Tuberculosis, Multidrug-Resistant

Hub will focus on supporting global use of new treatments that effectively treated drug-resistant TB in 98% of Filipino participants MANILA, Australia, March 24, 2024 /PRNewswire/ -- TB Alliance's new Peer-to-Peer Learning for Innovative Cures (PeerLINC) Knowledge Hub launched today in Manila, with funding from the Australian Government through the Partnerships for a Healthy Region initiative. PeerLINC, operating in partnership between TB Alliance and the Tropical Disease Foundation, Inc. (TDF), and in close collaboration with the Department of Health, Philippines, will help countries implement best practices in the treatment of drug-resistant tuberculosis (DR-TB) to help speed the worldwide programmatic implementation of innovative, more effective treatments for the disease, starting with the World Health Organization (WHO)-recommended six-month, all-oral BPaL/M regimens, composed of the antibiotics bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without moxifloxacin (M). PeerLINC will provide practical training and technical assistance to countries to support this objective, via experts from the Philippines and the Department of Health, including Lung Center of the Philippines and the National TB Reference Laboratory (NTRL). The Philippines has successfully and rapidly deployed new treatments through participation in TB Alliance's Leveraging Innovation for Faster TB Treatment (LIFT-TB) initiative. "TB Alliance works to minimize the gap between research and access, ensuring people anywhere in the world can have access to new treatments as soon as possible, maximizing the number of lives and livelihoods saved," said Sandeep Juneja, Senior Vice President of Market Access at TB Alliance. "PeerLINC will make training and knowledge on new treatments available swiftly and efficiently to ensure their rapid adoption and roll out. We are proud to launch PeerLINC in the Philippines with DOH and TDF and establish the first Knowledge Hub on the introduction of new DR-TB regimens, and we are grateful for the support of Australia in helping make this a reality." "It is important for the Philippines to share our knowledge and experience in using the BPaL/M regimens," said Dr. Mamel Quelapio, TDF Board of Trustees member and Programmatic Implementation Lead at PeerLINC. "DOH's leadership through the Disease Prevention and Control Bureau in partnership with TDF and TB Alliance in the LIFT-TB initiative has led to improved outcomes and treatment experiences for people. We are eager to help new treatments reach far and wide." The BPaL/M regimens combine the antibiotics bedaquiline (B), pretomanid (Pa), linezolid (L) with or without moxifloxacin (M). The BPaL regimen was first clinically studied by TB Alliance and the BPaL/M regimens are now recommended by WHO as the standard of care treatment for the vast majority of people with DR-TB. Prior to the initial study of the BPaL regimen, global treatment success rates for DR-TB were less than 50% and treatment options were limited, expensive, toxic, and lengthy – requiring individuals to take more than 14,000 pills over the course of treatment, which could last from nine months to two years or longer. Data to date reveals treatment success rates of 90% or higher with BPaL/M, in addition to reduced treatment duration and approximately 95% lower pill burden. TB Alliance's LIFT-TB initiative, which is co-funded by GDEF/KOICA, the South Korean Development agency, helped accelerate implementation of the regimen in the Philippines, Indonesia, Kyrgyzstan, Myanmar, Ukraine, Uzbekistan, and Vietnam. Interim data from these countries shows an average success rate of 92.5%, with the Philippines program reporting a 98% cure rate. Several key high-burden countries around the world, including the early adopting LIFT-TB countries, are now rolling out BPaL/M in their national programs. However, some countries have moved more slowly. Leveraging a group of experts and the experience garnered from those who have rapidly and successfully implemented the BPaL/M regimens, PeerLINC will focus on assisting other countries in doing the same. "In the Philippines, the new regimen exceeded all expectations," said Dr. Irene Flores, Medical Officer of the Jose B. Lingad Memorial Medical Center and Head of PeerLINC. "Every country with drug-resistant TB can benefit from widespread implementation of the best available TB treatment. With BPaL/M, we see a path toward transforming DR-TB treatment for everybody, anywhere in the world." "I tried everything before I was given BPaL as part of the research program," said Joegene Mangilaya, a participant from the Philippines who was treated with the BPaL regimen. "I was losing hope that I'd be cured, but shortly after I started on this new regimen, my body felt stronger and I had a new hope for my health and future. It is important to speed the availability of life-saving new therapies everywhere they are needed – the work of PeerLINC will help save lives." PeerLINC will offer support such as advice, assistance, training materials, tools, guides, and other materials to TB programs, clinicians, lab specialists, and community organizations, all delivered through peer-to-peer learning models. Trainings will be provided in-person in the Philippines or in the beneficiary country or remotely through virtual meetings. The expert team from PeerLINC will continue to guide countries after trainings, as they work to implement the regimens. A delegation from Peru is scheduled to visit PeerLINC in April 2024 and will be the first to receive training on BPaL/M from PeerLINC and its partners in the DOH. "We are excited to visit the PeerLINC Knowledge Hub and work with experts from the early implementers of the short, highly effective treatments for drug-resistant tuberculosis," said Dr. Valentina Alarcón, Executive Director at the Directorate of Tuberculosis Prevention and Control - MINSA Peru. "The communities affected by resistant tuberculosis in Peru deserve the best possible experiences and treatment schemes and we are taking measures to access the BPaL and BPaL/M regimens and make them available to people throughout Peru in a timely and rapid manner. Our experience with PeerLINC will help us achieve those goals." About TB TB is a difficult infection to cure, requiring patients to take a combination of medicines for at least four to six months. Even after symptoms disappear, medicines still need to be taken so that the disease can be fully eradicated. The scope and intensity of TB globally is in large part fueled by antiquated and inadequate TB drugs. Novel drug regimens are urgently needed to bring the TB pandemic under control. About BPaL The BPaL regimen—which combines the antibiotics bedaquiline (B), pretomanid (Pa), and linezolid (L)—was first designed and clinically studied by TB Alliance. Pretomanid, as part of the BPaL regimen, received its first regulatory approval in August 2019 for use against highly drug-resistant strains of TB. Prior to the initial BPaL clinical trial, less than one-third of drug-resistant TB patients around the world were being successfully treated. Treatment options were limited, expensive, toxic, and lengthy – requiring patients to take more than 20 pills per day for 9-20 months. About TB Alliance TB Alliance is a not-for-profit organization dedicated to finding faster-acting and affordable drug regimens to fight TB. Through innovative science and with partners around the globe, we aim to ensure equitable access to faster, better TB cures that will advance global health and prosperity. TB Alliance operates with support from Australia's Department of Foreign Affairs and Trade, Bill & Melinda Gates Foundation, Foreign, Commonwealth and Development Office (United Kingdom), Cystic Fibrosis Foundation, Germany's Federal Ministry of Education and Research through KfW, Global Disease Eradication Fund (South Korea), Global Health Innovative Technology Fund, Irish Aid, Korea International Cooperation Agency, National Institute of Allergy and Infectious Diseases, South Korea's Ministry of Foreign Affairs, Unitaid, and the United States Agency for International Development. For more information, please visit: . Contact: Jessica Wiggs, +1 (646) 616-8613 / [email protected] SOURCE TB Alliance

2024年3月24日是第29个“世界防治结核病日”，今年的主题是“你我共同努力，终结结核流行”。根据 2023 年全球结核病报告，2022 年全球结核病病例数约为 1060 万例，其中，耐多药 / 利福平耐药结核病（MDR/RR-TB）为 41 万例。中国不但是世界上结核病负担最高的22个国家之一，也是世界上耐多药/广泛耐药结核病负担最高的27个国家之一。耐药结核病目前我们所说的耐药结核病，包括：利福平耐药（RR-TB）：对利福平耐药，不论对其他抗结核药物是否耐药；耐多药结核病（MDR-TB）：对包括异烟肼和利福平在内的至少两种以上一线抗结核药物耐药；准广泛耐药结核病（Pre-XDR-TB）：符合MDR-TB/RR-TB定义，同时对任意一种氟喹诺酮类药物耐药；广泛耐药结核病（XDR-TB）：符合MDR-TB/RR-TB定义，同时对任意一种氟喹诺酮类药物耐药和贝达喹啉、利奈唑胺至少一种耐药。临床工作中，我们碰到最多的还是耐多药结核病。耐多药肺结核的危害与普通肺结核相比，耐多药肺结核拥有更严重的危害：1、病情重，难治愈，最严重的几乎无药可治；2、治疗时间长达 1.5～2 年，是普通肺结核的3～4倍；3、治疗费用可达普通肺结核的百倍；4、病程长，不治疗的话传播给他人的机会更多，且被传染者一旦发病就是耐药肺结核。   耐多药结核病的治疗药物有哪些？耐多药结核病的治疗方案有哪些？目前世界卫生组织（WHO）推荐的耐多药结核治疗方案包括长疗程治疗方案及短疗程治疗方案。长疗程治疗方案通常需要6～8个月的强化期，12个月的巩固期或者痰菌阴转后15～17个月的治疗，总疗程为18～20个月甚至更长。1、6个月BPaLM方案（氟喹诺酮类敏感）药物：贝达喹啉、普瑞玛尼（Pretomanid）、利奈唑胺(600mg/d)和莫西沙星注意：不适合既往暴露于贝达喹啉、普瑞玛尼尼或利奈唑胺超过1个月者，除非排除耐药性。2、6-9个月BPaL方案（氟喹诺酮类耐药）药物：贝达喹啉、普瑞玛尼（Pretomanid）、利奈唑胺(600mg/d)；注意：如果治疗反应较慢，但仍然良好，可使用9个月的治疗方案；不适合既往暴露于贝达喹啉、普瑞玛尼或利奈唑胺超过1个月者，除非排除耐药性；lBPaLM和BPaL方案仅限于以下患者：①年龄大于等于15岁；②无严重肺外疾病（粟粒状结核病，结核性脑膜炎，骨关节结核或心包结核）；③非妊娠期或哺乳期；   ④既往未使用贝达喹啉、普瑞玛尼或利奈唑胺超过1个月；3、9-11个月全口服方案适用人群：①证实对氟喹诺酮类药物敏感；②非广泛性肺疾病（胸片未见双侧空洞或广泛实质病变）或非严重肺外疾病（粟粒状结核病，结核性脑膜炎，骨关节结核或心包结核）；③适用于15岁以下儿童，排除其他肺外部位（不包括周围淋巴结或孤立的纵隔肿块，无压迫）④对其他一线或二线药物无额外耐药性（除了异烟肼；如果存在katG突变，则大剂量异烟肼无获益）或既往使用任何所包含药物的治疗方案超过一个月。治疗方案：初始阶段：4-6个月，贝达喹啉(6个月)、莫西沙星或左氧氟沙星、氯法齐明、乙硫异烟胺(或利奈唑胺2个月)、异烟肼(大剂量)、乙胺丁醇、吡嗪酰胺，然后持续阶段：5个月莫西沙星或左氧氟沙星、氯法齐明、乙胺丁醇、吡嗪酰胺；注意：乙硫异烟胺（或丙硫异烟胺）妊娠期禁用。4、全口服更长疗程方案对于那些疾病形式更广泛的患者，或者由于不符合标准、治疗失败或出现药物不耐受问题而不能使用较短疗程的患者，应考虑使用较长疗程的个体化治疗方案。方案基于WHO药物分类中优先选择药物，并应以药敏试验(DST)和对患者进行仔细的治疗前评估为依据。5、手术治疗（1）急诊手术适应证：   ①合并大咯血且危及生命；②出现自发性张力性气胸且危及生命。（2）择期手术适应证:①尽管有足够的抗结核化疗，但影像学显示为不可逆转的肺结核进展；②其他治疗方法无效且反复咯血；③经过2~8个月的有效抗结核化疗后，通过细菌学检查和痰结核菌培养证实MTB持续阳性的局限性空洞型病灶；④抗结核化疗失败；⑤治疗中出现以下情况：自发性气胸和脓气胸；脓胸伴或不伴支气管胸膜瘘；肺曲霉病；毁损肺；气管和大支气管结核性狭窄；慢性支气管扩张。（3）手术禁忌症：①有明显结核病中毒症状：如低烧、盗汗、乏力、体重逐渐减轻等，全身情况不许可者；②两肺广泛的空洞病变者；③肺功能减退者：FEV1<1.5 L，全肺切除术者FEV1<2.0 L；④未经过有效MDR/RR-PTB方案治疗者；⑤活动性支气管结核者；⑥合并有支气管哮喘及重度肺气肿等呼吸功能不全者；⑦合并有其他重要脏器严重病变而未得到有效控制者，如：严重肝功能损伤、肝硬化、严重肾功能不全、严重心血管疾病、甲状腺功能亢进症、糖尿病等；⑧合并进展期或者已转移的肿瘤者；⑨合并其他急性疾病者。耐多药肺结核的治愈率低、治疗周期长、治疗费用高、药物不良反应严重，对于患者来说，家庭、心理都承受着巨大的压力，因此，正确管理耐多药肺结核患者极其必要，可以通过医生与患者的共同努力，一起战胜耐多药结核病！撰文 | Anna.An编辑 | Swagpp● 惊讶！80岁老医生走路都不稳，却还被返聘拿高工资，合理吗？一半医生都想要被返聘，老医生的治疗死亡率比年轻医生高12%……● “辟谷”至少3天才有效？Nature子刊：7天不吃饭只喝水的人体试验显示，禁食3天后才有益健康！● 重磅！主任警告：严重不建议医护离职转行！你的光环是医院给的！想创业转行的医生已跌至43%，兼职只能是兼职，请不要入戏太深！版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。点击下方「阅读原文」 立刻下载梅斯医学APP！

众所周知，抗生素是指治疗细菌感染的药物，其通过杀死细菌或遏制细菌繁殖来彻底清除它们。研究发现人体在经历抗生素暴露后会发生胃肠道（GI）微生物组变化，例如促炎性群落的富集、包括腹泻在内的GI不适等等。但目前对于GI微生物群如何恢复到治疗前状态的研究还较少。近期，来自麻省大学医学院、纪念斯隆-凯特琳癌症中心等的研究人员在Science Translational Medicine上发表了题为“Commensal antimicrobial resistance mediates microbiome resilience to antibiotic disruption”的研究成果。通过检查临床队列，Bhattarai等人纵向研究了耐多药（MDR）结核病（TB）抗生素治疗对肠道微生物群的长期影响。虽然治疗严重破坏了患者肠道菌群的稳定性，但在6至24个月的治疗完成时，非致病性细菌开始重新繁殖，并逐渐恢复如初。研究证实药物作为一种选择性压力，影响着微生物群的进化动态。DOI：10.1126/scitranslmed.adi9711MDR TB治疗会严重破坏粪便微生物组的分类和功能组成研究招募了24名MDR TB患者（13名男性和11名女性），其中大多数人在之前的标准治疗中失败。图1A为患者粪便和血液样品的收集时间表，包括第0天（治疗前）、2周、1个月、2个月、6个月和治疗完成时的样品。研究人员通过在相同的时间点记录 BACTEC 培养阳性时间（TTP），来测量痰液中的TB细菌载量。图1B中显示，随着治疗，抗生素明显减少了痰中结核分枝杆菌（Mtb）的细菌量（P < 0.001）。为了研究伴随MDR TB治疗的GI微生物组变化，研究人员通过对患者粪便进行宏基因组测序，确定了其中的微生物组成和基因含量。结果显示，基线或治疗完成时采集的样本与早期样本（2周、2个月和6个月）在物种和功能途径丰度方面存在显著的统计学差异。其中，微生物组多样性从开始治疗后的两周内快速降低，代表着广泛的细菌耗竭，除此之外，致病菌开始扩增，包括Klebsiella pneumoniae, Klebsiella varicola, Escherichia coli等。图1. MDR TB治疗清除了患者肺部的结核杆菌，并导致微生物群的暂时性紊乱，而这种紊乱会在停止治疗后恢复而令人惊讶的是，如图1E中显示，GI微生物组的总体多样性在治疗过程后期反弹至治疗前水平，大多数被抗生素耗尽的物种也在6个月时恢复至治疗前基线，并且在治疗停止时几乎完全恢复代谢活力（图1F），这表明微生物组具有令人惊叹的恢复力。结核病的炎症消退是病原体杀灭和微生物组扰动的综合效应研究人员通过建立计算模型，推导出病原体和微生物组依赖性变化的主导效应——抗生素驱动的病原体减少，其伴随着常见炎症（IFN-α、IFN-γ、IL- 6等）、信号转导和转录激活子STAT3、信号传导通路TNF-α等的表达显著降低。其中，高丰度的产短链脂肪酸的梭菌属IV和XIVa（D. longicatena, Erysipelatoclostridium ramosum等）与外周炎症途径减少相关；而高丰度的耐氧菌如Enterobacteriaceae，则与外周炎症、免疫信号传导、TB相关基因的富集相关联。 图2. 结核病状态与微生物组扰动、病原体杀灭情况的关联性总之，研究分析表明，梭菌属IV和XIVa的丰度越高，与菌群失调相关的耐氧菌如Enterobacteriaceae的水平越低，结核病相关外周炎症的缓解速度就越快。并且与基线（第0天）相比，MDR TB治疗显著富集了微生物组中的抗生素抗性基因（ARGs）。MDR TB治疗期间微生物组恢复的特点是——共生菌的进化研究人员观察到MDR TB治疗后，患者的微生物组会恢复如初，其主要特征是梭菌目（Clostridiales）的恢复。通过分析患者治疗前后的Klebsiella 和E. coli宏基因组，他们发现治疗前和治疗中的Klebsiella 和E. coli与基线相比存在显著的突变（SNP分析），包括多种膜转运蛋白，如lsrA、mntB等。对治疗前存在但是治疗后迅速降低再恢复的弹性细菌，如Clostridia，显示出显著更高的SNP多样性。研究数据有力地表明，对抗TB药物并引发细菌耐药性突变的关键是细菌恢复力。为了确定宏基因组种内多样性分析（MIDAS）发现的药物靶点突变是否普遍存在于微生物组中，研究人员使用了对单核苷酸变异具有更高灵敏度的inStrain，检测到诸如 ATP 合成酶ε链和 glpK 中的许多变异。这些数据提供了强有力的证据，即所使用抗生素的耐药性突变在患者中会发生广泛的进化，这也表明，抗生素耐药共生菌和病原菌的选择可能会影响长期抗生素治疗过程中微生物组的动态变化，而且最终，微生物组的恢复力可能是由于共生菌竞争而导致的，即耐药性病原菌被更适合和更耐药的共生菌群代替。图3. 微生物群恢复力与共生菌出现抗菌药耐药性相对应治疗 TB 感染是人类持续接触抗生素时间最长的治疗之一。研究结果证实，无论是在疾病还是健康状态下，微生物组的组成都会对全身炎症的动态基调产生重大影响，诸如Clostridia的高丰度会诱导抗炎状态，而Enterobacteriaceae的大量繁殖则会引发炎症加重等。因此，微生物菌群的相对稳定，对于人体健康而言是至关重要的，并且，研究人员发现在持续的抗生素压力下，共生菌对长期微生物组动态平衡具有巨大的贡献，这意味着共生菌具有潜在超越病原菌的内在能力，如果其能够在抗生素的选择性压力下进化，那么它们就有能力超越病原菌及其编码的 ARGs。参考文献：1. Shakti K. Bhattarai et al. ,Commensal antimicrobial resistance mediates microbiome resilience to antibiotic disruption. Sci. Transl. Med.16,eadi9711(2024)撰文｜lcc编辑 |  lcc本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！精彩推荐：1、竟是真的！研究表明，吃辣不仅可以抗癌、长寿，还能抑制幽门螺杆菌生长2、想聪明多运动！斯坦福大学Nature发文：运动对大脑有保护作用，“换血”可升级抗炎能力，对神经发生和记忆大有裨益3、新技术！分娩期间母胎之间存在信号交流？Science子刊：人类胎盘单细胞图谱提示母胎信号转化变化，可有助于预测早产4、维C抗癌新发现！Nature子刊 ：中国科学家揭示大剂量维C促进肿瘤血管正常化，激活免疫系统5、Nature子刊最新发文，应用人脑类器官揭示衰老与帕金森病之间的关键联系Shakti K. Bhattarai et al