抗結核藥物介紹 - PDF Free Download

第二線抗結核藥物 Levofloxacin (Lfx,Cravit) Moxifloxacin (Mfx,Avelox) Streptomycin (Sm) Kanamycin (Km) Amikacin (Am) Rifabutin (RBT) Prothionamide (Pto, TBN) Para-AminoSalicylate (PAS) Cycloserine (Cs) Selman Abraham Waksman (1888-1973) 1952 Nobel Prize

Levofloxacin, Lfx (Cravit) Bactericidal against M. tuberculosis. MIC for M. tuberculosis 0.25-0.5 mcg/ml; Usual dose: Levofloxacin 500-1000 mg/d (10-15mg/kg/d) Toxicity: GI disturbance 0.5-1.8% Neurological effects: dizziness, insomnia 0.5% Cutaneous reactions: 0.2-0.4%

Moxifloxacin, Mfx (Avelox) Bactericidal against M. tuberculosis. MIC99 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

Streptomycin, Sm An aminoglycoside isolated from Streptomyces griseus, streptomycin is available for intramuscular and intravenous administration only. In the United States, it is the least-used first-line supplemental drug for tuberculosis because of its toxicity, the difficulty in obtaining adequate CSF levels, and the inconvenience of its parenteral administration. In developing countries, however, streptomycin is frequently used because of its low cost. The drug is active against untreated strains of M. tuberculosis, M. kansasii, and M. marinum and against some strains of MAI at readily achievable serum levels.

Mechanism of Action Streptomycin inhibits protein synthesis by disruption of ribosomal function.

Pharmacology Serum levels of streptomycin peak at 25 to 40 ug/ml after a 1.0-g dose. Streptomycin is bactericidal for rapidly dividing extracellular mycobacteria but is ineffective in the acidic environment within the macrophage. It diffuses poorly into the meninges and, in patients with meningitis, reaches CSF levels that are only 20% of serum levels. The usual adult dose of streptomycin is 0.5 to 1.0 g (10 to 15 mg/kg) daily or five times per week; the pediatric dose is 20 to 40 mg/kg daily, with a maximum of 1 g/d. Because streptomycin is eliminated almost exclusively by the kidneys, the dosage must be lowered and the frequency of administration reduced (to only two or three times per week) in most patients over 50 years of age and in any patient with renal impairment.

Adverse Effects Adverse reactions to streptomycin therapy occur in 10 to 20% of patients. Ototoxicity and renal toxicity are the most common and the most serious. Renal toxicity, usually manifested as nonoliguric renal failure, is less common with streptomycin than with other frequently used aminoglycosides, such as gentamicin. Ototoxicity involves both hearing loss and vestibular dysfunction. The latter is more common and includes loss of balance, vertigo, and tinnitus. Patients receiving streptomycin must be monitored carefully for these adverse effects. Less serious reactions include perioral paresthesia, eosinophilia, rash, and drug fever.

Resistance Spontaneous resistance to streptomycin occurs in 1 in 105 to 107 organisms. In two-thirds of streptomycin-resistant strains of M. tuberculosis, mutations have been identified in one of two targets: a 16S rrna gene (rrs) and the gene encoding ribosomal protein S12 (rpsl). Both targets are believed to be involved in streptomycin ribosomal binding. No mutational change has been identified in the other onethird of resistant isolates. Strains of M. tuberculosis that are resistant to streptomycin are not cross-resistant to capreomycin or amikacin.

Amikacin, Am Kanamycin, Km These well-known aminoglycosides are bactericidal to extracellular organisms. Kanamycin is rarely used because of its toxicity. Amikacin is active against M. tuberculosis and several of the nontuberculous species, including the rapidly growing mycobacteria, M. scrofulaceum, M. leprae, and MAI. The usual adult dosage is 10 to 15 mg/kg intramuscularly or intravenously three to five times per week. Resistance to both drugs relates to a single-base-pair change at position 1408 in the 16S ribosomal RNA gene.

Rifabutin (RFB) 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%

Ethionamide, Eto Prothionamide, Pto Like isoniazid and pyrazinamide, ethionamide is a derivative of isonicotinic acid. This agent is bacteriostatic against metabolizing M. tuberculosis and some nontuberculous mycobacteria. It is most useful in therapy for multidrug-resistant tuberculosis. However, its use is severely limited by its toxicity and frequent side effects, which include intense gastrointestinal intolerance (anorexia, vomiting, and dysgeusia), serious neurologic reactions, reversible hepatitis (5% of cases), hypersensitivity reactions, and hypothyroidism. Ethionamide is well absorbed orally and is widely distributed throughout the body at sites including the CSF.

Para-Aminosalicylic Acid (PAS) PAS, a calcium or sodium salt that inhibits the growth of M. tuberculosis by impairing folate synthesis, is rarely indicated for the treatment of tuberculosis because of its low level of antituberculous activity and its high level of gastrointestinal toxicity (manifesting as nausea, vomiting, and diarrhea). Enteric-coated PAS granules (4 g every 8 h) may be better tolerated than other formulations and produce higher therapeutic blood levels. PAS is well absorbed after oral administration but reaches only low concentrations in the CSF. The drug has a short half-life (1 h), and 80% of the dose is excreted in the urine.

Cycloserine Cycloserine (D-4-amino-3-isoxazolidinone) is produced by Streptomyces orchidaceus and is active against a broad spectrum of bacteria, including M. tuberculosis. Cycloserine is well absorbed after oral administration and is widely distributed throughout the body fluids, including the CSF. Serious side effects limit the use of this drug and include psychosis (with suicide in some cases), seizures, peripheral neuropathy, headaches, somnolence, and allergic reactions. Cycloserine should not be given to patients with epilepsy, active Nickname: Psycho-serine alcohol abuse, severe renal insufficiency, or a history of depression or psychosis.

抗結核藥物劑量及常見副作用 1 藥物給藥方式每日劑量 ( 最大劑量 ) 常見副作用 RMP (Rifampin) 口服 10 mg.kg (600mg) 肝炎腹部症候過敏血液學變化 INH (Isoniazid) 口服 5-10 mg/kg (600mg) 肝炎周圍神經炎過敏 PZA (Pyrazinamide) 口服 25 mg/kg (2 gm) 肝炎高尿酸血症過敏 EMB (Ethambutol) 口服 15 mg/kg (1.2 gm) 視神經炎過敏 LVX (Levofloxacin) 空腹口服 10-15 mg/kg (1 gm) 胃腸不適頭暈過敏反應頭痛躁動不安藥物交互作用 MOXI (Moxifloxacin) 空腹口服 400mg 胃腸不適頭暈過敏反應頭痛躁動不安藥物交互作用 RBT (Rifabutin) 口服 5 mg/kg (300 mg) 肝炎血液學變化腹部症候過敏眼葡萄膜炎 (uveitis) SM (Streptomycin) IM 或 IV drip 15 mg/kg (1 gm) 聽力平衡功能損害腎毒性過敏 KM (Kanamycin) IM 或 IV drip 15 mg/kg (1 gm) 聽力平衡功能損害腎毒性過敏 AMK (Amikacin) IM 或 IV drip 15 mg/kg (1 gm) 聽力平衡功能損害腎毒性過敏

抗結核藥物劑量及常見副作用 2 藥物 T1321 (Prothionamide) PAS ( Paraaminosalicylic acid) CS (Cycloserine) 給藥方式口服口服口服每日劑量 ( 最大劑量 ) 15 mg/kg (1 gm) 150 mg/kg (16 gm) 15 mg/kg (1 gm) 常見副作用胃腸不適肝炎金屬味胃腸不適肝炎過敏鈉滯留精神異常抽搐憂鬱症過敏複方藥物 RFT (Rifater) RFN (Rifinah) 給藥方式口服口服每錠藥物成分 RMP120mg INH 80mg PZA250mg RFN300: RMP300mg INH150mg RFN150: RMP150mg INH100mg 每日劑量每 10 公斤體重 1 錠 ( 最多 5 錠 ) 體重 50 公斤以上 : RFN300 每日 2 錠體重小於 50 公斤 : RFN150 每日 3 錠

MDR-TB 治療中副作用的發生頻率 (n=818) - 1 副作用噁心 / 嘔吐 (Nausea/vomiting) 腹瀉 (Diarrhoea) 關節痛 (Arthralgia) 頭暈 (Dizziness/vertigo) 聽力減退 (Hearing disturbances) 頭痛 (Headache) 失眠 (Sleep disturbances) 電解質失調 (Electrolyte disturbances) 腹痛 (Abdominal pain) 無胃口 (Anorexia) 胃炎 (Gastritis) 人數 (%) 268 (32.8) 173 (21.1) 134 (16.4) 117 (14.3) 98 (12.0) 96 (11.7) 95 (11.6) 94 (11.5) 88 (10.8) 75 (9.2) 70 (8.6) Nathanson E et al. Adverse events in the treatment of MDRTB: results for the DOTS-Plus initiatives. IJTLD 2004; 8: 1382

MDR-TB 治療中副作用的發生頻率 (n=818) - 2 副作用週邊神經炎 (Peripheral neuropathy) 憂鬱 (Depression) 耳鳴 (Tinnitus) 過敏反應 (Allergic reaction) 皮疹 (Rash) 視力降低 (Visual disturbances) 痙攣 (Seizures) 甲狀腺機能低下 (Hypothyroidism) 精神病 (Psychosis) 肝炎 (Hepatitis) 腎衰竭 (Renal failure/nephrotoxicity) 人數 (%) 65 (7.9) 51 (6.2) 42 (5.1) 42 (5.1) 38 (4.6) 36 (4.4) 33 (4.0) 29 (3.5) 28 (3.4) 18 (2.2) 9 (1.1) Nathanson E et al. Adverse events in the treatment of MDRTB: results for the DOTS-Plus initiatives. IJTLD 2004; 8: 1382

藥物副作用的處理 - 1 迅速的評估診斷處理副作用是非常重要的如果沒有適當處理, 病人的情緒反應會加重副作用的程度如果副作用是輕微的, 可以繼續原來的處方, 只需添加減緩副作用的藥品 MDR-TB 病人能使用的抗結核藥物已經有限, 如果因為副作用需停用某種藥物將使得治療非常困難有些副作用會隨著時間消失, 如果適當勸導病人, 病人可能可以繼續服用該藥品

藥物副作用的處理 - 1 某些二線藥的副作用是和劑量有關的, 所以減輕劑量是處理副作用的方式之一, 但是減輕的劑量應該可以產生適量的血清濃度, 才不至於影響藥效, 例如 Cycloserine 和 Ethionamide, 病人可能無法承受某種劑量, 但是減輕劑量後病人就可以忍受但是許多二線藥的治療範圍非常狹小, 減輕劑量可能影響療效, 因此還是要依照病人的體重維持適當的劑量服用 Cycloserine 的病人需要給予維他命 B6 以減少神經副作用, 推薦劑量是每 250 毫克的 Cycloserine 給予 50 毫克的維他命 B6 給予適當的精神支持, 可以幫助病人渡過副作用的困難這是關懷員的重要責任關懷員必需衛教病人和鼓勵病人繼續服藥

Pretreatment evaluation and monitoring during treatment of DRTB 抗藥性結核病治療前和治療中的評估 - 1 WHO/HTM/TB/2006.361. Guidelines for the programmatic management of drug-resistant tuberculosis

Pretreatment evaluation and monitoring during treatment of DRTB 抗藥性結核病治療前和治療中的評估 - 2 WHO/HTM/TB/2006.361. Guidelines for the programmatic management of drug-resistant tuberculosis

抗藥性結核病治療前和治療中的評估 1. 每個月至少要到門診由臨床醫師評估壹次醫生必須詳問病人的症狀是否有改善是否有副作用出現 2. 每個月量體重 3. 治療初始的 6 個月請每個月驗兩次痰 ( 塗片和培養 ), 如果第六個月還是陽性, 請繼續每個月驗痰直到痰陰轉治療六個月後可以改成毎 3 個月驗 2 次痰如果懷疑有惡化現象可以隨時驗痰 4. 實驗室檢查包括白血球計數血小板計數和血色素比 (hematocrit) 肝功能腎功能和尿酸服用 ethambutol 的病人皆須事前測量視力, 所有病人都會做 HIV 抗體檢驗 5. 胸部 X 光片應在治療後三個月六個月十二個月十八個月和預計停藥時施行如果懷疑病情惡化可以隨時做胸部 X 光片檢查 - 1 台灣 MDR TB 醫療照護體系 2008 研究計畫

抗藥性結核病治療前和治療中的評估 - 2 6. 肝腎功能 : 每隔壹至參個月驗一次肝腎功能 7. 病人如接受 Aminoglycocide 的注射時須每個月驗腎功能 8. HIV 檢驗 - 進入治療時須驗壹次, 以後視狀況而驗 9. 懷孕檢驗 - 生產年齡的女性進入治療時須驗壹次, 以後視狀況而驗 10. 視力檢查 - 病人如服用 EMB, 須每個月驗壹次 11. 關懷員須每天送藥到患者手上 ( 每週至少五次 ) 必須訓練關懷員了解治療的副作用, 如果有任何副作用發生須盡快通知醫護人員台灣 MDR TB 醫療照護體系 2008 研究計畫

副作用可能藥物和處理方法 - 1 副作用可能藥物處理方法備註痙攣 Cs, H, fluo roqui nol one s 1. 停用可能引起痙攣的藥物 2. 給予抗痙攣的藥物 ( 例如 phenytoin, valproic acid) 3. 增加維他命 B6 到最高劑量 ( 每天 200 毫克 ) 4. 如果藥物無法停用, 可重新嘗試低劑量 5. 如果還有其他藥物可用, 則完全停用引起痙攣的藥物 1. 繼續使用抗痙攣的藥物直到 MDR-TB 治療終止或可能藥物已停用 2. 如果病人以前即有痙攣病史但是接受抗痙攣藥物控制良好依然可以使用前列藥品 3. 有痙攣病史的病人在 MDR-TB 治療中有較高危險發生痙攣週邊神經炎 Cs, H, S, Km, Am, Cm, Eto/ Pto, fluo roqui nol one s 1. 增加維他命 B6 到最高劑量 ( 每天 200 毫克 ) 2. 如果 capreomycin 藥敏有效, 將注射藥物改為 capreomycin 3. 使用三環抗憂鬱藥如 amitriptyline NSAID 或 acetaminophen 可以減輕症狀 4. 減輕可能引起副作用藥品的劑量 5. 停用可能引起副作用的藥品 1. 病人合併糖尿病愛滋病酒精中毒時較易引起此副作用 2. 神經病變可能無法完全變好, 但是停用致病藥品可以減輕症狀 WHO/HTM/TB/2006.361. Guidelines for the programmatic management of drug-resistant tuberculosis

副作用可能藥物和處理方法 - 2 副作用可能藥物處理方法備註聽力減退 S, Km, Am, Cm, Clr 1. 確認聽力減退的程度 2. 如果 capreomycin 藥敏有效, 將注射藥物改為 capreomycin 3. 減輕可能引起副作用藥品的劑量 4. 停用可能引起副作用的藥品 1. 曾使用過 aminoglycosides 的病人聽力可能已減退, 開始 MDR-TB 治療前即須檢查聽力 2. 聽力減退通常無法回復 3. 進一步的聽力減退必須和停用注射藥品權衡輕重精神症狀 Cs, H, fluoroquinolones, Eto/Pt o 1. 短期 (1-4 週 ) 停用致病藥品, 直到症狀獲得控制 2. 開始抗精神病治療 3. 減輕可能引起副作用藥品的劑量 4. 停用可能引起副作用的藥品 1. 有些病人必須在 MDR-TB 療程中使用抗精神病治療 2. 曾有精神病史的病人仍可使用左列藥物, 但發病的機率較高 3. 完成 MDR-TB 治療或停用致病藥品通常可以解除精神病症狀憂鬱 Cs, fluoroquinolones H, Eto/Pto 1. 設法改善社會經濟環境 2. 精神科諮詢 3. 開始抗憂鬱的治療 4. 減輕可能引起副作用藥品的劑量 5. 停用可能引起副作用的藥品 1. 社會經濟環境和慢性疾病常會影響憂鬱的狀態 2. 憂鬱的症狀常會起伏不定, 結核病治療進步時憂鬱症狀也會減輕 3. 曾有憂鬱病史的病人仍可使用左列藥物, 但發病的機率較高 WHO/HTM/TB/2006.361. Guidelines for the programmatic management of drug-resistant tuberculosis

副作用可能藥物和處理方法 - 3 副作用甲狀腺機能低下噁心嘔吐胃炎可能藥物 PAS, Eto/ Pto Eto/Pto, PAS, H, E, Z PAS, Eto/ Pto 處理方法 1. 開始 thyroxine 的治療 1. 注意脫水現象 2. 開始止吐治療 3. 減輕可能引起副作用藥品的劑量 4. 停用可能引起副作用的藥品 1. 給予 H2-blockers protonpump inhibitors 或制酸劑 2. 減輕可能引起副作用藥品的劑量 3. 停用可能引起副作用的藥品備註 1. 停用 PAS 或 ethionamide/ protionamide 可以完全恢復 2. 合併使用 ethionamide/ protionamide 和 PAS 較容易引起甲狀腺機能低下 1. 治療前幾週常會有上述症狀, 會隨著治療減輕 2. 注意電解質平衡 3. 停用致病藥物可以完全恢復 4. 曾有報告 clofazimine 會引起急性腹部症狀, 如有上述 1. 很少出現嚴重的胃炎情況需停用此藥物 2. 給予制酸劑需小心不要影響抗結核藥物的吸收 3. 停用致病藥物可以完全恢復 WHO/HTM/TB/2006.361. Guidelines for the programmatic management of drug-resistant tuberculosis

副作用可能藥物和處理方法 - 4 副作用可能藥物處理方法備註肝炎 Z, H, R, Eto/P to, PAS, E, fluoro - quino lones 1. 肝炎時停用所有的治療 2. 評估可能引起肝炎的原因 3. 永遠停用可能引起副作用的藥品 4. 肝功能恢復正常後嘗試一個個添加抗結核藥物, 並小心監測肝功能 1. 曾有肝炎的病史時需小心用藥 2. 停用致病藥物可以完全恢復腎毒性 S, Km, Am, Cm 1. 停用可能引起副作用的藥品 2. 考慮使用 capreomycin 3. 打針藥品可改用每週 2 次或 3 次, 小心監測腎功能 4 依照腎功能的嚴重度調整所有藥品 1. 有糖尿病病史或腎臟病病史需小心使用左列藥品 2. 腎衰竭可能無法恢復 WHO/HTM/TB/2006.361. Guidelines for the programmatic management of drug-resistant tuberculosis

副作用可能藥物和處理方法 - 5 副作用可能藥物處理方法備註低血鉀低血鎂 Cm, Km, Am, S 1. 監測血鉀質 2. 如果血鉀質偏低, 需同時間測血鎂質和血鈣質 3. 補充缺乏的電解質 1. 如果血鉀質嚴重則需住院 2. 難治的病人可以使用 Amiloride 5 10 mg QD 或 spironolactone 25 mg QD 視神經炎 E 1. 停用 E 2. 轉介病人給眼科醫師 1. 停用 E 通常視力會恢復 2. 少見情況下 SM 也會引起視神經炎關節痛 Z, fluoroquinolone s 1. 給予 NSAID 2. 減輕可能引起副作用藥品的劑量 3. 停用可能引起副作用的藥品 1. 關節痛的症狀會隨著時間消失 2. 使用 PZA 的病人尿酸會升高, Allopurinol 通常無法在此類病人降低尿酸 WHO/HTM/TB/2006.361. Guidelines for the programmatic management of drug-resistant tuberculosis

常用的輔助藥品 - 1 適應症噁心嘔吐胃痛胃潰瘍口腔黴菌感染腹瀉憂鬱焦慮失眠精神病痙攣藥品 Metoclopramide, dimenhydrinate, prochlorperazine, promethazine, bismuth subsalicylate H2-blockers (ranitidine, cimetidine, famotidine, etc.), proton pump inhibitors (omeprazole, lansoprazole, Fluconazole, etc.) clotrimazole lozenges Loperamide Selective serotonin reuptake inhibitors (fluoxetine, sertraline), tricyclic antidepressants (amitriptyline) Lorazepam, diazepam, clonazepam Dimenhydrinate Haloperidol, thorazine, risperidone Phenytoin, carbamazepine, valproic acid, phenobarbita WHO/HTM/TB/2006.361. Guidelines for the programmatic management of drug-resistant tuberculosis

常用的輔助藥品 - 2 適應症預防神經病變週邊神經炎頭暈關節痛肌肉痛頭痛皮疹全身性過敏反應支氣管收縮甲狀腺機能低下電解質缺乏藥品 Pyridoxine (vitamin B6) Amitriptyline Meclizine, dimenhydrinate, prochlorperazine, Ibuprofen, promethazine paracetamol, codeine Hydrocortisone cream, calamine, caladryl lotions Antihistamines (diphenhydramine, chlorpheniramine, dimenhydrinate), corticosteroids (prednisone, dexamethasone) Inhaled beta-agonists (albuterol, etc.), inhaled corticosteroids (beclomethasone, etc.), oral steroids (prednisone), injectable steroids (dexamethasone, Levothyroxine methylprednisolone) Potassium and magnesium replacement WHO/HTM/TB/2006.361. Guidelines for the programmatic management of drug-resistant tuberculosis

結論迅速的評估診斷處理副作用是非常重要的如果沒有適當處理, 會增加失落和治療失敗甚至死亡的風險 DRTB 照護團隊必須熟悉常見的副作用, 病人發生副作用時必須及時照會有經驗的醫護團隊透過醫護人員關懷員社服員等團隊成員, 病人家族和社區成員, 與病人通力合作, 給予病人充分的支持, 多可幫助病人渡過難關, 順利完成治療

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