簡歷 內科專科醫師職業醫學專科醫師胸腔暨重症醫學專科醫師結核病專科醫師 索任 現任 1979 台灣大學醫學院醫學系 2005/5 - 中華民國防癆協會第一胸腔病防治所所長 2002- 中華民國防癆協會常務理事 2002- 中華民國職業病醫學會常務理事 1994- 台灣結核病醫學會理事 ( 長 ) 曾任 2002/7 2005/3 行政院衛生署桃園醫院內科師一級主治醫師 2002/2 2002/7 行政院衛生署胸腔病院代理院長 2001/8 2002/1 行政院衛生署慢性病防治局代理局長 1999/7 2001/8 行政院衛生署慢性病防治局副局長 1997/1 1999/6 台北縣慢性病防治所醫師 1989/3 1997/1 台灣省慢性病防治局技正兼主任 1984/4 1989/3 台灣省防癆局技正兼主任 1983/7 1984/4 台灣省防癆局主治醫師 1979/7 1983/7 台灣省防癆局住院醫師及總住院醫師
結核病的治療 中華民國防癆協會第一胸腔病防治所所長內科 / 職業醫學科索任醫師 solo@tstb.org
傳染 化學治療 結核病防治 醫師延誤 Prophylactic treatment 預防性治療 病人延誤 傳染性結核病 接觸 結核潛伏感染 非傳染性結核病 死亡 卡介苗接種 Source: Interventions for Tuberculosis Control and Elimination, IUATLD 2002
抗結核藥物介紹
抗結核藥物 (1) 初次治療常規用藥 First-line Anti-tuberculosis Drugs Isoniazid (INH) Rifampin (RMP) Pyrazinamide (PZA) Ethambutol (EMB)
Isoniazid (INH) Bactericidal Usual dose: 5 mg/kg daily Peak plasma level 3-5 mcg/ml (2 hours after oral dose) Usual MIC (0.025-0.05 mcg/ml) Toxicity Hepatitis Peripheral neuropathy Mild CNS effects Cost: NT$0.2/100mg tab
Rifampin (RMP, RIF) Bactericidal Usual dose: 10 mg/kg daily Peak plasma level 10-20 mcg/ml (2 hours after oral dose) Usual MIC (0.06-0.25 mcg/ml) Toxicity GI intolerance Hepatitis Flulike symptoms Bleeding problems Cost: 300mg NT$10.12, 150mg NT$5.62
Pyrazinamide (PZA) Bactericidal Usual dose: 30 mg/kg daily Peak plasma level 30-40 mcg/ml (2 hours after oral dose) Usual MIC : 50 mcg/ml at ph5.5 Toxicity Hepatitis GI intolerance Rash Hyperuricemia, Arthralgia Cost: 500mg NT$2.92, 250mg NT$2.6
Ethambutol (EMB) Bacteristatic Usual dose: 15 mg/kg daily Peak plasma level 3-5 mcg/ml (2 hours after oral dose) Usual MIC : 0.95-3.8 mcg/ml Toxicity Optic neuritis GI distress Hyperuricemia (rare) Cost: NT$2.9/400mg tab
Second-line Anti-tuberculosis Drugs Levofloxacin (Cravit) Moxifloxacin (Avelox) Streptomycin (SM) Kanamycin (KM) Amikacin (AMK) Rifabutin (RBT) Prothionamide (T1321) Ethiomide (T1314) Para-AminoSalicylate (PAS) Cycloserine (CS) Selman Abraham Waksman (1888-1973) 1952 Nobel Prize 因抗藥或副作用而不能使用第一線藥時, 才選用第二線藥
Levofloxacin (Cravit) Bactericidal against M. tuberculosis. MIC for M. tuberculosis 0.25-0.5 mcg/ml; Usual dose: Levofloxacin 500-1000 mg/d (10mg/kg/d) Toxicity: GI disturbance 0.5-1.8% Neurological effects: dizziness, insomnia 0.5% Cutaneous reactions: 0.2-0.4%
Moxifloxacin (Avelox) Bactericidal against M. tuberculosis. MIC 99 for M. tuberculosis 0.037 mcg/ml; Usual dose: Moxifloxacin 400 mg/d (5mg/kg) Adverse reactions* : Nausea 0.47%, Diarrhoea 0.38% Vomiting: 0.18%, Abdominal pain: 0.16% Vertigo: 0.22% Headache: 0.16% * 16,007 PMS data. H Landen et al., JIMR 2001
Aminoglycosides Bactericidal Usual dose: 15 mg/kg/d i.m. for 3m then 15mg/kg 3x/wk for 3m Toxicity Renal toxicity Auditory toxicity Rash Streptomycin (SM) Amikacin (AMK) Kanamycin (KM)
結核病的治療原理
Objectives of Treatment Rapid reduction of the number of bacilli Preventing acquired drug resistance Sterilization to prevent relapses 治療目標 1. 快速減少病人體內結核菌數量, 以迅速遏止傳染及改善病人症狀 2. 杜絕續發性抗藥性的發生 3. 持續殺滅緩慢分裂的結核菌, 預防日後的復發 Iseman M. D. A clinician s guide to tuberculosis. Lippincott Williams & Wilkins, 2000
抗藥性結核菌如何發生 R H INH+RMP+PZA 合併藥物治療 無菌 Z H R Z INH 單一治療 INH 抗藥 RMP 抗藥 PZA 抗藥無抗藥 H H H H H H H H H H H H INH 抗藥性結核菌
抗藥性結核菌如何發生 ( 續 ) H H H H H H H H H H H H 分裂突變 H H H H H H H H H H H H H HR HZ H INH+RMP 多重抗藥性結核菌 HR HR HR HR H HR HZ INH 抗藥 INH+RMP 抗藥 INH+PZA 抗藥 INH + RMP 單一治療 HR HR HR HR HR HR HR HR HR
Fall and Rise Phenomenon Number of bacilli per ml of sputum 1.E+08 1.E+07 1.E+06 1.E+05 1.E+04 1.E+03 1.E+02 1.E+01 1.E+00 0 3 6 9 12 15 18 Weeks of Treatment
Example of mal-treatment 阮氏 X 水 1984/12/18 F 越南新娘 初診 : 2004/11/30 桃醫新屋分院 #80139974 過去治療史 at 北部某醫學中心 2003/07 RFT+EMB C+ M.tb R:H,R 2003/09 RFT+EMB+Cipro 2003/12 improve HER+Cipro 03/11 CXR 2004/08 worse HERZ+Cipro 04/06;08 CXR 2004/10 improve RFT+Cipro 04/10 CXR No sputum follow-up during treatment Symptoms cough with sputum wean and wane; weight loss(-) MDR-TB should never be treated without expert consultation.
Preventing acquired drug resistance Errors in prescription of anti-tb chemotherapy The prescription of inadequate chemotherapy to the multibacillary pulmonary tuberculosis The addition of one extra drug in the case of failure, and repeating the addition of a further drug when the patient relapses after what amounts to monotherapy WHO. Guidelines for the management of drug-resistant tuberculosis, 1997
結核病的治療原則 多種有效的抗結核藥物合併使用 藥物須按規服用 治療期間須夠長
診斷肺結核的基本檢查 胸部 X 光 驗痰 : 塗片顯微鏡檢及結核菌培養 ( 連續 3 套痰間隔 8-24 小時 ) 第一次培養陽性應常規作 INH, RIF, 及 EMB 的藥物敏感性試驗
何時考慮開始治療 痰陽 ( 塗片 / 培養 ) 若臨床符合以下特點, 而高度懷疑肺結核時, 不宜因塗片陰性而延誤治療 長期咳嗽和體重減輕的病史 胸部 X 光有典型肺結核變化 肺結核發病高危險群
治療前評估 ( 個案分類 ) * 依過去治療史分類 新案 (new case): 不曾接受過抗結核藥治療或曾接受少於 4 週抗結核藥治療之病人 復發 (relapse): 曾接受一個完整療程之抗結核藥治療並經醫師宣告治癒而再次痰塗片陽性之病人 失落復治 (Treatment after default): 中斷治療兩個月以上而再次痰塗片陽性之病人 失敗復治 (treatment after failure): 治療五個月後依然痰塗片陽性的病人, 或者治療前痰塗片陰性 治療二個月後變成痰塗片陽性的病人 慢性病人 (chronic case): 在監督下接受完整之復治處方治療後依然痰塗片陽性之病人 WHO. Treatement of tuberculosis, 3 nd ed. 2003. WHO/CDS/TB 2003.313
Drug Resistance of MTB for each Treatment Categary in Taiwan 70 60 50 40 30 20 10 0 Treatment failure MDR Any drug Default Relapse New case * Chiang CY,et al. Formos Med Assoc, 2004. * Jen-Jyh Lee et al, Tzu Chi Med J, 2003.
治療前評估 * * 依過去治療史分類 TB Case 初治 過去治療史 N 新案 Y Return after default Relapse Failure Chronic case 再治 標準初次治療 照會專業醫師 Never treat multidurg-resistant TB (MDR-TB) without expert consultation WHO. Treatement of tuberculosis, 3 nd ed. 2003. WHO/CDS/TB 2003.313
結核病初次治療 * 如證實無 INH 或 RMP 抗藥, 則停用 EMB 標準治療 2HRZE/4HRE 每日一次口服 前 2 個月 INH+RMP+PZA+EMB 後 4 個月 INH+RMP+EMB 成人劑量 Isoniazid (INH) 5mg/kg/d Rifampin (RMP) 10mg/kg/d Pyrazinamide (PZA) 30mg/kg/d Ethambutol (EMB) 15mg/kg/d * 適用初治新案 (new case): 不曾接受過抗結核藥治療或曾接受少於 4 週抗結核藥治療之病人
Fixed Drug Combination Rifater (RFT) + EMB Rifater (each tab) = INH 80mg + RMP 120mg + PZA 250mg >=50kg 每日 5 錠體重每減 10kg 減 1 錠 Rifinah (RFN) + EMB Rifinah300 (each tab) = RMP 300mg + INH 150mg Rifinah150 (each tab) = RMP 150mg + INH 100mg >=50kg RFN300 每日 2 錠 <50kg RFN150 每日 3 錠
Other Examinations to Conduct When TB Treatment Is Initiated 治療前檢查 GOT, GPT, Bil, AlkP UA (when PZA is used) CBC, Cr, BUN, VA and color vision (when EMB is used)
Treatment Monitoring (1) Monthly sputum for AFB smear and culture (until 2 consecutive cultures negative) Serial sputum smears every 2 weeks to assess early response Additional drug-susceptibility tests if culture-positive after 3 months of treatment
送藥到手 TB 服藥入口 嚥下再走
Treatment Monitoring (2) Periodic (minimum monthly) evaluation to assess adherence and identify adverse reactions Repeat chest x-ray: At completion of initial treatment phase for patients with initial negative cultures At end of treatment for patients with culturenegative TB Generally not necessary for patients with culture positive TB
Treatment Monitoring (3) 評估副作用 治療前檢查 GOT, GPT. Bil, UA, CBC, Cr, BUN, VA, color vision 治療間檢查 GOT, GPT, Bilirubin, UA 治療後 2 週, 1 月, 2 月 Visual acuity, color visoin 每次回診 症狀評估 每次回診, 疑異狀時須作相關檢驗
完成治療 痰陰 ( 塗片及培養 ) 症狀改善 胸部 X 光改善 服藥期滿
常見副作用 ( 一線抗結核藥物 ) 皮膚炎 肝炎 胃炎 週邊神經炎 關節症狀 腎症狀 血液學變化 視力變化
常見副作用 ( 一線抗結核藥物 ) 皮膚炎 癢, 疹, 腫, 水泡, 發燒,Steven- Jhonson syndrome PZA, RMP, INH, 偶 EMB 抗組織胺, 類固醇, 改藥
04/08/13 Toxicoderma 04/06/25 PZA or Allopurinol
Toxicoderma EMB 04/08/26 04/11/18
常見副作用 ( 一線抗結核藥物 ) 肝炎 厭食, 噁心, 嘔吐, 黃疸 RMP, PZA, INH 改藥
Isoniazid-related Hepatitis Case Rate (/1000) 25 20 15 10 5 Probable Possible 0 < 20 20-34 35-49 50-64 > 64 Age Group (yr) Kopanoff DE et al. Am Rev Respir Dis 1978;117:991-1001.
藥物性肝炎 : results of a meta-analysys 藥物種類 研究數 評估人數 肝炎人 % 數 只有 INH 6 38257 210 0.55 INH 及其他, 無 RMP INH + RIF (+/- 其他 ) RIF 及其他, 無 INH 10 19 5 2053 33 1.61 6105 156 2.55 1264 14 1.11 Steele MA, Chest 1991
Other considerations 懷孕, 哺乳, 避孕藥 合併症 免疫異常 : AIDS, DM 腎功能異常 CrCl 10-50 EMB q36h CrCl <10 EMB q48h Hemodialysis: HR no change; ZE thrice a week after HD 慢性肝炎, 肝硬化 類固醇的使用
Treatment of Drug-Resistant TB Resistance Suggested regimen Duration of Treatment (M) INH RMP, PZA, EMB 6-9 RMP INH, PZA, EMB 6-9 (12M) INH, PZA ± SM RMP, EMB, FQ, AMK 6-9 INH, EMB ± SM RMP, PZA, FQ, AMK 6-12 INH, RMP ± SM PZA, EMB, FQ, AMK 18-24 INH, RMP, EMB ± SM PZA, FQ, AMK + 2 * 24 (sputum conversion) INH, RMP, PZA ± SM EMB, FQ, AMK + 2 * 24 (sputum conversion) INH, RMP, PZA, EMB FQ, AMK + 3 * 24 (sputum conversion) * : ethionamide, cycloserine, PAS, clofazimine, capreomycin FQ: fluoroquinolones, AMK: amikacin Drugs 2000 Feb; 59(2): 171-179
結核病再治療 Retreatment of Tuberculosis 治療失敗後再治療 Retreatment after Treatment Failure 失落 / 治療中斷後再治療 Retreatment after Default/Interruption 完成治療後復發 Retreatment after Relapse
Example of mal-treatment Example #1 過去治療史 at 北部某區域教學醫院 Pulm TB irregularly treated since 1998 with HERZ Presented to clinic in 2002 with RMP resistance. HEZ prescribed 2002 HR resistance noted in late 2003 Retreated with EZ + Ofloxacin (100mg) bid 3wk then add SM in Feb. 2004 MDR-TB should never be treated without expert consultation.
Treatment of MDR-TB Drug treatment of MDRTB is time consuming and demanding on both patient and physician. In UK, the treatment should be carried out by: Physicians with substantial experience in managing complex resistant cases, and Only in hospitals with appropriate isolation facilities, and In very close liaison with Mycobacteriology Reference Centers. 規則而不中斷地供應所有必要的抗結核藥物 Madkour MM. Tuberculosis, 2004
Treatment of MDR-TB Levofloxacin/Moxifloxacin (new quinolone) (one of new quinolone) and streptomycin (one aminoglycoside) are bactericidal and are better choices among those more toxic and less potent second-line drugs in treating MDR-TB. The main determinants for successful treatment of MDR-TB are the number of effective drugs available, the patient s compliance, and drug side effects. Surgery may be beneficial in some selective patients
抗藥性結核病的治療 前 1-2 個月住院隔離治療 對所選用的治療藥物沒有明顯副作用 連續 3 次痰塗片陰性或 臨床及 X 光進步 出院須通知衛生所, 並預約門診 門診至少每月 1 次 每月追蹤痰塗片及培養 ( 住院初期可每 2 週驗 3 套 ) 每 3 月追蹤胸部 X 光
治療失敗 Treatment Failure 先照原來的治療方式繼續治療, 同時作結核菌抗藥性試驗 或 如病情嚴重惡化, 來不及等待須時二個月的抗藥性試驗結果, 可保留原來的治療藥物, 並依治療病史, 加入至少三種從未用過的其他抗結核藥物治療 待抗藥性試驗結果出來後, 再依 [ 抗藥性結核病 ] 治療原則治療
治療中斷後再治療 Retreatment after Interruption 曾接受結核病初次治療但因治療中斷而未完成治療, 結核病仍具活動性者 治療未滿 2 個月即中斷 : 重新治療 治療滿 2 個月後中斷 : 痰陽或病情惡化 : 重新治療 痰陰且病情穩定或改善 : 繼續服滿原來療程 WHO: 2HRZES/1HRZE/5HRE 如懷疑結核菌有抗藥性時, 依 [ 抗藥性結核病 ] 原則處理
完成治療後復發 Retreatment after Relapse 曾接受一個完整療程之抗結核藥治療並經醫師宣告治癒而再次痰塗片陽性之病人 除非懷疑結核菌有抗藥性 原則上使用原來的治療方式重新治療 如懷疑結核菌有抗藥性時, 依 [ 抗藥性結核病 ] 原則處理 WHO: 2HRZES/1HRZE/5HRE
誰是下一個犠牲 肺結核不治療 5 年致死率 50% 結核還沒有根除 因為 好像沒有誰關心 921227 930722
Preventing TB Infection Prompt and effective treatment of the most infectious (smear positive) cases Thank you for your attention
Rifabutin (RBT) Bactericidal Usual dose: 5mg/kg/d Toxicity: Hematological toxicity: neutropenia GI disturbance: Polyarthritis: 2-3% Hepatotoxicity <1% Flu-like symptoms <0.1% Uveitis <0.01%
結核病人體內結核菌的分佈 細胞外快速分裂繁殖的結核菌, 常分布在空洞內, 數量最多, 約 10 9-12, 是造成傳染性和抗藥性的主要部分 吞噬細胞內的酸性環境中, 分裂緩慢的結核菌, 數量約 10 2-5 固態乾酪壞死組織中的中性環境下, 分裂緩慢的結核菌, 數量約 10 2-5, 不易殺滅, 是將來結核病復發的主要族群 Iseman M. D. A clinician s guide to tuberculosis, 2000
Bactericidal Activity and Sterilizing Effect # Bacilli A B C Pop. A=Rapidly multiplying (caseum) Drug activities: INH>>SM>RIF>EMB Pop. B=Slowly multiplying (acidic) Drug activities: PZA>>RIF>INH Pop. C=Sporadicaly multiplying Drug activities: RIF>>INH 0 1 2 3 4 5 6 Months of Therapy 3 Populations of bacilli in cavitary TB Variables of these populations: anatomic and/or metabolic Iseman M. D. A clinician s guide to tuberculosis, 2000
Objectives of Treatment Rapid reduction of the number of bacilli Preventing acquired drug resistance Sterilization to prevent relapses 治療目標 1. 快速減少病人體內結核菌數量, 以迅速遏止傳染及改善病人症狀 2. 杜絕續發性抗藥性的發生 3. 持續殺滅緩慢分裂的結核菌, 預防日後的復發 Iseman M. D. A clinician s guide to tuberculosis. Lippincott Williams & Wilkins, 2000
結核菌發生抗藥性突變菌株的機率 藥名 機率 Rifampin 10-8 Isoniazid, Ethambutol, 10-6 Streptomycin, Kanamycin, Para-AminoSalicylate Ethionamide, Enviomycin, 10-3 Cycloserine, Capreomycin, Viomycin, Thiacetazone Shimao T. Tubercle 1988;68(supp):5-15.
DOTS = 最有效的結核病防治策略 DOTS The recommended strategy for TB control 政府承諾 : 保障持續的 周全的結核病防治動力 以病人因症就診, 及痰塗片鏡檢來發現結核病人 以標準 6-8 個月的短程治療, 至少對所有證實為痰塗片陽性 ( 塗陽 ) 的病人 好的病人管理包括對所有塗陽新病人的加強治療期間及使用含 Rifampin 處方的持續治療期間, 以及所有再治療的全程治療期間進行直接觀察治療 (DOT) 規則而不中斷地供應所有必要的抗結核藥物 能評估病人發現, 每個病人治療成果及結核病防治計畫整體成效的標準化記錄及報告系統 Int J Tuberc Lung Dis 2001: 5:213-215