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大家好
-Hello.

我是Nicolas Veziris博士
-My name is Dr. Nicolas Veziris.

我在巴黎为法国国家分枝杆菌研究中心工作
I work for the French national reference center for mycobacteria, in Paris.

今天
Today,

我将探讨结核病的治疗
I will talk to you about the treatment of tuberculosis,

包括药物敏感 
drug-susceptible,

MDR和XDR病例的治疗
and MDR and XDR cases.

我们将从药物敏感结核病的
We will start with the first-line treatment

一线药物治疗开始
of drug-susceptible TB.

如您所知
As you know,

它需要四种药物
it relies on four drugs.

异烟肼最低抑菌浓度（minimum inhibitory concentration; 简称“MIC”）为0.5 ㎎/L
Isoniazid has an MIC of 0.5 milligram per liter.

通常的血清峰值水平是3-5㎎/L
The usual peak serum level is around 3 to 5 milligrams per liter.

异烟肼是需要结核分枝杆菌
Isoniazid is a prodrug which is activated in M. tuberculosis by enzymes,

通过katG基因编码的过氧化氢酶活化的前药
the catalase encoded by the katG gene.

然后
Then,

活化的化合物通过抑制
the activated compound will have the bactericidal activity

参与霉菌酸合成的烯酰-ACP还原酶
by inhibiting the enoyl-ACP reductase

而具有杀菌活性
which is an enzyme involved in mycolic acid synthesis.

利福平MIC为0.5㎎/L
Rifampin has an MIC of 0.5 milligram per liter.

通常的血清峰值水平是10㎎/L
The usual peak serum level is 10 milligrams per liter.

它是唯一一个不抑制细胞壁合成
It is the only first-line drug that does not inhibit cell-wall synthesis

而抑制rpoB基因编码的
but rather inhibits the RNA polymerase

RNA聚合酶的一线药物
which is encoded by the rpoB gene.

吡嗪酰胺的MIC为6-50㎎/L
Pyrazinamide has an MIC of 6 to 50 milligrams per liter,

取决于培养基的pH值
depending on the pH of the medium.

通常的血清峰值水平是30㎎/L
The usual peak serum level is 30 milligrams per liter.

它也是一种由pncA基因编码的
It is also a prodrug activated by the pyrazinamidase

吡嗪酰胺酶活化的前药
encoded by the pncA gene.

然后活化的化合物
And the activated compound

会抑制细胞壁中的脂肪酸合成酶
will then inhibit the cell wall, the fatty acid synthetase.

对吡嗪酰胺天然耐药的
Mycobacterium bovis, which is naturally resistant to pyrazinamide,

牛分枝杆菌的pncA基因H57D具有多态性
harbors a polymorphism in this pncA gene, H57D.

最后
Finally,

乙胺丁醇的MIC通常为1㎎/L
ethambutol usually has an MIC of 1 milligram per liter.

血清峰值浓度为2-3㎎/L
The peak serum level is 2 to 3 milligrams per liter

也抑制细胞壁中阿拉伯半乳糖的合成
and it also inhibits the cell wall, the arabinogalactane synthesis.

结核病治疗的诸多风险之一是
One of the many risks in TB treatment is that,

如果使用单一药物
if you use a single drug,

将产生选择耐药性
you will select for drug resistance.

这是怎么发生的
How does that happen?

如果病人感染了易感菌株
If patient are infected by a susceptible strain,

当您看到他们出现肺部症状时
when you see them, they harbor,

患者体内贮有108-109个杆菌
when they have pulmonary symptoms, 10 to the 8, 10 to the 9 bacilli.

这么大菌量中
In this very large population,

存在很低概率的耐药性突变体
there are some resistant mutants at a very low frequency.

例如
For example,

对于利福平耐药性
for rif,

概率大约是10-8
there are approximately 10 to the -8,

即从统计学角度讲
which means that in the lung cavity of a patient,

患者的肺内空洞会有1个耐利福平的杆菌
there will be statistically 1 bacillus that will be resistant to rif.

在患者服用利福平之前
That is not a problem until the patient receives rifampin because then,

这没问题如果只服用利福平
the rifampin, if given alone,

利福平会杀死所有敏感性杆菌
will start killing all the susceptible bugs,

就是蓝色的部分
the blue ones,

但耐药性杆菌将存活下来
but the resistant one will remain.

这个过程需要2到3个月
So that will take 2 to 3 months and then,

然后 这个耐药性杆菌开始分裂
this resistant one will start dividing.

2〜3个月后
And 2 to 3 months later,

即始治后的4〜6个月
which is 4 to 6 months after the start of treatment,

又会有108个杆菌
there will be again 10 to the 8 bacilli

但它们都来自这个标记为红色的细胞
but that will come from just one single cell, the red one,

都对利福平有耐药性
and they will all be resistant to rif,

因为它们都来源于这个耐药性杆菌
because they all come from this resistant bug.

这是获得性耐药
It is acquired resistance

又称作二代耐药
or secondary resistance.

当然
Of course,

这些患者患有肺结核
these patients have pulmonary TB,

有传染性
are contagious,

在他们周围可能会出现
and could create secondary cases around them

原发性耐药的二代病例
that will have primary resistance.

他们患有原发性耐药结核病
They have primary-resistant TB

既往没有服用抗结核药物
without having received an anti-TB drug in their lives.

综合结核病治疗的所有理念来看
If we synthesize all the concepts of the TB treatment,

由于细菌数量之巨大
we have a large bacillary population

加之对耐药突变体的选择
for which there is a risk of failure

我们始终面临失败的风险
due to the selection of drug-resistant mutants.

为了防止这种情况
In order to prevent that,

要联合使用多种抗生素
we will use a combination of antibiotics

一线药物中主要是利福平
and that is mainly the role of rif,

异烟肼和乙胺丁醇
isoniazid and also ethambutol in the first-line treatment.

然后会得到第二个细菌种群
Then, we will have a second bacillary population

您可以在这里看到
that you can see here,

这是一个小群体
this one, which is a small population,

105个杆菌
10 to the 5 bacilli.

我们通常说他们是酪状碎屑
We usually say that they are in the caseum.

它们是非繁殖的细菌
They are the non-multiplying bugs,

也被称为休眠菌
also called the persisters.

如果长时间不治疗
If you do not treat for a long duration,

并且不使用灭菌药物
and if you do not use a sterilizing drug,

那么存在易感细菌复发的风险
there is a risk of relapse with susceptible bugs.

因此
So,

有两种风险 第一个是治疗失败
two risks: failure,

预防措施是进行抗生素联合使用
we use a combination of antibiotics,

第二个是易感细菌复发
and relapse with susceptible bugs,

预防措施是进行长期治疗并使用灭菌药物
we use a long treatment and sterilizing drugs.

我个人对抗结核病治疗的历史做以下总结
If I summarize all that in the history of the anti-TB treatments.

从20世纪40年代开始单独使用链霉素
We start in the 1940s with streptomycin alone and then,

然后出现了选择耐药性
we had selection of drug resistance.

加入对氨基水杨酸的联合治疗方案
We added PAS and it was demonstrated

可以预防耐药性已被证明
that the combination prevents drug resistance.

然后加入异烟肼
Then isoniazid was added

这是第一次真正的结核病治疗
and it was the first real TB treatment.

然后加入利福平
Then,

将结核病治疗时间
rifampin was added and reduced the duration of TB treatment

从18个月缩短至9个月
from 18 to 9 months.

疗程缩短了一半
It divided the duration by 2.

然后
Then,

吡嗪酰胺把时间缩短到6个月
pyrazinamide reduced it to 6 months.

您看到加粗的这两种药物
What you see is that the two drugs in bold,

利福平和吡嗪酰胺
rifampin and pyrazinamide,

是可消灭休眠菌的杀菌药物
are the sterilizing drugs

它们大大地缩短了疗程
which are active against the persisters,

如果想要短期治疗
the dormant bacilli.

您需要多种灭菌药物
They most reduced the duration of treatment.

现在让我们来看看耐药性
If you want to have a short treatment, you need sterilizing drugs.

在了解如何治疗耐药病例之前
Let us move now to drug resistance.

最好的办法是防止耐药性产生
Before trying to understand how to treat drug-resistant cases,

因为耐药性是医疗产物
the best thing to do is to prevent resistance

因此 如果您想预防一线药物耐药性
because resistance is a medical creation.

可以阅读这篇论文
So if you want to prevent first-line resistance, you can read this paper,

其中总结了导致耐药性的常见错误
which summarizes the most usual errors which lead to drug resistance.

第一个是仅含一种药物的失败的治疗方案
The first one is to add a single drug to a failing regimen.

您绝不能犯这个错误
You must never do this mistake.

因为通常患者对所有给定的药物都有耐药性
It means that, usually, the patient is resistant to all the given drugs

如果只给予一种药物
and if you add just one,

就会增加产生耐药性的风险
there is a risk of increased resistance.

第二个错误 没有进行耐药性实验室检测
The second error: you do not detect drug resistance in the lab.

如果您对治疗结果没有信心
That means that if you are not confident with your results,

可以使用更多的药物
use more drugs.

第三个错误
Third error,

选择错误的治疗方案
the wrong choice of treatment regimen.

如果您不是专家
That means that if you are not an expert,

就向他人寻求帮助
ask someone else.

第四个错误
Fourth error,

没有考虑患者的依从性
not taking into account the compliance problem.

必须要进行治疗管理
That means that you have to supervise the treatment.

最后一个错误
And, last error,

您认为您正在治疗潜伏性结核
you thought you were treating latent TB

但实际上是结核病
but actually it was a TB disease,

所以您需要一个良好的临床评估
so you need a good clinical evaluation.

如果您这样做
If you do all that,

您可以预防获得性耐药发生
you prevent secondary resistance.

当然
Of course,

还需要预防原发性耐药
you also need to prevent primary resistance

这意味着您必须防止医院内外传播
which means that you must prevent in- and out-of-hospital transmission.

所以我们需要对新发结核病患者
So we need respiratory isolation

进行呼吸道隔离治疗
for new TB cases.

现在简短地谈谈MDR和XDR患者的治疗
Now, a few words on the management of MDR and XDR cases.

耐多药者至少对异烟肼和利福平耐药
The multidrug-resistant ones are resistant to at least isoniazid and rifampin.

XDR在MDR治疗药物之外
And the extensively-drug-resistant ones, XDR, are also resistant,

也对氟喹诺酮类药物
on top of the MDR,

和二线注射类药物具有耐药性
to fluoroquinolones and second-line injectables.

世卫组织的治疗建议是吡嗪酰胺
The WHO's advice for a treatment is a combination of pyrazinamide,

氟喹诺酮和注射剂联合使用
a fluoroquinolone, and an injectable.

我们必须选择含5种药物的
We have to complete it with the group-C drugs here

C组方案进行治疗
to reach 5.

如果您在C组方案的5种药物不全
If you do not have enough in the group C,

可以选择含有5种药物的D组方案
we use the group-D drugs to reach 5.

整个疗程为20个月
The duration of treatment is 8 months with an injectable

其中注射剂注射时间为8个月
and 20 months for the total duration.

当然
Of course,

治疗疗程很长
it is a very long treatment,

毒性很大
very toxic,

存在疗程缩短和疗效改善的空间
and there is some room for shorter and better treatments.

现有的短期治疗方案
Now, we have the short regimen

只持续9到12个月
which only lasts 9 to 12 months.

如果病人患有单纯的MDR
If the patient has a simple MDR case,

我的意思是没有任何额外的耐药性
I mean without any additional resistance,

我们可以使用这个短期方案
we can use this short regimen

只需要9至12个月
which only lasts 9 to 12 months.

最后
Finally,

我在这里介绍的
what I present here

是我们在法国治疗这些耐多药病例的方法
is what we do in France for the management of these MDR cases.

如果疑似患有MDR
If we have MDR suspicion,

我们将检测rpoB
we will test for rpoB,

这是利福平耐药性的基因型检测
which is the genotypic test for rifampin.

如果没有突变
If there is no mutation,

这就是一个敏感性病例
it is a susceptible case,

使用标准的一线药物治疗方案
we go to a standard first-line regimen.

如果有突变
If there are mutations,

就是MDR病例
it is an MDR case

因为90％的耐利福平病例
because 90% of rifampin-resistant cases

对INH也有耐药性
are also resistant to INH so they are MDR.

所以是MDR
Then,

那么问题是 是XDR吗
the question is: is it XDR?

我们将对这些基因
We will do a genotypic test

进行氟喹诺酮类和氨基糖苷类耐药性的
for fluoroquinolones and aminoglycosines

基因型检测
with these genes here.

如果没有相关突变
If there is no mutation,

那就不是XDR
it is not XDR.

如果有
If there is a mutation,

就是XDR
it is XDR.

然后
And then,

我们完成表型和基因型的药敏试验
we do complete phenotypic and genotypic susceptibility testing.

因为试验需要持续数周或数天
In the meantime, of course, that lasts weeks or days,

同时您又要治疗患者
you need to treat the patient and for that,

为此 我们将在结核病专家组的帮助下
we will go from a probabilistic to a final treatment

从概率性治疗转向最终治疗专家
with the help of a TB consilium which is a mix of experts,

肺科医生 外科医生 微生物学家
pulmonary, ID physicians, microbiologists,

儿科医生等组成的专家组定期会诊
pediatricians, who meet on a regular basis

为耐多药结核病的治疗提供建议
to give treatment advice for MDR-TB.

感谢您的关注
Thank you for your attention

我希望您喜欢这门课程
and I hope you enjoyed the course.