視 神 經 炎 台 北 醫 學 大 學 市 立 萬 芳 醫 院 胸 腔 內 科 余 明 治
In this first report of eye complications following the use of EMB, 18 patients throughout USA received EMB at doses of 60 100 mg/kg. Of these, 8 (44%) developed either severe or mild toxic amblyopia. Ocular manifestations of ethambutol. Arch Opthalmol 1962; 67: 566 571.
Ophthalmic Toxicity The most common drug causing toxicity it to the optic nerve is EMB Ethionamide, linezolid, rifabutin, INH, and clofazimine are rare causes of ocular toxicity
台 灣 結 核 病 診 治 指 引 藥 理 作 用 EMB 可 抑 制 結 核 菌 蛋 白 質 的 合 成 和 破 壞 細 菌 的 代 謝, 因 而 阻 斷 細 菌 的 增 殖 可 避 免 結 核 菌 產 生 抗 藥 性, 為 目 前 抗 結 核 藥 物 中 最 常 用 的 抑 菌 劑
台 灣 結 核 病 診 治 指 引 ( 新 病 人 的 藥 物 選 擇 與 治 療 時 間 ) 優 先 處 方 :INH + RMP + EMB + PZA 2 個 月, 再 INH + RMP + EMB 4 個 月 其 次 處 方 : INH + RMP + EMB 9 個 月 嚴 重 痛 風 病 人, 或 無 法 忍 受 pyrazinamide 的 病 人 尚 未 得 知 藥 敏 試 驗 結 果,Ethambutol 必 須 全 程 使 用 避 免 產 生 抗 藥 治 療 過 程 中 藥 敏 試 驗 如 發 現 isoniazid 及 rifampin 均 有 效 時, 可 停 止 使 用 ethambutol Ethambutol 的 使 用 與 否 並 不 影 響 治 療 的 效 果 與 治 療 所 需 的 時 間
台 灣 結 核 病 診 治 指 引 世 界 衛 生 組 織 另 外 建 議 針 對 痰 塗 片 陰 性 的 肺 結 核 或 輕 度 的 肺 外 結 核 病 人, 如 果 HIV 陰 性, 可 在 治 療 加 強 期 不 使 用 Ethambutol 在 驗 痰 品 質 未 臻 完 善, 結 核 病 人 尚 未 普 遍 接 受 HIV 篩 檢 的 前 提 下, 不 建 議 採 行 此 處 方
ATS/CDC/IDSA Recommendations Treatment regimen for all adults with previously untreated TB should consist of a 2-month initial phase of INH, RIF, PZA, and EMB Resistant to isoniazid If (when) drug susceptibility test results are known and the organisms are fully susceptible, EMB need not be included. If PZA cannot be included in the initial phase of treatment, the initial phase should consist of INH, RIF, and EMB given daily for 2 months EMB should be included in the initial phase until drug susceptibility is determined
WHO Recommendations (1) Patients with a large bacillary load (smear-positive pulmonary TB and many HIV-infected if td patients t with smear-negative pulmonary TB) An increased risk of selecting resistant bacilli A large population of bacilli develops spontaneous resistance Short-course chemotherapy regimens, consisting of 4 drugs during the initial phase and 2 drugs during the continuation phase, reduce this risk Highly effective in patients with susceptible bacilli, and almost as effective in patients with initially isoniazid-resistant organisms
WHO Recommendations (2) Ethambutol may be omitted for patients with Noncavitary, smear-negative pulmonary TB who are known to be HIV-negative Known to be if infected td with fll fully drug-susceptible bacilli Young children with primary TB Since initial resistance to isoniazid is common in many areas, and HIV testing of tuberculosis patients is not routinely practiced Ethambutol be included as a fourth drug during the initial phase of treatment for most patients with smear-negative and extrapulmonary TB
WHO Recommendations (3) At the dosages necessitated ittd by the unacceptable levels of toxicity it at higher h dosages, EMB is at best bacteriostatic t ti and has a limited influence upon the outcome in adult pulmonary TB
台 灣 結 核 病 診 治 指 引 治 療 劑 量 成 人 口 服 每 日 劑 量 ( 一 次 口 服 ) 800 mg ( 體 重 40~55 kg) 1200 mg ( 體 重 56~75 kg) 1600 mg ( 體 重 76~90 kg) 或 依 體 重 15 mg/kg 在 治 療 加 強 期 使 用 高 劑 量 (25 mg/kg) 此 劑 量 較 可 能 造 成 視 神 經 的 傷 害 主 要 經 腎 臟 排 泄 腎 功 能 不 全 的 病 人 ( 從 CCr < 30 到 透 析 的 病 人 ) 每 次 依 正 常 劑 量 給 藥, 但 每 週 投 予 三 次
台 灣 結 核 病 診 治 指 引 眼 球 後 視 神 經 炎 (Retrobulbar neuritis) EMB 最 常 見 的 副 作 用 腎 衰 竭 的 病 人 較 易 發 生 與 劑 量 有 關, 每 日 劑 量 小 於 15mg/kg, 機 率 小 於 1% 25 mg/kg,5% 30 mg/kg,18%
Characteristics of Ocular Toxicity of Ethambutol Classically, the ocular toxicity is described as Dose- and duration-related Reversible on drug withdrawal This has been recently challenged Ocular toxicity of ethambutol. Hong Kong Med J 2006; 12 :56-60. 60.
Int J Tuberc Lung Dis 2006; 10:1318 1330. 1330
Int J Tuberc Lung Dis 2006; 10:1318 1330. 1330
Dose-related (1) The reported incidence of ethambutol-related retrobulbar neuritis varies between > 35 mg/kg per day :18% 25 mg/kg per day: 5% to 6% 15 mg/kg per day: less than 1% (more than 2 months) No safe dose of ethambutol Ocular toxicity of ethambutol. Hong Kong Med J 2006; 12 :56-60. Reversibility of ethambutol optic neuropathy. J Ocul Pharmacol Ther 1997;13:473-7. Toxicity observed at doses as low as 12.3 mg/kg per day Optic neuropathy associated with ethambutol in Koreans. Korean J Ophthalmol 1997;11:106-10.
Dose-related (2) Major excretion pathway of ethambutol is via the kidneys Poor renal function: at higher risk of ocular toxicities Other factors that predispose subjects to toxicity Diabetes Optic neuritis related to tobacco and alcohol consumption Ocular toxicity of ethambutol. Hong Kong Med J 2006; 12 :56-60.
Between July 2002 and December 2003
台 灣 結 核 病 診 治 指 引 眼 球 後 視 神 經 炎 (Retrobulbar neuritis) 症 狀 包 括 視 力 模 糊 中 央 盲 點 (central scotoma) 紅 綠 色 盲 可 能 發 生 於 一 側, 亦 可 能 發 生 於 雙 側
Clinical Presentation (1) The clinical course can be acute or chronic and is typically progressive The onset of ocular symptoms is usually delayed and may occur months following commencement of therapy The mean interval between onset of therapy and toxic effects has been reported to be 3 to 5 months No study has reported onset after withdrawal of ethambutol Ocular toxicity of ethambutol. Hong Kong Med J 2006; 12 :56-60.
Clinical Presentation (2) Although rare, cases of toxicity occurring a few days after initiation iti have been reported A case report of very rapid (3 days) onset of ocular toxicity associated with EMB at 15 mg/kg, which h led to irreversible ibl blindness. Ocular toxicity following ethambutol in standard dosage. Br J Dis Chest 1986;80: 288-91. Case report of toxicity arising within 2 days of starting therapy with EMB, 1700 g for a 70-kg patient, i.e. approximately 25 mg/kg. Rapid-onset reversible ocular toxicity from ethambutol therapy. Am J Med 1991;90:404-6.
Clinical Presentation (3) Presenting ocular symptoms vary among affected idiid individuals Patients may complain of bilateral progressive painless blurring of vision i or decreased d color perception Central vision is most commonly affected Other visual field loss has also been described d Some individuals may be asymptomatic with abnormalities detected only by vision tests Ocular toxicity of ethambutol. Hong Kong Med J 2006; 12 :56-60.
Clinical Presentation (4) The findings of physical examination : variable Both eyes are usually symmetrically affected, if any abnormality is detected Visual acuity drop varies greatly from nil or minimal i reduction to no light perception Central scotoma is the most common visual field defect Bitemporal defects or peripheral field constriction have been reported Dyschromatopsia (abnormal color perception) may be the earliest sign of toxicity Classically documented to be red-green color changes Ocular toxicity of ethambutol. Hong Kong Med J 2006; 12 :56-60.
台 灣 結 核 病 診 治 指 引 眼 球 後 視 神 經 炎 (Retrobulbar neuritis) 一 旦 發 現 視 力 減 退, 若 立 即 停 藥, 可 恢 復 視 力 故 應 預 囑 患 者 一 旦 發 現 視 力 有 任 何 改 變, 須 立 即 告 知 其 主 治 醫 師
Reversibility (1) Views on the issue of reversibility of ethambutol toxicity are dividedid d Classically described as reversible on discontinuation of ethambutol t With visual acuity recovery over a period of weeks to months Permanent visual impairment without recovery Within a follow-up period ranging from 6 months to 3 years in some patients in whom there was prompt p ethambutol discontinuation Ocular toxicity of ethambutol. Hong Kong Med J 2006; 12 :56-60
Reversibility (2) 10 patients treated with presumably safe dosages of ethambutol, t ranging from 13 to 23 mg/kg per day No patients had diabetes, hypertension, or other ocular disease, and all had normal renal function All 10 presented with sudden decrease in vision, and ethambutol was discontinued promptly on diagnosis Only 5 patients had any degree of visual improvement with a mean ± SD follow-up of 21.8±8.8 8 months Among those with some improvement in visual acuity, none described complete recovery after the episode Reversibility of ethambutol optic neuropathy. J Ocul Pharmacol Ther. 1997;13:473-477.
Reversibility (3) Progressive worsening of vision after ethambutol discontinuation has also been documented Ocular toxicity from ethambutol: a review of 4 cases and recommended precautions. NZ Med J 1998;111:428-30.
台 灣 結 核 病 診 治 指 引 應 即 停 止 用 藥 有 肝 炎 症 狀 AST/ALT 3 倍 以 上 的 上 昇, 或 無 肝 炎 症 狀 AST/ALT 5 倍 以 上 的 上 昇 嚴 重 之 貧 血 血 小 板 下 降 泛 血 球 寡 少 症, 及 急 性 腎 功 能 受 損 紫 斑 嚴 重 無 法 緩 解 之 痛 風 症 狀 或 血 清 尿 酸 值 高 於 13 mg/dl 無 法 改 善 或 高 血 清 尿 酸 症 併 急 性 腎 功 能 惡 化 嚴 重 無 法 緩 解 之 皮 疹 搔 癢 或 併 發 Steven-Johnson syndrome 視 力 模 糊 其 他 任 何 導 致 病 人 無 法 規 則 服 藥 的 副 作 用 或 不 適 反 應
Management Ethambutol must be immediately discontinued when ethambutol-induced t id d ocular toxicity iit is recognized Therapy discontinuation is the only effective management that t can halt the progression of vision i loss and allow recovery of vision The patient referred to an ophthalmologist for further evaluation When severe ocular toxicity occurs, both isoniazid and ethambutol should be stopped immediately Ocular toxicity of ethambutol. Hong Kong Med J 2006; 12 :56-60.
台 灣 結 核 病 診 治 指 引 視 力 辨 色 力 檢 查 ( 每 月 ) 使 用 Ethambutol 病 人, 應 按 月 檢 查 視 力 及 辨 色 力
Monitoring and Preventive Measures Remains to be determined whether regular visual tests to achieve early detection ti of ocular toxicity it are effective in clinical practice Most guidelines do not recommend regular visual acuity assessment May be normal in the early stages of toxicity
Chemotherapy and Management of Tuberculosis in the United Kingdom: Recommendations 1998 Because of the possible (but rare) toxic effects of ethambutol on the eye, it is recommended that visual acuity should be tested by Snellen chart before it is first prescribed The drug should only be used in patients who have reasonable visual acuity and who are able to appreciate and report visual symptoms or changes in vision The notes should record that the patient has been told to stop the drug immediately if such symptoms occur, and to report to the physician In small children and in those with language difficulties ethambutol t should be used where appropriate, with the above advice given to parents or other family members
ATS/CDC/ISDA Recommendations (1) Patients should have baseline visual acuity testing and testing ti of color discrimination i i At each monthly visit patients should be questioned regarding possible visual disturbances including blurred vision or scotomata Monthly testing of visual acuity and color discrimination is recommended for patients Taking doses greater than 15 20 mg/kg Patients receiving the drug for longer than 2 months Any patient with renal insufficiency
ATS/CDC/ISDA Recommendations (2) Patients should be instructed to contact their physician or public health clinic lii immediately ditl if they experience a change in vision EMB should be discontinued immediately and permanently if there are any signs of visual toxicity
Dosage WHO Recommendations (1) (Ethambutol) Must always be carefully calculated on a weight basis to avoid toxicity, and should be reduced in patients with impaired renal function Precautions Patients should be advised to discontinue treatment immediately and to report to a clinician if their sight or perception of color deteriorates
WHO Recommendations (2) Adverse effects (Ethambutol) Dose-dependent optic neuritis can result in impairment of visual acuity and color vision Early changes are usually reversible, but blindness can occur if treatment is not discontinued promptly Ocular toxicity is rare when used for 2-3 months at recommended doses
行 政 院 衛 生 署 函 ( 衛 署 藥 字 第 0970323935 號 ) 本 署 核 准 含 Ethambutol 成 分 藥 品 之 適 應 症 為 肺 結 核 症, 依 據 結 核 病 診 治 指 引 及 本 署 核 准 該 成 分 藥 品 仿 單 所 載,Ethambutol 常 引 起 視 力 模 糊 之 不 良 反 應, 其 中 球 後 視 神 經 炎 是 較 常 見 的 副 作 用, 且 和 劑 量 有 關, 以 每 日 15 mg/kg 的 使 用 劑 量, 其 發 生 率 小 於 1% 若 使 用 劑 量 逾 15 mg/kg 時, 需 每 個 月 施 行 視 力 檢 查, 一 旦 發 現 視 力 減 退, 若 立 即 停 藥, 可 恢 復 視 力
行 政 院 衛 生 署 函 ( 衛 署 藥 字 第 0970323935 號 ) 本 署 藥 害 救 濟 審 議 委 員 會 審 議 藥 害 救 濟 申 請 案 件 時, 發 現 有 因 使 用 Ethambutol 導 致 視 力 受 損, 並 致 殘 障 之 不 良 反 應 案 例, 惟 經 查, 病 患 服 藥 期 間 並 未 定 期 追 蹤 視 力 變 化, 出 現 視 力 模 糊 之 不 良 反 應 時, 也 未 立 即 停 藥, 致 使 該 申 請 案 件 未 能 符 合 藥 害 救 濟 之 給 付 標 準 請 貴 會 轉 知 所 屬 會 員, 為 病 患 處 方 Ethambutol 治 療 結 核 病 感 染 時, 應 依 本 署 核 准 之 藥 品 仿 單 所 載, 定 期 為 病 患 進 行 視 力 檢 查, 同 時 應 提 醒 病 患, 於 服 藥 期 間 應 注 意 視 力 變 化 情 形, 倘 若 出 現 視 力 模 糊 現 象, 應 立 即 停 藥 並 儘 速 回 診 與 處 方 醫 師 討 論
行 政 院 衛 生 署 函 ( 衛 署 藥 字 第 0970323935 號 ) 使 用 Ethambutol 產 生 視 力 模 糊 之 不 良 反 應, 屬 於 常 見 可 預 期 ( 發 生 率 約 大 於 1% 和 小 於 10 %) 之 不 良 反 應, 依 據 藥 害 救 濟 法 第 13 條 第 9 款 之 規 定, 不 得 申 請 藥 害 救 濟 惟 該 藥 品 之 治 療 劑 量 小 於 15 mg/kg( g( 球 後 視 神 經 炎 不 良 反 應 之 發 生 率 小 於 1%), 且 服 藥 期 間 追 蹤 視 力 變 化, 發 現 視 力 減 弱 立 即 停 藥, 停 藥 後 視 力 缺 損 未 回 復, 繼 續 發 生 視 神 經 萎 縮 或 導 致 障 礙 者, 非 屬 前 述 之 常 見 可 預 期 之 不 良 反 應
Tuberculosis Chemotherapy Still a Double-edged Sword Am J Respir Crit Care Med 2003; 167: 1461 2 To Assess the Risk-Benefit RikB of EMB