多重抗藥性結核病（ MDR-TB) 的防治 周振興

「多重抗藥性結核病」（ MDR-TB ）是指 結核病人的痰檢體經培養及藥物敏感性試 驗後發現至少同時對 Isoniazid （ INH ）及 Rifampin （ RMP ）二種第一線藥物具有 抗藥性的病人

( 廣泛抗藥性結核菌 Extensively drug resistant tuberculosis,XDR-TB ) 若更嚴重進一步對任何 藥性，且對於 fluoroquinolone 藥物有抗 3 種注射型的抗結核病二線藥物 （ capreomycin, kanamycin, amikacin ）中至少 1 種出現抗藥性者，就會成為所謂超級抗藥性結 核 (Extensively drug resistant tuberculosis, XDR-TB ；亦有翻譯為廣泛抗藥性結核菌 ) XDR-TB 的出現無異使結核病防治上更加困難， 治療上比 MDR-TB 更為棘手，一旦被感染，其治 療成功率有可能會降至 50% 以下

廣泛抗藥性結核菌

美國疾病管制中心和世界衛生組織 於 2006 年初發 出警告，一種全新、致命性高的廣泛抗藥性結核 菌正在全球擴散。 2006 年 8 月在加拿大多倫多舉行的「國際世界愛 滋病會議」 (International World AIDS Conference ) 中，與會人士報告了南非東南部省 分夸祖魯 納塔爾 (KwaZulu-Natal ) 發生 53 例 XDR-TB 病人中，有 52 人平均在二十五天內死亡， 且 44 病人合併感染愛滋病

Prevalence of drug resistance among new TB cases

12 10 8 6 4 2 0 10.8

2.9 2.8

MDR 2.1

0.1

China Henan Russia (Ivanovo) China (Zhejiang) China (Shandong) China (Guangdong) Korea Thailand Taiwan(CDCB) HongKong Singapore Malaysia Anti-tuberculosis drug resistance in the world, report No.2 WHO 2000

The World Health Organization (WHO) surveyed 62,746 M. tuberculosis isolates from 81 countries between 2002 and 2006 multidrug-resistant tuberculosis (MDR-TB) represented 5.3 percent of all new and previously treated TB cases worldwide.

 surveyed in 66 countries, resistance to at least one drug ranged from zero percent in three European countries to 86 percent in Tashkent, Uzbekistan.  The highest proportions of MDR-TB were from Tashkent, Uzbekistan (60 percent) and Baku, Azerbaijan (56 percent).

China, India, and the Russian Federation, are estimated to carry the highest number of MDR TB cases. China and India have approximately 50 percent of the global burden of MDR-TB cases The rates of MDR-TB are increasing in Peru, the Republic of Korea, and some parts of the Russian Federation (Orel and Tomsk)

Of the 4,012 MDR cases that were reported, 301 (7 percent) were XDR-TB. The proportion of XDR-TB among MDR TB ranged from zero percent in 11 countries to 30 percent in Japan.

國內的抗藥性監測資料在 來自於各醫院的研究資料收集得之，多重 抗藥性結核病的比率從 0.2% （ 1984 1990 ）一直逐年往上升至 2000 ）。 2006 年底以前是 2% （ 1997-

When organisms are resistant to both isoniazid and rifampin, the course of treatment increases from 6 months to 18 24 months, and the cure rate decreases from nearly 100% to less than or equal to 60%.

結核初次治療的藥品費用

(

複方

)

藥品 RFT RFN300 RFN150 EMB 單價 11.5

13.5

7.5

1.9

每日平均劑量 5 2 3 2 每日費用 57.5

27 22.5

3.8

>50kg 初治 初治 [2 (RFT+E)/4 (RFN+E)] 藥品費用： [9 (RFN+E) 藥品費用： 8316 7374

抗藥性結核治療的藥品費用

藥品 Levofloxacin (500) PAS TBN CS 健保單價 152 6.5

6.5

46.9

每日平均劑量 1.5

20 3 2 每日費用 223 130 19.5

93.8

SM 52 1 52 KM 15.0

1 15.0

LEVO+PAS+TBN+CS+SM 每月藥品費用： 15549 治療 21 個月 藥品費用： 298449

MDR-TB

產生原因

結核菌發生抗藥性突變的機率

藥名 機率 Rifampin Isoniazid, Streptomycin, Ethambutol, Kanamycin, Para-AminoSalicylate Ethionamide, Enviomycin, Cycloserine, Capreomycin, Viomycin, Thiacetazone 10 10 10 -8 -6 -3

Shimao T. Tubercle 1988;68(supp):5-15.

抗藥性結核菌如何發生

(

續

)

分 裂 突 變 INH 抗藥 INH+RMP 抗藥 INH+PZA 抗藥 INH + RMP 單一治療 INH+RMP 多重抗藥 性結核菌

“Fall and Rise” Phenomenon

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 Sensitive Resistant 3 6 9 12 Weeks of Treatment 15 18

人為因素

診療醫師處方錯誤： （一） 針對活動性結核病人施行預防治療。 （二） 未依標準處方及劑量開立結核藥物。 （三） 未注意到病人服藥順服度不佳，或雖知道但未採 取行動。 （四） 未注意到病人已經罹患抗藥結核病。 （五） 在失敗的處方每次新增 1 種藥物。 （六） 過度信賴 streptomycin 及 fluoroquinolone ， 誤以為已使用 2 種新藥，卻忽略了 streptomycin 無法在 18-24 個月的療程中全程使用，以及 streptomycin 可能與 isoniazid 共同出現抗藥的問題。

人為因素

來自病人的問題如下： （一） 服藥順服度差導致續發性多重抗藥 菌株的產生。 （二） 因藥物副作用導致不規則服藥。 （三） 遭原發性多重抗藥菌株感染。 （四） 因肺生理結構扭曲所導致的生理性 抗藥（ Physiological resistance ）。

診斷

Persons at Increased Risk for Drug Resistance

• • • • • History of treatment with TB drugs Contacts of persons with drug-resistant TB Foreign-born persons from high prevalent drug resistant areas Smears or cultures remain positive despite 2 months of TB treatment Received inadequate treatment regimens for >2 weeks

Culture and sensitivity

The diagnosis of drug-resistant tuberculosis depends upon the collection and processing of adequate specimens for culture and sensitivity testing Need 2 more months

MOLECULAR BASIS OF DRUG-RESISTANT TUBERCULOSIS Isoniazid resistance

— Alterations in either the katG, kasA, or inhA genes

Rifampin resistance

gene — Mutations in the rpoB

Pyrazinamide resistance

gene pncA —mutations in the Ethambutol resistance--- amino acid replacements at position 306 of an arabinosyltransferase encoded by the embB gene

Streptomycin

— Resistance is conferred by mutations in the rpsL and rrs genes

Rapid testing

A molecular probe capable of detecting resistance mutations in three TB genes: rpoB (associated with rifampin resistance), and katG and inhA (mutations associated with isoniazid resistance) the molecular probe was

≥99

percent sensitive and specific for multidrug TB resistance, compared with standard drug-susceptibility testing;

results were available in 1 to 2 days.

Since the assay does not depend on culture, it yielded results even in specimens that were contaminated or had no growth.

TREATMENT OF MDR-TB

antituberculosis drugs

Empiric

Include the standard recommendations plus at least four drugs effective against the most prevalent drug-resistant strains This may require that six or more drugs be given until drug susceptibility results are obtained

Documented MDR

discontinue the drugs to which the isolate is resistant and to add at least two new drugs to which the isolate is susceptible most experts recommend that a parenteral aminoglycoside ( streptomycin , kanamycin , amikacin , or capreomycin ) and a quinolone ( levofloxacin and moxifloxacin ) be added. Treatment with parenteral agents is usually given for six months, and cures rates are high with medical therapy alone (in the 85 percent range) for MDR-TB regimens that include these two classes of drugs

Treatment with at least four effective drugs should be continued for 18 to 24 months appropriate laboratory facilities to document drug susceptibility and monitor response should be available. These regimens should be administered by

direct observation

Adjunctive therapies

Uncontrolled trials and anecdotal reports suggest that adjunctive immunotherapy with interferon-gamma (IFNg) may be useful in the management of multidrug resistant tuberculosis Small observational studies suggested benefit in MDR-TB. However, a randomized trial of IFNg failed to confirm efficacy

Criteria for Surgery in MDR-TB

Localized lesions Reasonable lung function Two or more susceptible drugs available

Directly observed therapy

A decrease in the incidence rate of pulmonary TB (from 42 to 19 per 100,000 population) A decreases in the rate of primary drug resistance (from 9.4 to 1.5 per 100,000 population) A decrease in treatment failures (from 11 to 2 percent) A decrease in the rate of MDR-TB (from 10 to 4.3 per 100,000 population)

治療照護

治療多重抗藥及慢性病人應有下列資源到位，診療醫師如資 源不足，應儘速將其轉診至適當醫療團隊。 1. 經驗豐富的結核病醫療團隊，含醫師、護理人員， 社會工作人員、營養師等。 2. 能提供高品質藥敏試驗、菌種鑑定的結核菌實驗室。 3. 充足且來源穩定的二線藥物。 4. 多重抗藥及慢性病人如有住院需求，應安置於具完善院 內感染控制的病房。 世界衛生組織建議：如以良好的居家照護為基礎，在合格 的醫療團隊指導下，可由經完整訓練的健康照護工作人員 提供多重抗藥與慢性病人全程居家治療，以避免抗藥結核 病的院內感染。

政府作為

有鑑於多重抗藥性結核病的治療複雜及嚴重影響 國人健康，現在國內已建置更專業的多重抗藥 （ MDR ）醫療照護體系可協助這些病人的醫療 照護 ; 包括「台北市立萬芳醫院團隊」、「行政院 衛生署桃園醫院團隊」、「行政院衛生署台中醫 院團隊」、「行政院衛生署胸腔病院團隊」、 「中華民國防癆協會團隊」的成立 2006 患。 年起建立 治計畫（ MDR-TB 通報系統，推動進階都 DOTS plus ）以及時監控所有多重抗藥 性結核病患，避免衍生出更多超級抗藥性結核病

預防

針對無抗藥性結核病，正確的一線藥物治 療、適當的管理是預防抗藥性結核病產生 的最佳方法。

Drug-susceptible TB and MDR TB are spread the same way shaking someone’s hand sharing food or drink touching bed linens or toilet seats sharing toothbrushes kissing

How can MDR TB be prevented?

take all of their medications exactly as prescribed by their health care provider. Health care providers can help prevent MDR TB by quickly diagnosing cases, following recommended treatment guidelines, monitoring patients’ response to treatment, and making sure therapy is completed. avoid exposure to known MDR TB patients in closed or crowded places such as hospitals, prisons, or homeless shelters.

In the United States drug-resistant tuberculosis prevalence has decreased compared with the early 1990s (3.5 percent in 1991 versus 1.1 percent in 2006) and has remained stable between 2005 (1.2 percent) and 2006.

Improvements in hospital infection control measures the widespread use of an initial four-drug chemotherapy regimen directly observed therapy

醫院防護

isolation of suspected tuberculosis cases rapid examination of sputum smears personal protection with particulate respirators germicidal ultraviolet irradiation HEPA filters, frequent air exchanges, and negative pressure ventilation.

Exposure to multidrug-resistant tuberculosis

Potential regimens that have been suggested include pyrazinamide and ethambutol , or pyrazinamide and a quinolone, 12 months in immunocompromised patients, and at least 6 months in patients who are immunocompetent

結語

外勞引進、國際往來頻繁、愛滋病併發結 核病例數增加 , 造成防治的困難 多重抗藥性結核病患者需更多的心力 , 更多的耐心 衛教 透過「多重抗藥性結核病醫療照護體系」， 為難治療的多重抗藥性結核病個案開創新 契機，也使我國結核病防治與國際接軌， 向結核病「十年減半」之路邁開大步