台灣防癆工作之回顧

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1 Treatment of Tuberculosis 1 結核病的治療 ( 一 ) 陸坤泰

2 Contents History of tuberculosis treatment Anti-TB agents Principles of anti-tb chemotherapy Initial treatment Retreatment Treating drug resistant tuberculosis Monitoring during therapy Treatment for special groups

3 History of Tuberculosis Through Treatment 1. The classical approach 2. Sanatoria 3. Collapse therapy 4. Surgery 5. Chemotherapy

4 抗結核化學療法發展史上重要事件 1938 磺胺劑在天竺鼠體內可抑止結核菌生長 1944 發現鏈黴素 streptomycin (SM) 1949 合併藥物療法,SM+PAS 或 SM+TB Isoniazid (INH) 問世 1956 門診通院居家療法 1964 每日單次服藥法間歇性化學療法 1972 短程療法 (Rifampicin 於 1965 年問世 ) 1980s Pyrazinamide 之再評估, 兩階段治療 1990s 短程直接觀察治療法 (DOTS, 都治 ) Directly Observed Treatment,Short-Course

5 抗結核藥物之發展 1938 Sulfonilamide 1940 Dapson 1944 Streptomycin ( 注 ) 1946 PAS 1946 Thiacetazone,TB Pyrazinamide 1952 Isoniazide 1955 d-cycloserine 1957 Kanamycin ( 注 ) 1958 Viomycin ( 注 ) 1959 Ethionamide, T Ethambutol 1962 Capreomycin ( 注 ) 1963 Prothionamide,T Rifampicin 1971 Tuberactionmycin ( 注 ) 1972 Amikacin ( 注 ) 1980s New fluoroquinolones 1981 Rifapentin 1983 Rifabutin

6 First-Line Drugs Isoniazid, rifampin, pyrazinamide, ethambutol, rifapentine, rifabutin *, Bactericidal (except for ethambutol) Quite effective when used in combination May be adapted to intermittent therapy given 2 or 3 times weekly * Not approved by the FDA for use in the treatment of TB Blumberg HM et al JAMA 2005; 293:

7 Second-Line Drugs Moxifloxacin*, cycloserine, ethionamide, levofloxacin*, gatifloxacin*, PAS, streptomycin, amikacin/kanamycin*, capreomycin More toxic and less well tolerated Reserved for the treatment of drug-resistant TB Adaptation to intermittent therapy has not been well studied (except for PAS) * Not approved by the FDA for use in the treatment of TB Blumberg HM et al JAMA 2005; 293:

Antituberculosis Drugs GROUPING Group 1 1st-line oral anti-tb agents Group 2 - Injectable anti-tb agents Group 3 - Fluoroquinolones Group 4 - Oral bacteriostatic 2nd-line anti-tb agents Group 5

8 Antituberculosis Drugs GROUPING Group 1 1st-line oral anti-tb agents Group 2 - Injectable anti-tb agents Group 3 - Fluoroquinolones Group 4 - Oral bacteriostatic 2nd-line anti-tb agents Group 5 Anti-TB agents with unclear efficacy (not recommended by WHO for routine use in MDR-TB patients) DRUGS (ABBREVIATION) Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z) Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vi) Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofolxacin (Lfx); Moxifloxacin(Mfx) Ethionamide (Eto); Protionamide (Pto); Cycloserine (Cs); Terizidone (Trd); P-aminosalicylic acid (PAS); Thioacetazone(Th) Clofazimine(Cfz); Amoxicillin/Clavulanate (Amx/Clv); Clarithromycin (Clr); Linezolid (Lzd)

9 The new TB drug pipeline Novel chemical entities Compounds originating from existing families of drugs, where innovative chemistry is used to optimize the compounds

10 The new TB drug pipeline Novel chemical entities Diarylquinoline TMC207 (Johnson & Johnson) Nitroimidazole PA-824 (Chiron Corp-TB Alliance) Nitroimidazole OPC (Otsuka Pharmaceuticals, Japan) Pyrrole LL-3858 (Lupin Limited, India) Pleuromutilins (GSK-TB Alliance Partnership) Dipiperidine SQ-609 (Sequella Inc.) ATPSynthase Inhibitor FAS (FASgene) Translocase I Inhibitor (Sequlla Inc.) InhA Inhibitor (GSK-TB Alliance) Isocitrate Lyase Inhibitors (GSK-TB Alliance)

11 The new TB drug pipeline Compounds originating from existing families of drugs Using existing fluoroquinolones for TB Gatifloxacin Moxifloxacin New Quinolones Non-fluorinated Quinolones Diamine SQ-109 Macrolides Thiolactomycin analogs Nitrofuranylamide Nitroimidazole Analogs New rifamycin derivative Oxazolidones (Linezolid)

12 Global TB Drug Pipeline March 2006 Preclinical Diamin SQ-109 Squella Inc. Dipiperidine SQ-609 Squella Inc. Nitroimidazo-oxazole Back-up Otsuka Synthase Inhibitor FAS20013 FASgen Translocase I Inhibitor Squella Inc. Sankyo Non-Fluorinated Quinolones TaiGen Clinical Diarylquinoline TMC207 Johnson & Johnson Gatifloxacin OFLOTUB Consodium, Lupin, NIAID TBRU Tuberculosis Research Center WHO Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID, TBRU,TB Alliance Nitroimidazole PA-824 Chiron Cooperation, TB Alliance Nitroimidazooxazole OPC Otshka Pyrrole LL-3858 Lupin Limited

13 Expected timelines towards approval for new candidate drugs Global TB Alliance Annual report

14 第一線抗結核藥物 Isoniazid (INH) 伊娜 Rifampin (RMP) 立復黴素 Pyrazinamide (PZA) 吡羧胺 Ethambutol (EMB) 孟表多

15 Isoniazid (INH) Bactericidal Usual dose: 5 mg/kg daily Peak plasma level 3-5 μg/ml (2 hours after oral dose) Usual MIC ( μg/ml) Toxicity Hepatitis Peripheral neuropathy Cost: NT$ 0.2/100 mg tab

16 Rifampin (RMP, RIF) Bactericidal Usual dose: 10 mg/kg daily Peak plasma level μg/ml (2 hours after oral dose) Usual MIC ( μg/ml) Toxicity Hepatitis Flu syndrome GI distress Cost: 300mg NT$ 10.12, 150 mg NT$ 5.62

Pyrazinamide (PZA) Bactericidal Usual dose: 30 mg/kg daily Peak plasma level 30-40 μg/ml (2 hours after oral dose)

17 Pyrazinamide (PZA) Bactericidal Usual dose: 30 mg/kg daily Peak plasma level μg/ml (2 hours after oral dose) Usual MIC : μg/ml at ph5.5 or 6.0 Toxicity Hepatitis Hyperuricemia Arthralgia Cost: 500 mg NT$ 2.92, 250 mg NT$ 2.6

18 Ethambutol (EMB) Bacteriostatic Usual dose: 15 mg/kg daily Peak plasma level 3-5 μg/ml (2 hours after oral dose) Usual MIC : 1-5 μg/ml Toxicity Optic neuritis Hyperuricemia GI distress Cost: NT$ 2.9/400 mg tab

抗結核藥物的最高血清濃度與最小抑菌濃度範圍 Peloquin CA, et al. IJTLD 1999;3:703-10. Acocella G.

J Clin Pharm Ther 1999;24:219-25. Davidson PT, et al.

19 抗結核藥物的最高血清濃度與最小抑菌濃度範圍 Peloquin CA, et al. IJTLD 1999;3: Acocella G. Clin Pharmacokinetics 1978;3: Pähkla R. J Clin Pharm Ther 1999;24: Davidson PT, et al. Clin Chest Med 1986;7: Grosset J, et al. Adv Tuberc Res 1970;17: Zierski M. Pneumologie 1981;35:

20 Rifabutin (RFB) Bactericidal, equal or better than rifampicin M. avium Cross resistance rate to RMP is high A lower enzyme-inducing effect than RMP Usual dose: 5 mg/kg/d (standard dose:300 mg/d) Toxicity: Hematological toxicity: neutropenia GI disturbance: Polyarthritis: 2-3% Hepatotoxicity <1% Flu-like symptoms <0.1% Uveitis <0.01% Cost: NT$ 93/150 mg cap

21 Rifapentine A newer rifamycin with a long half-life of about 14 hours A candidate for twice and once weekly therapy Once weekly dosing after a 2-months daily course of standard 4 drugs Unsatisfactory efficacy and development of acquired RMP monoresistance among HIV-infected patients (complete cross-resistance with RMP) Might be ideal for the treatment of latent TB

22 治療結核病的目的治癒結核病患者預防活動性結核病患者之死亡及其後期影響預防結核病之再發減少傳染結核病給別人預防發生獲得性抗藥性 WHO Guidelines 2003

23 Am J Respir Crit Care Med 2003;167:1461

24 Successful treatment of tuberculosis depends on more than the science of chemotherapy, and should be provided within a clinical and social frame work based on the patient s circumstances The responsibility for prescribing an appropriate drug regimen and ensuring that treatment is completed is assigned to the public health program or private provider, not the patient ATS Documents 2003

25 Basic Principles of Anti-TB Chemotherapy Appropriate regimen with the right dosage Intensive initial therapy: at least 3 drugs. Should never be treated with a single drug. A single drug should never be added to a failing regimen Adequate duration Continuous phase: treatment well even after amelioration of clinical disease Prolonged therapy, never < 6 mos Regular treatment continue uninterrupted treatment Care for drug interaction

26 Causes of Treatment Failure in Pulmonary TB Resistance Strains Inadequate Regimen Irregular treatment

27 Probability Distribution of Drug-Resistant Mutants in Unselected Populations of M. tuberculosis Isoniazid 3.5 x 10-6 Streptomycin 3.8 x 10-6 Ethambutol 0.5 x 10-4 Rifampicin 3.1 x 10-8 David HL App Microbiol 1970; 20: 810-4

28 Probability of Incidence of Drug-Resistant Mutants Rifapmicin 10-8 Isoniazid, streptomycin, 10-6 ethmbutol, kanamycin, PAS Ethionamide, capreomycin, 10-3 viomycin, enviomycin, cycloserine, thiacetazone Shimao, Tubercle 1988:68 (supp):5-15

30 Probability of Drug-Resistant Cases Number of drug used Number of Mutants Number of bacilli in lesion One Two Three Shimao, Tubercle 1988;68 (supp):5-15

31 FATEOF BACILLARY CASES OF PULMONARY TUBERCULOSIS

32 Treatment Completion Rates for Pulmonary Tuberculosis Treatment No. of Completing therapy studies for PTB,% Enhanced DOT DOT Modified DOT Nonsupervised therapy Chaulk et al JAMA 1998;279:943-9

33 High Hypothetical Model of TB Chemotherapy A Continuous growth INH (RMP, SM) PZA RMP Speed of metabolism & growth B Acid inhibition C Spurts of Metabolism Low D Dormant Mitchison DA J R Coll Physicians Lond 1980;14:91-9

34 Hypothetical Model of TB Chemotherapy # Bacilli Bactericidal Activity and A Sterilizing Effect B C Pop. A = Rapidly multiplying (caseous) Drug activities: INH>SM>RIF>EMB Pop. B = Slowly multiplying (acidic) Drug activities: PZA>>RIF>INH Pop. C = Sporadically multiplying Drug activities: RIF>>INH

35 Grading of Activities of Anti-TB Drugs Extent of Activity Prevention of resistance Early bactericidal Sterilizing High INH INH RIF RIF PZA EMB EMB RIF INH SM SM SM PZA PZA TB-1 Low TB1 TB-1 EMB Mitchison DA. Tubercle 1985;66:

36 抗結核化學療法發展史上重要事件 1938 磺胺劑在天竺鼠體內可抑止結核菌生長 1944 發現鏈黴素 streptomycin (SM) 1949 合併藥物療法,SM+PAS 或 SM+TB Isoniazid (INH) 問世 1956 門診通院居家療法 1964 每日單次服藥法間歇性化學療法 1972 短程療法 (Rifampicin 於 1965 年問世 ) 1980s Pyrazinamide 之再評估, 兩階段治療 1990s 短程直接觀察治療法 (DOTS, 都治 ) Directly Observed Treatment,Short-Course

37 Results of British Research Council Streptomycin Trial No. of X-ray Culture (-) Regimen patients Death improvement 3 mo 6 mo SM * 8 Control * 41 patients with resistant strains, 2 with sensitive strains BMJ 1948;2:469-82

38 The fall and rise phenomenon TOMAN S TUBERCULOSIS 2nd ed WHO 2004 p 201

39 PAS + SM reduces the emergence of SM resistance Medical Research Council BMJ 1952;1:

40 Emergence of Failures due to Drug Resistance during Double Drug Therapy Study Place Isoniazid with No. of Patients Failure of Treatment (%) East Africa Rifampin Streptomycin 96 2 Madras Ethambutol* PAS East Africa Thiacetazone *With initial supplement of streptomycin daily for 2 weeks Mitchison DA J R Coll Physicians Lond 1980;14:91-9

41 The effect of Adding RMP to a Regimen on Sputum Conversion at 2 mo and the Relapse Rate Calculated over 24 mo after Therapy Study Place Regimen* No. of Patients % of Patients Culture (+) Relapse at 2 mo 1 East Africa 6SH SHR Madras 2SHZ/5SHZ SHRZ/5SHZ Madras 3SHZ/2SHZ SHRZ/2SHZ 2 4 3SHRZ 29 Mitchison DA Am J Respir Care Med 2005;171: 699 (Mitchison DA J Appl Baceriol 1996;81:72S-80S)

42 Sterilization by HZ Redrawn by Mitchison DA (Am J Respir Care Med 2005;171: 699) from McCune RM et al J Exp Med 1956;104:763

43 The effect of Adding PZA to a Regimen on Sputum Conversion at 2 mo and the Relapse Rate Calculated over 24 mo after Therapy Study Place Regimen No. of patients Cultures (+) at 2 mo. % Relapse 1 East Africa 6SH SHZ East Africa 2SHR/4TH SHRZ/4TH Hong Kong 2SHRE/4SHE SHRZ/4SHZ East Africa 6SHR * 2SHRZ/7HR * 7 UK 2EHR/4TH * 2EHRZ/4HR * 2SHRZ/4HR * Mitchison DA Am J Respir Care Med 2005;171: 699 (Mitchison DA J Appl Baceriol 1996;81:72S-80S)

44 PZA in continuation phase does not reduce the relapse rate Mitchison DA Am J Respir Care Med 2005;171:

45 Titration of dose sizes of INH, RMP, and SM against their early bactericidal activity (EBA) during the first 2 days of monotherapy with each drug Mitchison DA Am J Respir Care Med 2005;171:

46 USPHS Tuberculosis Short-Course Chemotherapy Trial 21 Effectiveness, Toxicity, and Acceptability. A Report of Final Report Combs DL et al Ann Intern Med 1990;112: TB clinics in PHD and hospitals in the US 6-mo: (INH 300 mg + RIF 600 mg)/d for 36 wks 9-mo: (INH 300 mg + RIF 600 mg + PZA 30 mg/kg)/d for 8 wks followed by (INH 300 mg + RIF 600 mg)/d for 16 wks Results 6-mo 617/823 9-mo 445/628 Conversion rate after 16 wk 94.6% 89.6% Adverse drug reaction Noncompliance rate Relapse rate at 96 wks after completing therapy Successfully completed therapy

47 Short-Course Chemotherapy Mechanism: Prevention of drug resistance Early bactericidal activity Sterilizing action Principle: Multiple drug combined chemotherapy; Two phase chemotherapy and/ or intermittent chemotherapy Advantages: Initial bactericidal and sterilizing action Less maintainance drug without influence on treatment result

48 Intermittent Anti-TB Chemotherapy Twice or thrice weekly Less cost Better compliance, easy supervision Less adverse reaction Same effect

49 都治 (DOTS) 策略之五大要素結核病防治之政治承諾痰塗片檢驗因症就診之被動式病人發現法標準化之短程治療, 且至少前兩個月之直接監督療法充足之藥物供應標準化之登記與通報系統以進行結核防治計劃之評估 WHO Guidelines 2003

50 結核病診治指引

51 各類結核病人之治療處方治療之分類結核病人初期治療治療處方 * 繼續治療第一類痰塗片陽性之新肺結核病人, 痰塗片陰性之新肺結核病人併肺部廣泛病灶者, 嚴重型之新肺外結 # 核病人 2 EHRZ(SHRZ) 2 EHRZ(SHRZ) 4HER 4H 3 E 3 R 3 第二類 # 復發失落再治失敗再治之痰塗片陽性肺結核病人 2 SHRZE /1 HRZE 2 SHRZE /1 HRZE 5HRE 5H 3 R 3 E 3 第三類痰塗片陰性之新肺結核病人, 非嚴重型之新肺外結核病人 2 EHRZ 2 EHRZ 4HER 4H 3 R 3 E 3 第四類經過監督再治 (retreatment) 依然痰塗片陽性之慢性開放病人轉診專責機構接受二線藥治療 * E=ethambutol, H=isoniazid, R=Rifampin, Z=pyrazinamide, S=streptomycin, 2EHRZ=2 個月每日一次 EHRZ, 4H 3 R 3 E 3 =4 個月每週三次 HRE # 嚴重型肺外結核 : 腦膜炎粟粒性心包炎腹膜炎兩側或巨量胸水脊椎腸殖泌系 # 第二類病人宜進行結核菌藥敏試驗, 若藥敏試驗果為多重抗藥性結核病, 宜轉診專責機構接受二線藥治療非嚴重型肺外結核 : 淋巴結單側胸水骨骼 ( 脊椎除外 ) 周邊關節皮膚 WHO 2003

52 結核病人的治療分類 1 adapted from WHO 新病人 (new case) 2HRZE+4HRE or 9HRE -- 不曾接受過結核藥物治療或曾接受少於 4 週結核藥物治療的病人再治病人 (retreatment case) 2SHERZ+1HERZ+5HER 復發 (relapse) -- 曾接受一個完整療程之結核藥物治療並經診療醫師宣告治癒而再次痰塗片或培養陽性的病人失落再治 (treatment after default) 中斷治療 2 個月以上而再次痰塗片或培養陽性的新病人或再治病人失敗再治 (treatment after failure) 前次治療失敗後重啟再次治療之病人治療 4 個月後痰結核菌培養陽性或治療 5 個月後痰抗酸菌塗片陽性或治療前痰陰性治療 2 個月後變成痰塗片或痰培養陽性的新病人

53 結核病人的治療分類 2 adapted from WHO 其他病人 (other) - 在監督下接受完整之再治處方治療後依然痰塗片或培養 (+) 之病人, 或使用二線藥物之多重抗藥病人多重抗藥病人 (MDR-TB) - 藥敏試驗顯示至少對 Isoniazid 及 Rifampin 抗藥之病人慢性病人 (chronic case) 在監督下接受完整之二線藥物治療後依然痰塗片或培養 (+) 的病人 ; 對大多數一線二線藥物抗藥, 致無法選用足夠有效藥物治療的結核人 ; 因嚴重藥物副作用無法接受治療的病人

54 Recommended Treatment Regimens for TB Diagnostic Category I TB patients New smear-(+) patients; New smear-(-) PTB with extensive parenchymal involvement; Severe concomitant HIV disease or severe forms of EPTB Initial phase (Daily or 3 times weekly) 2 HRZE (SM may be used instead of EMB, in meningeal TB, EMB should be replaced by SM) Continuation phase (Daily or 3 times weekly) 4 HR or 6 HE daily (a higher rate of treatment failure and relapse WHO Guidelines 2003

55 第一次就治好你的病人 Initial Treatment 新病人的治療不曾接受過結核藥物治療或曾接受少於四週結核藥物治療的病人

56 新病人治療的時機兩套痰抗酸菌塗片檢查 (+), 且臨床懷疑肺結核痰結核菌培養 (+), 且臨床懷疑肺結核組織病理學或組織培養證實之肺外結核其他安排各項檢查給予廣效性抗生素 * 治療, 經蒐集完整臨床資料後, 如認為仍須接受結核藥物治療, 方可開藥治療診療醫師應盡可能避免在缺乏臨床證據下, 以嘗試性治療 (therapeutic trial) 為由給予結核藥物極度重症的疑似結核病人可於驗痰結果未明時, 先行給予結核藥物治療 * 應避免使用 fluoroquinolone 及 aminoglycoside

57 Prevalence of Antituberculosis Drug Resistance Among New Tuberculosis Patients in Northern Taiwan, Year Strains no. Percentage of resistance to anti-tuberculosis d Any INH SM EMB RMP MDR

58 新病人標準治療方式 2HRZE+4HRE - 通常日劑量 :INH 300 mg;emb 800 mg*; RMP 450/600 mg;pza mg - 儘可能每日一次優先使用固定成分複方藥物不必刻意空腹同一藥物避免分次服用 9HRE - 嚴重痛風病人或無法使用 PZA 的病人採之 E: 除非已有藥敏試驗證實 HR 有效, 否則須常規使用 *Optic neuritis: <1% with 15 mg/kg; 5% with 25 mg/kg; 18% >30 mg/kg

59 第一線抗結核藥物 : WHO/IUATLD/CDC 建議劑量 * DOT is mandatory for t.i.w. regimens Dose in mg/kg (range, max. dose) Drug Route Daily 3* times/week Isoniazid Oral A: 5 (4-6, 300 mg) 10 (8-12, 600 mg) C: 10-15, 300 mg Rifampin Oral A: 10 (8-12, 600 mg) 10 (8-12, 600 mg) C: 10-20, 600 mg Pyrazinamide Oral A: 25 (20-30, 2 g) 50 (40-60, 4 g) C: 10-30, 2g Ethambutol Oral A: 15 (15-20) 45 (40-50) C: 15-20, 1 g Streptomycin IM or IV A: 15 (12-18, 1 g) 15 (12-18, 1.5 g) C: 20-40, 1g Abbreviations: A: Adult, C:Children

60 High clinical suspicion for active TB Treatment Algorithm for Drug Susceptible Pulmonary TB Cavitation on CXR or (+) AFB smear at 2 months INH/RIF/EMB/PZA 2 month culture (-) INH/RIF 2 month culture (+) INH/RIF INH/RIF No cavitation Cavitation ATS Guidelines 2003 INH/RIF No cavitation on CXR & (-) AFB smear at 2 month INH/RIF INH/RPT Time (months)

61 Recommended Treatment Regimens for TB Diagnostic Category Ⅲ TB Patient New smear (-) PTB (other than in Category I); Less severe forms of EPTB Initial phase (Daily or 3 times weekly) 2 HRZE (EMB may be omitted during the initial phase of treatment for patients with non-cavitary, smear (-) PTB who are known to be HIV(-), patients known to be infected with drug-susceptible bacilli, and young children with primary TB) Continuation phase (Daily or 3 times weekly) 4 HER or 6 HE daily (a higher rate of treatment failure and relapse) WHO Guidelines 2003

62 Treatment Algorithm for Active, Culture-negative pulmonary tuberculosis At-risk patient Abnormal CXR Smear negative No other diagnosis Tuberculin test (+) Initial cultures(-) No change in CXR Low suspicion INH/RIF/EMB/PZA High suspicion 4 month RIF +/- INH 9 month INH 2 month RIF/PZA No treatment Initial Cultures (-) Clinical CXR improved 2 month INH/RIF Treatment complete Initial cultures (-) No change in CXR or Sx ATS Guidelines 2003 Initial Evaluation Repeat Evaluation Time (months)

63 Thank You

Microsoft PowerPoint - 結核病治療-I 2009 [相容模式]

Microsoft PowerPoint - 結核病治療-I 2009 [相容模式] Treatment of Tuberculosis 1 結核病的治療 ( 一 ) 陸坤泰 Contents History of tuberculosis treatment Anti-TB agents Principles of anti-tb chemotherapy Initial treatment Retreatment Treating drug resistant tuberculosis