Treatment for MDR-TB and XDR-TB

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1 結核病藥物副作用處理指引台北醫學大學市立萬芳醫院胸腔內科余明治醫師

2 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

5 Adding Moxifloxacin is Associated with a Shorter Time to Culture Conversion in Pulmonary Tuberculosis Int J Tuberc Lung Dis 2010;14:65 71

6 Risk Groups/Factors for Adverse Antituberculous Drug Reactions Advanced age Malnutrition Pregnancy Alcoholism Liver failure Chronic renal failure HIV infection Disseminated and advanced TB Atopy Anaemia Diabetes mellitus Family history of adverse anti-tb drug reactions Patients receiving irregular anti-tb treatment Patients receiving medication for other disorders, in addition to anti-tb drugs

7 Age Transition of Tuberculosis Patients in Taiwan > 65y/o: 52% J Formos Med Assoc 2006;105:25 30

8 Factors Influencing Time to Smear Conversion in Patients with Smear-positive Pulmonary Tuberculosis Respirology 2009;14:

9 Radiological Presentation of Pulmonary Tuberculosis Infected by the W-Beijing Mycobacterium tuberculosis Strain Int J Tuberc Lung Dis 2009;13:

10 Male, 69 y/o Treatment regimen Rifater+ EMB Skin rash and itching GOT: 75 U/L, GPT:125 U/L Uric acid: 15.7 mg/dl

11 Tuberculosis Chemotherapy Still a Double-edged Sword Am J Respir Crit Care Med 2003; 167:

14 何種藥物會產生肝毒性? Rifater Isoniazid 80 mg Rifampin 120 mg Pyrazinamide 250 mg Ethambutol AST: 228 ALT: 105

15 Isoniazid Asymptomatic elevation of aminotransferases Elevations up to five times the upper limit of normal: 10 20% Usually return to normal even with continued administration of the drug Clinical hepatitis: the risk increases Increasing age (< 20 y/o: uncommon; y/o: 2%) Underlying liver disease Heavy alcohol consumption Fatal hepatitis Associated with continued administration of INH despite onset of symptoms of hepatitis

Isoniazid: Peripheral Neurotoxicity Dose

Nutritional deficiency Diabetes HIV infection

16 Isoniazid: Peripheral Neurotoxicity Dose related Uncommon (< 0.2%) at conventional doses The risk is increased Associated with neuropathy Nutritional deficiency Diabetes HIV infection Renal failure Alcoholism Pregnant and breastfeeding women Pyridoxine supplementation 25 mg/day

17 Isoniazid Central nervous system effects Reported but have not been quantified Such as dysarthria, irritability, seizures, dysphoria, and inability to concentrate Lupus-like syndrome Hypersensitivity reactions Such as fever, rash, Stevens-Johnson syndrome, hemolytic anemia, vasculitis, and neutropenia are rare

18 Isoniazid 副作用肝炎約 10-20% 的病人血中轉胺酶 (transaminase) 值會暫時輕微升高多發生於用藥後十週內, 但也可能在治療中任何期間出現通常不需停藥即會恢復正常嚴重肝炎發生率約 % 多出現在投藥後三個月內發生率和年齡有關 35 歲以下約為 0.3% 歲 1.2% 歲 2.3% 常停藥後即可恢復正常

19 Isoniazid 副作用周邊神經炎最常見的症狀為對稱性肢端麻木或刺痛感孕婦或合併糖尿病尿毒症癲癇, 酗酒或營養不良之患者最好同時投予 pyridoxine( 一般不建議常規使用 pyridoxine) 過敏性反應如發熱皮疹 Stevens-Johnson syndrome 溶血性貧血血管炎白血球偏低, 及消化道反應其他較不常見的神經毒性包括痙攣毒性腦病變視神經炎及萎縮記憶障礙與毒性精神病症類狼瘡症候群 (Lupus-like syndrome); 發生率小於 1%

20 Rifampin (RIF): Orange Discoloration of Bodily Fluids (sputum, urine, sweat, tears)

21 Rifampin (RIF) Hepatotoxicity Transient asymptomatic hyperbilirubinemia Clinical hepatitis Typically: a cholestatic pattern

22 Rifampin (RIF) Cutaneous reactions ( Pruritis with or without rash): 6% Generally self-limited Continued treatment with the drug may be possible More severe, occurring in % of patients

23 Rifampin (RIF) Gastrointestinal reactions (nausea, anorexia, abdominal pain) Rarely severe enough to necessitate discontinuation of the drug Flu-like syndrome More likely to occur with intermittent administration of a higher dose Severe immunologic reactions: (rare < 0.1%) Thrombocytopenia, hemolytic anemia, acute renal failure

24 Rifampin 副作用食慾不振噁心嘔吐胃痛下痢皮疹肝炎間歇治療時, 若劑量大於 10 mg/kg, 偶有血小板減少感冒的症狀溶血性貧血及急性腎衰竭等副作用 RMP 會加速肝臟對藥物的代謝, 同時服用其他經肝代謝的藥物時, 如口服避孕藥,RMP 會降低避孕藥的效果, 故服用 RMP 期間應改用其他避孕方法同時服用 coumadin 類抗凝血劑口服糖尿病藥副腎皮質賀爾蒙毛地黃製劑,RMP 會減弱其作用

25 何種藥物會導致痛風發作? Rifater Isoniazid Rifampin Pyrazinamide Ethambutol

26 Pyrazinamide Hepatotoxicity: about 1% Gastrointestinal symptoms: common Asymptomatic hyperuricemia An expected effect of the drug Generally without adverse consequence Nongouty polyarthralgia: may occur in up to 40% of patients The pain usually responds to aspirin or other nonsteroidal antiinflammatory agents Acute gouty arthritis Rare except in patients with preexisting gout Transient morbilliform rash: usually self-limited

27 Pyrazinamide 副作用肝毒性, 在高劑量 (3 gm/day) 較常發生, 使用劑量小於 25 mg/kg, 發生率低於 5%, 與 INH 及 RMP 同時使用會增加肝毒性的機會 PZA 會干擾尿酸代謝而導致高尿酸血症, 血清尿酸濃度小於 13 mg/dl 時, 通常不需要藥物治療偶爾合併關節痛, 以水楊酸劑 (salicylates) 即可緩解, 急性痛風則較為少見皮疹及胃腸不適

28 Rifater 何種藥物可能會導致病患視力減弱, 甚至完全喪失? Isoniazid Rifampin Pyrazinamide Ethambutol

29 Ethambutol Retrobulbar neuritis Decreased visual acuity or red-green color discrimination Dose related Minimal risk at a daily dose of 15 mg/kg In patients with renal insufficiency Cutaneous reactions Skin reactions requiring discontinuation of the drug occur in % of patients

30 Ethambutol 副作用眼球後視神經炎 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 15 mg/kg 時, 其發生率小於 1% 症狀包括視力模糊中央盲點及紅綠色盲一旦發現視力減退, 若立即停藥, 可恢復視力過敏性反應皮膚炎皮膚搔癢食慾不振噁心嘔吐胃腸不適腹痛

31 Fixed-Dose Combination Preparations Reducing the risk of monotherapy The ease of administration The potential for reducing medication errors Fixed-dose combinations are highly recommended

33 Streptomycin Ototoxicity (vestibular and hearing disturbances) Most important adverse reaction The risk is increased Age Increasing single doses The cumulative dose (especially above g) Neurotoxicity Circumoral parasthesias immediately after injection Nephrotoxicity

34 Streptomycin 副作用常見的副作用為耳毒性暈眩或聽力障礙腎毒性偶亦發生耳毒性或腎毒性較易發生在高齡病人, 且與累積劑量及最高血中藥物濃度有關累積劑量最好不超過 120 gm

35 GOT: 777 U/L GPT: 1333 U/L

and color vision should be performed when EMB is to be used All patients with tuberculosis have

36 Baseline Evaluations Measurements of AST, bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained for all adults (uric acid and sugar) Testing of visual acuity and color vision should be performed when EMB is to be used All patients with tuberculosis have counseling and testing for HIV infection (U.S.) 使用藥物前應安排血液及生化檢查 CBC AST/ALT bilirubin uric acid BUN/Cre Sugar

effects of the anti-tb medications To assess adherence

37 Follow-Up Evaluations (1) It is essential that patients have clinical evaluations at least monthly To identify possible adverse effects of the anti-tb medications To assess adherence 為能確實掌握病人服藥依附醫囑性, 診療醫師應鼓勵病人 ( 尤其是痰塗片陽性病人 ) 接受 DOT, 觀察用藥, 尤其不應以開立慢性病連續處方箋的方式減少病人回診追蹤的頻率

Follow-Up Evaluations (2) It is not necessary to monitor liver or renal function or platelet count for patients being treated with first-line drugs unless

function at baseline should have repeat measurements early in the course of treatment, then less frequently to ensure that there has not been worsening

38 Follow-Up Evaluations (2) It is not necessary to monitor liver or renal function or platelet count for patients being treated with first-line drugs unless there were abnormalities at baseline or there are clinical reasons to obtain the measurements Patients who have stable abnormalities of hepatic or renal function at baseline should have repeat measurements early in the course of treatment, then less frequently to ensure that there has not been worsening Patients be clinically monitored during treatment so that adverse effects can be detected promptly and managed properly Routine laboratory monitoring is not necessary

39 Follow-Up Evaluations (3) 使用藥物後的第週均應追蹤檢查

visual acuity and color vision is recommended for Receiving an EMB dose

40 Follow-Up Evaluations (4) Patients receiving EMB should be Questioned regarding visual disturbances at monthly intervals Monthly repeat testing of visual acuity and color vision is recommended for Receiving an EMB dose exceeding mg/kg Receiving the drug for more than 2 months 使用 Ethambutol 病人, 應按月檢查視力及辨色力

41 To Assess the Risk-Benefit of Anti-TB Drugs

42 Transmission

43 Anti-TB chemotherapy: Three Basic Principles Multiple drugs to which the organisms are susceptible The drugs must be taken regularly Therapy must continue for a sufficient period of time Six-month regimens 2HERZ/4HR Nine-month regimen 2HER/7HR ATS/CDC Am J Respir Crit Care Med 1994;149: ATS/CDC/IDSA Am J Respir Crit Care Med 2003;167:

44 Alternative Regimens (1A)

45 Alternative Regimens (1B)

46 Symptom-based Approach to Managing Side-effects of Anti-TB drugs Minor adverse effects Continue the TB treatment and be given symptomatic treatment Major side-effect The treatment or the responsible drug is stopped

47 The Management Approach to Adverse Drug Reactions (1) With regards to the anti-tb treatment regimen following an adverse reaction As many first-line drugs should be tried as possible More effective and less toxic than the second-line agents Early detection is essential Clearly affect the associated morbidity and mortality Most adverse reactions are attributable to a single drug Can be resolved by designing a treatment regimen to exclude that agent

timing of administration If these measures prove to be unsuccessful, suspension of

48 The Management Approach to Adverse Drug Reactions (2) Mild or moderate adverse reactions To provide symptomatic treatment for the reaction, adjust the drug dose, or change the timing of administration If these measures prove to be unsuccessful, suspension of treatment should then be considered A serious adverse reaction All treatment should be suspended

49 Management of Drug-related Hepatitis (1) The first-line antituberculosis drugs, INH, RIF, and PZA, can cause drug-induced liver injury An asymptomatic increase in AST concentration occurs in nearly 20% of patients treated with the standard four-drug regimen In most patients, asymptomatic aminotransferase elevations resolve spontaneously In addition to AST elevation, occasionally there are disproportionate increases in bilirubin and alkaline phosphatase This pattern is more consistent with rifampin hepatotoxicity

50 Management of Drug-related Hepatitis (2) If AST levels are more than five times the upper limit of normal (with or without symptoms) or more than three times normal in the presence of symptoms hepatotoxic drugs should be stopped immediately and the patient evaluated carefully Drug-induced hepatitis is usually a diagnosis of exclusion Serologic testing for hepatitis A, B, and C should be performed Carefully regarding symptoms suggestive of biliary tract disease Exposures to other potential hepatotoxins, particularly alcohol and hepatotoxic medications

51 Management of Drug-related Hepatitis (3) To give at least three nonhepatotoxic anti-tb drugs Until the specific cause of hepatotoxicity can be determined and an appropriate longer term regimen begun Restarted one at a time After the AST concentration returns to less than two times the upper limit of normal In patients with elevated baseline AST from preexisting liver disease, drugs should be restarted when the AST returns to near baseline levels

52 Liver Disease Caused by the Anti-TB Drugs All drugs should be stopped If the patient is severely ill with TB and it is considered unsafe to stop TB treatment A non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be started Once drug-induced hepatitis has resolved The drugs are reintroduced one at a time If symptoms recur or liver function tests become abnormal as the drugs are reintroduced, the last drug added should be stopped

53 Management of Drug-related Hepatitis (3) 治療改為併用 SM EMB 或 Quinolone 等兩種以上抗結核藥物肝功能恢復後, 依 INH RMP PZA 順序, 再重新進行小量漸進式給藥試驗 If RIF and INH are tolerated, and hepatitis was severe, PZA should be assumed to be responsible and should be discontinued

54 Gastrointestinal Upset Nausea, Vomiting, Poor Appetite, Abdominal Pain Many of the antituberculosis drugs can cause gastrointestinal upset Particularly in the first few weeks of therapy Serum AST and bilirubin should be measured The initial approach to gastrointestinal intolerance, not associated with hepatic toxicity To change the hour of drug administration and/or to administer the drugs with food

55 Drug Administration The first-line anti-tb medications should be administered together as single dose rather than in divided doses Ingestion with food delays or moderately decreases the absorption of anti-tb drugs The effects of food are of little clinical significance The wide therapeutic margin of the first-line agents Epigastric distress or nausea with the first-line drugs Dosing with food is recommended Preferable to splitting a dose or changing to a second-line drug Antacids have minimal effects on the absorption of the first-line anti-tb drugs

continued If there is a generalized erythematous rash (especially if it is associated with fever and/or mucous membrane

56 Rash All drugs used in treating tuberculosis can cause a rash The rash may be minor (affecting a limited area or being predominantly manifested as itching) Antihistamines should be given for symptomatic relief All anti-tb medications can be continued If there is a generalized erythematous rash (especially if it is associated with fever and/or mucous membrane involvement) All drugs should be stopped immediately When the rash is substantially improved The medications can be restarted one by one

57 結核藥物副作用的處理原則結核藥物副作用無法獲得妥善處理是病人不能按規服藥的主要原因診療醫師如對其副作用掉以輕心或草率處理, 往往會使病人對治療失去信心斷續用藥, 導致續發性抗藥性菌株的產生, 後果非常嚴重病人抱怨的副作用, 無論如何微不足道對身體無傷 ; 無論多麼千奇百怪匪夷所思, 只要足以影響病人服藥意願, 診療醫師即應認真面對

58 嚴密觀察即可, 不必停藥無症狀 AST/ALT 5 倍以內的輕度上昇, 或血球輕微減少輕微的皮膚搔癢初用藥時的全身倦怠, 可予心理支持, 或改睡前服藥血清尿酸濃度在 13 mg/dl 以下時, 請病人多喝水, 暫不停藥, 也不用降尿酸藥物

59 症狀治療緩解, 不必停藥病人發生腸胃不適症狀, 可將藥物改飯後服用, 或併用 primperan 等來緩解輕度皮膚搔癢, 可開立長效抗組織胺劑來緩解輕度痛風關節酸痛, 先以短暫非類固醇抗發炎藥物作症狀處理使用 isoniazid 病人的末梢神經麻木, 可以 pyridoxine 緩解

60 應即停止用藥 (1) 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

61 應即停止用藥 (2) 結核病人於治療中如發生上述藥物副作用時, 除非該副作用非常明確是由某一特定結核藥物所致 ( 如視力模糊之於 ethambutol 高血清尿酸之於 pyrazinamide), 可以直接停止該藥建議先停止所有可能造成此副作用之結核藥物, 俟副作用消失後, 以逐一緩慢嘗試用藥方式 (rechallenge) 找出導致此副作用之藥物

62 Male, 56 y/o, Uremia GOT: 1704 U/L GPT: 1481 U/L

<4D6963726F736F667420506F776572506F696E74202D20B5B2AED6AF66C3C4AAABB0C6A740A5CEAABAB342B27A28A745A9FAAA76292E707074205BACDBAE65BCD2A6A15D>

<4D6963726F736F667420506F776572506F696E74202D20B5B2AED6AF66C3C4AAABB0C6A740A5CEAABAB342B27A28A745A9FAAA76292E707074205BACDBAE65BCD2A6A15D> 結核病藥物副作用的處理台北醫學大學市立萬芳醫院結核病中心余明治醫師 Standard 8 All patients who have not been treated previously should receive an internationally ti accepted first-line treatment regimen