Download MOLECULAR BASIS OF DRUG-RESISTANT TUBERCULOSIS

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 fluoroquinolone 藥物有抗
藥性，且對於 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
10
8
6
4
2.9 2.8
2
0
2.1
0.1
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)
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 MDRTB 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 MDRTB ranged from zero percent in 11
countries to 30 percent in Japan.
國內的抗藥性監測資料在 2006 年底以前是
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 0.2% （ 19841990 ）一直逐年往上升至 2% （ 19972000 ）。
When organisms are resistant to both
isoniazid and rifampin, the course of
treatment increases from 6 months to 1824 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
單價
每日平均劑量
每日費用
RFT
11.5
5
57.5
RFN300
13.5
2
27
RFN150
7.5
3
22.5
EMB
1.9
2
3.8
>50kg 初治 [2 (RFT+E)/4 (RFN+E)] 藥品費用： 7374
初治 [9 (RFN+E) 藥品費用： 8316
抗藥性結核治療的藥品費用
藥品
健保單價
每日平均劑量
每日費用
Levofloxacin 152
(500)
1.5
223
PAS
6.5
20
130
TBN
6.5
3
19.5
CS
46.9
2
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
10-8
10-6
-3
10
Shimao T. Tubercle 1988;68(supp):5-15.
抗藥性結核菌如何發生 (續)
INH+RMP
多重抗藥
性結核菌
分
裂
突
變
INH 抗藥
INH+RMP 抗藥
INH+PZA 抗藥
INH + RMP
單一治療
Number of bacilli per ml of sputum
“Fall and Rise” Phenomenon
1.E+08
Sensitive
Resistant
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
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 — Mutations in the rpoB
gene
Pyrazinamide resistance —mutations in the
gene pncA
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 multidrugresistant 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 年起建立 MDR-TB 通報系統，推動進階都
治計畫（ 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
患。
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