。)

    • Form pores in the plasma membrane. (在質膜中形成孔。)

    • Cause leakage of potassium (K+) and magnesium (Mg2+) ions. (導致鉀 （K+） 和鎂 （Mg2+） 離子洩漏。)

    • Leads to lysis (cell death). (導致裂解（細胞死亡）。)

    • Fungicidal, depending on ergosterol concentration. (殺菌，取決於麥角甾醇濃度。)

  • Azoles: Mechanism of Action (唑類藥物：作用機制)

    • Inhibit lanosterol 14 alpha-demethylase (a Cytochrome P450 enzyme). (抑制羊毛甾醇 14 α-去甲基化酶 （一種細胞色素 P450 酶）。)

    • Interfere with ergosterol biosynthesis. (干擾麥角甾醇的生物合成。)

    • Disrupt the plasma membrane, leading to a fungistatic effect. (破壞質膜，導致抑菌作用。)

    • Ergosterol biosynthesis pathway: (AcetylCoA→FarnesylPyrophosphate→Squalene→Squaleneepoxide→Lanosterol) (麥角甾醇生物合成途徑：AcetylCoA→FarnesylPyrophosphate→角鯊烯→角鯊烯環氧化物→羊毛甾醇)

    • Lanosterol is then converted to ergosterol via multiple steps, including: (LanosterolLanosterol14α−demethylase​…→Ergosterol) (然後，通過多個步驟將羊毛甾醇轉化為麥角甾醇，包括：Lanosterol \xrightarrow{羊毛甾醇 14 \α-去甲基化酶} ... \rightarrow 麥角甾醇)

  • Allylamines: Mechanism of Action (烯丙胺：作用機制)

    • Example: Terbinafine (Lamisil). (示例：特比羋芬 （Lamisil）。)

    • Spectrum: Mainly dermatophytes, effective against nail infections and ringworm. (譜系：主要是皮膚癬菌，對指甲感染和癣有效。)

    • Mechanism of action: Inhibits squalene epoxidase, preventing the generation of lanosterol from squalene in ergosterol biosynthesis. (作用機制： 抑制角鯊烯環氧酶，阻止麥角甾醇生物合成中角鯊烯產生羊毛甾醇。)

    • Fungistatic/fungicidal. (抑菌/殺菌。)

    • Ergosterol biosynthesis pathway: (AcetylCoA→FarnesylPyrophosphate→SqualeneSqualeneEpoxidase​Squaleneepoxide→Lanosterol) (麥角甾醇生物合成途徑：AcetylCoA→FarnesylPyrophosphate→角鯊烯角鯊烯環氧化物酶​角鯊烯環氧化物→羊毛甾醇)

  • Morpholines: Mechanism of Action (嗎啉：作用機制)

    • Example: Amorolfine (synthetic). (示例：阿莫羅芬（合成）。)

    • Spectrum: Broad, effective against dermatophytes and yeast. (譜：廣泛，對皮膚癣菌和酵母菌有效。)

    • Mechanism of action: Inhibits $Δ$14 reductase and $Δ$7-8 isomerase, interfering with ergosterol biosynthesis. (作用機制：抑制 $Δ$14 還原酶和 $Δ7−8異構酶，干擾麥角甾醇的生物合成。)∗Usuallyfungicidal.(通常具有殺真菌作用。)∗Ergosterolbiosynthesispathway:(LanosterolDelta14reductase​…→Ergosterol)(麥角甾醇生物合成途徑：LanosterolDelta14還原酶​...→麥角甾醇$)

  • Echinocandins (棘白菌素)

    • Type: Lipopeptides, e.g., Caspofungin. (類型：脂肽，例如卡泊芬凈。)

    • Route: IV administration (once daily). (途徑：靜脈給葯（每天一次）。)

    • Spectrum: Broad, used for serious systemic infections (Candida, Aspergillus). (譜系：廣譜，用於嚴重的全身感染（念珠菌、曲黴菌）。)

    • Not effective for CNS infections or Cryptococcus. (對 CNS 感染或隱球菌無效。)

    • Mechanism of Action: Inhibits the production of β(1-3)-glucan, a part of the fungal cell wall, via inhibition of 1-3-β-glucan synthase. (作用機制：通過抑制 1-3-β-葡聚糖合酶，抑制真菌細胞壁的一部分 β（1-3）-葡聚糖的產生。)

    • Fungicidal (depending on concentration). (殺真菌（取決於濃度）。)

  • Flucytosine (氟胞嘧啶)

    • Type: Fluoropyrimidine (synthetic). (類型： 氟嘧啶（合成）。)

    • Route: Oral or IV. (途徑：口服或靜脈注射。)

    • Well-absorbed, including into the cerebrospinal fluid (CSF). (吸收良好，包括進入腦脊液 （CSF）。)

    • Spectrum: Used in combination with other drugs for severe cryptococcal or Candida systemic infections. (譜系：與其他藥物聯合用於嚴重的隱球菌或念珠菌全身感染。)

    • Mechanism of Action: Converted into 5-FU, which disrupts RNA/DNA synthesis (fungistatic). (作用機制：轉化為 5-FU，破壞 RNA/DNA 合成（抑菌）。)

  • Griseofulvin (灰黃黴素)

    • Source: Penicillium patulum. (來源： 青黴菌。)

    • Type: Benzofuran. (類型：苯並呋喃。)

    • Route: Oral (tablets or suspension). (途徑：口服（片劑或混懸液）。)

    • Spectrum: Limited to dermatophytes, usually for tinea capitis. (譜系：僅限於皮膚癬菌，通常用於頭癬。)

    • Mechanism of Action: Binds to polymerized microtubules, inhibiting mitosis (cell division) and halting growth (fungistatic). (作用機制： 與聚合的微管結合，抑制有絲分裂（細胞分裂）並停止生長（抑菌）。)

    • Side effects: Rash, urticaria, nausea, vomiting, anorexia. (副作用：皮疹、蕁麻疹、噁心、嘔吐、厭食。)

  • Vulvovaginal Candidiasis (外陰陰道念珠菌病)

    • Symptoms: (Differential diagnosis with STIs - Bacterial Vaginosis vs Thrush vs Trichomoniasis) (癥狀：（與性傳播感染的鑒別診斷 - 細菌性陰道病 vs 鵝口瘡 vs 滴蟲病）)

      • White vaginal discharge, usually odorless, with a curd-like appearance. (白色陰道分泌物，通常無臭，外觀呈凝乳狀。)

      • Itching and irritation (vulva and vagina). (瘙癢和刺激（外陰和陰道）。)

      • Pain on urination or intercourse. (排尿或疼痛。)

    • Note: Men can have genital candidiasis with similar symptoms, including: (注意：男性可能患有生殖器念珠菌病，並伴有類似癥狀，包括：)

      • Burning, irritation, itching, redness on the penis tip and foreskin. (陰莖尖端和包皮灼熱、刺激、瘙癢、發紅。)

  • Vulvovaginal Candidiasis Treatment (外陰陰道念珠菌病治療)

    • Adults: (成年人：)

      • Vulvitis: Topical imidazole creams (e.g., clotrimazole 1% or 2% cream 2-3 times per day, or ketoconazole 2% 1-2 times per day). (外陰炎：外用咪唑乳膏（例如，1% 或 2% 克黴唑乳膏，每天 2-3 次，或 2% 酮康唑，每天 1-2 次）。)

      • Vaginal/vulvovaginal: Intravaginal cream or pessary (often combined with topical cream if vulval symptoms). (陰道/外陰陰道：陰道內乳膏或子宮托（如果出現外陰癥狀，通常與局部乳膏聯合使用）。)

        • Options: econazole, miconazole, clotrimazole, fenticonazole. (選項：依康唑、咪康唑、克黴唑、芬替康唑。)

        • Examples: 10% clotrimazole cream 5g inserted at night (single dose) or 500mg single-dose pessary at night (some options require 3 or 6 nights). (例如：晚上插入 10% 克黴唑乳膏 5 克（單劑量）或晚上 500 毫克單劑量子宮托（某些選項需要 3 或 6 晚）。)

      • Oral: fluconazole 150mg single dose or itraconazole 200mg twice daily for 1 day. (口服：氟康唑 150 毫克單劑量或伊曲康唑 200 毫克，每天兩次，持續 1 天。)

    • Girls (12-15 years): Oral/intravaginal options not typically used; topical treatments are considered. (女孩（12-15 歲）：通常不使用口服/陰道內選擇;考慮局部治療。)

    • Pregnant adults (16+ years): Intravaginal clotrimazole or miconazole for at least 7 days; oral treatment not recommended. Refer to NICE guidance. (孕婦 （16+ 歲）：陰道內注射克黴唑或咪康唑至少 7 天;不建議口服治療。請參閱 NICE 指南。)

  • Candidiasis of the Nail (Onychomycosis) (指甲念珠菌病（甲癣）)

    • Symptoms: Abnormal and discolored nails, overlapping with symptoms of dermatophyte infections. (癥狀：指甲異常和變色，與皮膚癬菌感染的癥狀重疊。)

    • Diagnosis: Confirmation via microscopy and culture is recommended. (診斷：建議通過顯微鏡檢查和培養進行確認。)

    • Self-care: Good hygiene, appropriate footwear, regular nail clipping, and avoiding damp conditions and nail trauma. (自我護理：良好的衛生習慣、合適的鞋子、定期剪指甲，避免潮濕的環境和指甲創傷。)

    • Treatment: (治療：)

      • Initially, topical use of 5% amorolfine lacquer (OTC) for 6 months (fingernails) or 9-12 months (toenails). (最初，局部使用 5% 阿莫羅芬漆 （OTC） 6 個月（指甲）或 9-12 個月（腳趾甲）。)

      • If topical treatment is inappropriate or ineffective, oral antifungals may be considered. (如果局部治療不合適或無效，可以考慮口服抗真菌葯。)

      • First-line: Pulsed therapy with itraconazole 200mg twice daily for 1 week (repeated x2 or x3, 21 days apart) – fungicidal for Candida. (一線治療：伊曲康唑 200 毫克脈衝療法，每天兩次，持續 1 周（重複 x2 或 x3，間隔 21 天）——對念珠菌有殺菌作用。)

      • Terbinafine is an alternative but off-label for non-dermatophyte infections. (特比美芬是非皮膚癬菌感染的替代藥物，但標籤外。)

  • Dermatophytosis (Tinea Infections) (皮膚癬菌病（癬感染）)

    • Types: Caused by three species of filamentous fungi: Epidermophyton, Microsporum, and Trichophyton. Trichophyton is the most common. (類型： 由三種絲狀真菌引起：表皮真菌、小孢子菌和毛癬菌。 毛癬菌是最常見的。)

    • Also referred to as Tinea. (也稱為癣。)

    • Clinical diagnosis is based on the site of infection: (臨床診斷基於感染部位：)

      • Tinea capitis (head/scalp). (頭癬（頭部/頭皮）。)

      • Tinea corporis (trunk, arms, legs). (體癬（軀幹、手臂、腿）。)

      • Tinea pedis (athlete’s foot). (足癬（腳癣）。)

      • Tinea cruris (groin, inner thighs, buttocks). (股癬（腹股溝、大腿內側、臀部）。)

      • Tinea manuum (hands). (Tinea manuum （手）。)

      • Tinea unguium (nails). (Tinea unguium （指甲）。)

  • Dermatophytosis Symptoms (皮膚癬菌病的癥狀)

    • Symptoms: (癥狀：)

      • Red, scaly patch-like lesions (skin). (紅色鱗狀斑塊狀病變（皮膚）。)

      • Nail discoloration and thickening (nails). (指甲變色和增厚（指甲）。)

      • Hair loss and scarring (scalp). (脫髮和瘢痕形成（頭皮）。)

      • May be itchy but rarely painful. (可能發癢，但很少疼痛。)

  • Dermatophytosis Treatment (皮膚癬菌病治療)

    • Treatment depends on location: (治療取決於部位：)

      • Head/scalp: Systemic griseofulvin or terbinafine (to reach the follicle), often combined with topical imidazole or selenium sulfide shampoo or imidazole cream. (頭部/頭皮：全身性灰黃黴素或特比萘芬（到達卵泡），通常與局部咪唑或硫化硒洗髮水或咪唑乳膏聯合使用。)

      • Skin (corporis, pedis, cruris, manuum): Initially topical imidazoles (clotrimazole, econazole, ketoconazole, miconazole); topical terbinafine is effective for athlete’s foot (also topical griseofulvin). (皮膚（體、足、鈧、手缽）：最初局部使用咪唑類藥物（克黴唑、益康唑、酮康唑、咪康唑）;外用特比羋芬對腳癬有效（也外用灰黃黴素）。)

      • Nails: Follow Candida nail infection treatment options for topical treatments. (指甲：遵循念珠菌指甲感染治療方案進行局部治療。)

      • If topical treatment fails, first-line oral therapy is terbinafine (allylamine) 250mg once daily for 6 weeks to 3 months (fingernails) or 3-6 months (toenails). Itraconazole is an alternative. (如果局部治療失敗，一線口服治療是特比羋芬（烯丙胺）250 毫克，每天一次，持續 6 周至 3 個月（指甲）或 3-6 個月（腳趾甲）。伊曲康唑是一種替代藥物。)

  • Pityriasis Versicolor (偽色糠疹)

    • Common, superficial skin infection. (常見的淺表皮膚感染。)

    • Cause: Malassezia (yeast normally found on skin but overgrows). (原因： 馬拉色菌 （酵母菌通常存在於皮膚上，但過度生長）。)

    • Symptoms: Changes to skin color in patches (hypo- or hyperpigmentation), can be itchy. (癥狀：斑塊的膚色變化（色素減退或色素沉著過度）可能會發癢。)

    • Diagnosis: Possible skin scraping and examination. (診斷：可能有皮膚刮擦和檢查。)

    • Treatment: (治療：)

      • Topical antifungal creams if small areas are affected for 2-3 weeks (e.g., clotrimazole, ketoconazole). (如果小面積受累 2-3 周，則使用局部抗真菌乳膏（例如，克黴唑、酮康唑）。)

      • Antifungal shampoo for larger areas (e.g., ketoconazole 2% once daily for 5 days). (用於較大面積的抗真菌洗髮水（例如，2% 酮康唑，每日一次，持續 5 天）。)

      • Oral antifungals (e.g., itraconazole or fluconazole) only if widespread or if treatment fails. (口服抗真菌葯（例如伊曲康唑或氟康唑），僅在廣泛使用或治療失敗時使用。)

  • Recap of Learning Outcomes (學習成果回顧)

    • Understand fungal infections and their transmission. (瞭解真菌感染及其傳播。)

    • Recognize the most frequent fungal infections and their symptoms. (識別最常見的真菌感染及其癥狀。)

    • Know the common anti-fungal treatments. (瞭解常見的抗真菌治療方法。)

    • Be able to explain the mechanism of action of anti-fungal drugs. (能夠解釋抗真菌藥物的作用機制。)

    • Be able to make decisions about the most suitable treatment options as well as other self- care measures. (能夠決定最合適的治療方案以及其他自我保健措施。)

    • Appreciate the significance of AMR for the treatment of fungal infections. (瞭解AMR治療真菌感染的重要性。)

  • References (引用)

    • Books - as for previous lectures (書籍 - 與以前的講座相同)

    • CDC Threats 2019 document (CDC 威脅 2019 文件)

    • Shalini et al., 2011. Advances in synthetic approach to antifungal activity of triazoles. Beilstein J. Org. Chem 7:668-677 (Shalini 等人，2011 年。三唑類抗真菌活性的合成方法的進展。Beilstein J. Org. 化學 7：668-677)

    • Mazu et al., 2016. The Mechanistic targets of antifungal agents: an overview. Mini Rev Med Chem 16(7):555-578 (Mazu 等人，2016 年。抗真菌劑的機械目標：概述。迷你 Rev Med 化學 16（7）：555-578)

    • Self-directed reading of literature articles including rise of resistance to antifungal agents. (自主閱讀文學文章，包括對抗真菌劑耐藥性的上升。)