多重抗藥性結核病（ 多重抗藥性結核病（ MDR-TB)MDR-TB) 的防治的防治

周振興周振興

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

(( 廣泛抗藥性結核菌廣泛抗藥性結核菌 Extensively drug resistant tubeExtensively drug resistant tuberculosis,XDR-TB )rculosis,XDR-TB )

若更嚴重進一步對任何 若更嚴重進一步對任何 fluoroquinolone fluoroquinolone 藥物有藥物有抗藥性，且對於 抗藥性，且對於 3 3 種注射型的抗結核病二線藥物種注射型的抗結核病二線藥物（ （ capreomycin, kanamycin, amikacin capreomycin, kanamycin, amikacin ）中至少 ）中至少 1 1 種出現抗藥性者，就會成為所謂超級抗藥性結種出現抗藥性者，就會成為所謂超級抗藥性結核 核 (Extensively drug resistant tuberculosis,(Extensively drug resistant tuberculosis,XDR-TB XDR-TB ；亦有翻譯為廣泛抗藥性結核菌 ；亦有翻譯為廣泛抗藥性結核菌 ))

XDR-TB XDR-TB 的出現無異使結核病防治上更加困難，的出現無異使結核病防治上更加困難，治療上比 治療上比 MDR-TB MDR-TB 更為棘手，一旦被感染，其更為棘手，一旦被感染，其治療成功率有可能會降至 治療成功率有可能會降至 50% 50% 以下以下

廣泛抗藥性結核菌 廣泛抗藥性結核菌 美國疾病管制中心和世界衛生組織 於美國疾病管制中心和世界衛生組織 於 20062006 年初年初發出警告，一種全新、致命性高的廣泛抗藥性結發出警告，一種全新、致命性高的廣泛抗藥性結核菌正在全球擴散。核菌正在全球擴散。 20062006 年年 88 月在加拿大多倫多舉行的「國際世界月在加拿大多倫多舉行的「國際世界愛滋病會議」愛滋病會議」 (International World AIDS Confere(International World AIDS Conference ) nce ) 中，與會人士報告了南非東南部省分夸祖中，與會人士報告了南非東南部省分夸祖魯魯 -- 納塔爾 納塔爾 (KwaZulu-Natal ) (KwaZulu-Natal ) 發生發生 5353 例例 XDR-TXDR-TBB 病人中，有病人中，有 5252 人平均在二十五天內死亡，且人平均在二十五天內死亡，且 4444 病人合併感染愛滋病 病人合併感染愛滋病

Prevalence of drug resistance Prevalence of drug resistance among new TB casesamong new TB cases

10.8

2.9 2.82.1

0.10

2

4

6

8

10

12

MDR

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) survThe World Health Organization (WHO) surveyed 62,746 M. tuberculosis isolates from eyed 62,746 M. tuberculosis isolates from 81 countries between 2002 and 2006 81 countries between 2002 and 2006

multidrug-resistant tuberculosis (MDR-TB) multidrug-resistant tuberculosis (MDR-TB) represented 5.3 percent of all new and prerepresented 5.3 percent of all new and previously treated TB cases worldwide. viously treated TB cases worldwide.

surveyed in 66 countries, resistance to at surveyed in 66 countries, resistance to at least one drug ranged from zero percent in least one drug ranged from zero percent in three European countries to 86 percent in three European countries to 86 percent in Tashkent, Uzbekistan. Tashkent, Uzbekistan.

The highest proportions of MDR-TB were The highest proportions of MDR-TB were from Tashkent, Uzbekistan (60 percent) from Tashkent, Uzbekistan (60 percent) and Baku, Azerbaijan (56 percent).and Baku, Azerbaijan (56 percent).

China, India, and the Russian Federation, are China, India, and the Russian Federation, are estimated to carry the highest number of MDR-estimated to carry the highest number of MDR-TB cases. TB cases.

China and India have approximately 50 percent China and India have approximately 50 percent of the global burden of MDR-TB casesof the global burden of MDR-TB cases

The rates of MDR-TB are increasing in Peru, the The rates of MDR-TB are increasing in Peru, the Republic of Korea, and some parts of the Republic of Korea, and some parts of the Russian Federation (Orel and Tomsk) Russian Federation (Orel and Tomsk)

Of the 4,012 MDR cases that were Of the 4,012 MDR cases that were reported, 301 (7 percent) were XDR-TB. reported, 301 (7 percent) were XDR-TB.

The proportion of XDR-TB among MDR-The proportion of XDR-TB among MDR-TB ranged from zero percent in 11 TB ranged from zero percent in 11 countries to 30 percent in Japan. countries to 30 percent in Japan.

國內的抗藥性監測資料在 國內的抗藥性監測資料在 2006 2006 年底以前年底以前是來自於各醫院的研究資料收集得之，多是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 重抗藥性結核病的比率從 0.2% 0.2% （ （ 1984-11984-1990 990 ）一直逐年往上升至 ）一直逐年往上升至 2% 2% （ （ 1997-201997-2000 00 ）。）。

When organisms are resistant to both isoniWhen organisms are resistant to both isoniazid and rifampin, the course of treatment iazid and rifampin, the course of treatment increases from 6 months to 18-24 months, ncreases from 6 months to 18-24 months, and the cure rate decreases from nearly 1and the cure rate decreases from nearly 100% to less than or equal to 60%. 00% to less than or equal to 60%.

結核初次治療的藥品費用 結核初次治療的藥品費用 (( 複複方方 ))

藥品藥品 單價單價 每日平均劑量每日平均劑量 每日費用每日費用

RFTRFT 11.511.5 55 57.557.5

RFN300RFN300 13.513.5 22 2727

RFN150RFN150 7.57.5 33 22.522.5

EMBEMB 1.91.9 22 3.83.8

>50kg >50kg 初治 初治 [2 (RFT+E)/4 (RFN+E)] [2 (RFT+E)/4 (RFN+E)] 藥品費用： 藥品費用： 73747374 初治 初治 [9 (RFN+E) [9 (RFN+E) 藥品費用： 藥品費用： 83168316

抗藥性結核治療的藥品費用抗藥性結核治療的藥品費用

藥品藥品 健保單價健保單價 每日平均劑量每日平均劑量 每日費用每日費用LevofloxacinLevofloxacin(500)(500)

152152 1.51.5 223223

PASPAS 6.56.5 2020 130130

TBNTBN 6.56.5 33 19.519.5

CSCS 46.946.9 22 93.893.8

SMSM 5252 11 5252

KMKM 15.015.0 11 15.015.0

LEVO+PAS+TBN+CS+SM LEVO+PAS+TBN+CS+SM 每月藥品費用：每月藥品費用： 1554915549治療 治療 21 21 個月 藥品費用：個月 藥品費用： 298449298449

MDR-TBMDR-TB 產生原因產生原因

結核菌發生抗藥性突變的機率結核菌發生抗藥性突變的機率藥名 機率

Rifampin 10-8 Isoniazid, Streptomycin,

Ethambutol, Kanamycin, Para-AminoSalicylate

10-6

Ethionamide, Enviomycin, Cycloserine, Capreomycin, Viomycin, Thiacetazone

10-3

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

分裂突變

抗藥性結核菌如何發生 抗藥性結核菌如何發生 (( 續續 ))

INH 抗藥INH+RMP 抗藥INH+PZA 抗藥

INH+RMP 多重抗藥性結核菌

INH + RMP單一治療

““Fall and Rise” PhenomenonFall and Rise” Phenomenon

1.E+00

1.E+01

1.E+02

1.E+03

1.E+04

1.E+05

1.E+06

1.E+07

1.E+08

0 3 6 9 12 15 18

Weeks of Treatment

Num

ber

of baci

lli p

er

ml o

f sp

utu

m

Sensitive

Resistant

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

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

診斷診斷

Persons at Increased Risk for Persons at Increased Risk for Drug ResistanceDrug Resistance

• History of treatment with TB drugsHistory of treatment with TB drugs• Contacts of persons with drug-resistant TBContacts of persons with drug-resistant TB• Foreign-born persons from high prevalent Foreign-born persons from high prevalent

drug resistant areasdrug resistant areas• Smears or cultures remain positive despite Smears or cultures remain positive despite

2 months of TB treatment2 months of TB treatment• Received inadequate treatment regimens Received inadequate treatment regimens

for >2 weeksfor >2 weeks

Culture and sensitivityCulture and sensitivity

The diagnosis of drug-resistant tuberculosiThe diagnosis of drug-resistant tuberculosis depends upon the collection and processs depends upon the collection and processing of adequate specimens for culture and ing of adequate specimens for culture and sensitivity testing sensitivity testing

Need 2 more monthsNeed 2 more months

MOLECULAR BASIS OF DRUG-RESISTANT MOLECULAR BASIS OF DRUG-RESISTANT

TUBERCULOSISTUBERCULOSIS Isoniazid resistanceIsoniazid resistance — Alterations in either the  — Alterations in either the katG, kasA, or inhA geneskatG, kasA, or inhA genesRifampin resistanceRifampin resistance — Mutations in the rpoB g — Mutations in the rpoB gene ene Pyrazinamide resistancePyrazinamide resistance —mutations in the ge —mutations in the gene pncAne pncAEthambutol resistance--- amino acid replacemenEthambutol resistance--- amino acid replacements at position 306 of an arabinosyltransferase ents at position 306 of an arabinosyltransferase encoded by the embB gene coded by the embB gene StreptomycinStreptomycin —  Resistance is conferred by m —  Resistance is conferred by mutations in the rpsL and rrs genes utations in the rpsL and rrs genes

Rapid testingRapid testing  

A molecular probe capable of detecting resistance mutatiA molecular probe capable of detecting resistance mutations in three TB genes: rpoB (associated with ons in three TB genes: rpoB (associated with rifampinrifampin re resistance), and katG and inhA (mutations associated with sistance), and katG and inhA (mutations associated with isoniazidisoniazid resistance) resistance)

the molecular probe was the molecular probe was ≥99≥99 percent sensitive percent sensitive and s and specific for multidrug TB resistance, compared with standpecific for multidrug TB resistance, compared with standard drug-susceptibility testing; ard drug-susceptibility testing; results were availablresults were available in 1 to 2 days. e in 1 to 2 days. Since the assay does not depend on culture, it yielded reSince the assay does not depend on culture, it yielded results even in specimens that were contaminated or had nsults even in specimens that were contaminated or had no growth. o growth.

TREATMENT OF MDR-TBTREATMENT OF MDR-TB

antituberculosis drugs antituberculosis drugs

EmpiricEmpiric  

Include the standard recommendations Include the standard recommendations plus plus

at least four drugs effective against the at least four drugs effective against the most prevalent drug-resistant strainsmost prevalent drug-resistant strains

This may require that six or more drugs This may require that six or more drugs be given until drug susceptibility results be given until drug susceptibility results are obtained are obtained

Documented MDRDocumented MDR   

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

Treatment with at least four effective drugs Treatment with at least four effective drugs should be continued for 18 to 24 months should be continued for 18 to 24 months

appropriate laboratory facilities to appropriate laboratory facilities to document drug susceptibility and monitor document drug susceptibility and monitor response should be available. response should be available.

These regimens should be administered These regimens should be administered by by direct observationdirect observation

Adjunctive therapiesAdjunctive therapies

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

Criteria for Surgery in MDR-TBCriteria for Surgery in MDR-TB

Localized lesionsLocalized lesions

Reasonable lung function Reasonable lung function

Two or more susceptible Two or more susceptible drugs availabledrugs available

Directly observed therapyDirectly observed therapy   

A decrease in the incidence rate of pulmonary A decrease in the incidence rate of pulmonary TB (from 42 to 19 per 100,000 population) TB (from 42 to 19 per 100,000 population)

A decreases in the rate of primary drug A decreases in the rate of primary drug resistance (from 9.4 to 1.5 per 100,000 resistance (from 9.4 to 1.5 per 100,000 population) population)

A decrease in treatment failures (from 11 to 2 A decrease in treatment failures (from 11 to 2 percent) percent)

A decrease in the rate of MDR-TB (from 10 to A decrease in the rate of MDR-TB (from 10 to 4.3 per 100,000 population) 4.3 per 100,000 population)

治療照護 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。 源不足，應儘速將其轉診至適當醫療團隊。 1. 1. 經驗豐富的結核病醫療團隊，含醫師、護理人員，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。 社會工作人員、營養師等。 2. 2. 能提供高品質藥敏試驗、菌種鑑定的結核菌實驗室。能提供高品質藥敏試驗、菌種鑑定的結核菌實驗室。3. 3. 充足且來源穩定的二線藥物。 充足且來源穩定的二線藥物。 4. 4. 多重抗藥及慢性病人如有住院需求，應安置於具完善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。 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。病的院內感染。

政府作為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（ 國人健康，現在國內已建置更專業的多重抗藥（ MDR MDR ）醫療照護體系可協助這些病人的醫療照）醫療照護體系可協助這些病人的醫療照護護 ; ; 包括「台北市立萬芳醫院團隊」、「行政院包括「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」、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 「中華民國防癆協會團隊」的成立 2006 2006 年起建立 年起建立 MDR-TB MDR-TB 通報系統，推動進階都通報系統，推動進階都治計畫（ 治計畫（ DOTS plus DOTS plus ）以及時監控所有多重抗）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藥性結核病患，避免衍生出更多超級抗藥性結核病患。 病患。

預防預防

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

Drug-susceptible TB and MDR TB are spreaDrug-susceptible TB and MDR TB are spread the same way d the same way

shaking someone’s hand shaking someone’s hand

sharing food or drink sharing food or drink

touching bed linens or toilet seats touching bed linens or toilet seats

sharing toothbrushes sharing toothbrushes

kissing kissing

How can MDR TB be prevented?How can MDR TB be prevented?

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

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

Improvements in hospital infection control Improvements in hospital infection control measuresmeasures

the widespread use of an initial four-drug the widespread use of an initial four-drug chemotherapy regimenchemotherapy regimen

directly observed therapydirectly observed therapy

醫院防護醫院防護isolation of suspected tuberculosis casesisolation of suspected tuberculosis cases

rapid examination of sputum smearsrapid examination of sputum smears

personal protection with particulate personal protection with particulate respiratorsrespirators

germicidal ultraviolet irradiationgermicidal ultraviolet irradiation

HEPA filters, frequent air exchanges, and HEPA filters, frequent air exchanges, and negative pressure ventilation. negative pressure ventilation.

Exposure to multidrug-resistant tExposure to multidrug-resistant tuberculosisuberculosis

Potential regimens that have been suggestPotential regimens that have been suggested include pyrazinamide and ethambutol, ed include pyrazinamide and ethambutol, or pyrazinamide and a quinolone, or pyrazinamide and a quinolone,

12 months in immunocompromised patient12 months in immunocompromised patients, and at least 6 months in patients who ars, and at least 6 months in patients who are immunocompetent e immunocompetent

結語結語外勞引進、國際往來頻繁、愛滋病併發結外勞引進、國際往來頻繁、愛滋病併發結核病例數增加核病例數增加 ,,造成防治的困難造成防治的困難多重抗藥性結核病患者需更多的心力多重抗藥性結核病患者需更多的心力 , , 更多的耐更多的耐心衛教心衛教透過「多重抗藥性結核病醫療照護體系」，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，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 向結核病「十年減半」之路邁開大步