Drug‐resistant tuberculosis: An update on disease burden,diagnosis and treatment

The emergence of antimicrobial resistance against Mycobacterium tuberculosis , the leading cause of mortality due to a single microbial pathogen worldwide, represents a growing threat to public health and economic growth. The global burden of multidrug‐resistant tuberculosis (MDR‐TB) has recently increased by an annual rate of more than 20%. According to the World Health Organization approximately only half of all patients treated for MDR‐TB achieved a successful outcome. For many years, patients with drug‐resistant tuberculosis (TB) have received standardized treatment regimens, thereby accelerating the development of MDR‐TB through drug‐specific resistance amplification. Comprehensive drug susceptibility testing (phenotypic and/or genotypic) is necessary to inform physicians about the best drugs to treat individual patients with tailor‐made treatment regimens. Phenotypic drug resistance can now often, but with variable sensitivity, be predicted by molecular drug susceptibility testing based on whole genome sequencing, which in the future could become an affordable method for the guidance of treatment decisions, especially in high‐burden/resource‐limited settings. More recently, MDR‐TB treatment outcomes have dramatically improved with the use of bedaquiline‐based regimens. Ongoing clinical trials with novel and repurposed drugs will potentially further improve cure‐rates, and may substantially decrease the duration of MDR‐TB treatment necessary to achieve relapse‐free cure.     

Current therapies for the treatment of multidrug-resistant tuberculosis in children in India

Introduction: Multidrug-resistant tuberculosis (MDR-TB) is a serious life threatening condition affecting children as well as adults worldwide. Timely diagnosis and effective treatment, both of which are complex in children, are the prerogatives for a favorable outcome.

Areas covered: This review covers epidemiology, treatment regimen and duration, newer drugs and adverse events in children with MDR-TB. Special note has been made of epidemiology and principles of treatment followed in Indian children.

Expert opinion: High index of suspicion is essential for diagnosing childhood MDR-TB. If there is high probability, a child can be diagnosed as presumptive MDR-TB and started on empiric treatment in consultation with experts. However, every effort should be made to confirm the diagnosis. Backbone of an effective MDR-TB regimen consists of four 2nd line anti-TB drugs plus pyrazinamide; duration being 18–24 months. The newer drugs delamanid and bedaquiline can be used in younger children if no other alternatives are available after consultation with experts. Wider availability of these drugs should be ensured for benefit to all concerned. More research is required for development of new and repurposed drugs to combat MDR-TB. Children need to be included in clinical trials for such life-saving drugs, so that nobody is denied the benefits.     

不同起始剂量利奈唑胺联合贝达喹啉治疗耐多药结核病的疗效及安全性观察

目的 评价不同起始剂量利奈唑胺联合贝达喹啉治疗耐多药结核病（multidrug-resistant tuberculosis, MDR-TB）的疗效及安全性。方法 回顾性分析2018年3月—2021年4月成都市公共卫生临床医疗中心门诊及住院部予贝达喹啉联合利奈唑胺抗痨并已完成疗程的MDR-TB患者51例,根据利奈唑胺起始剂量不同分为2组,其中1 200 mg/d组23例,600 mg/d组28例,比较两组临床资料,统计并分析两组患者的流行病学特征、治疗、不良事件及预后。结果 在联合贝达喹啉治疗耐多药结核的患者中,利奈唑胺起始剂量1 200 mg/d与起始剂量600 mg/d组患者的治疗成功率相当,分别为82.6%（19/23）和96.4%（27/28）,差异无统计学意义（P>0.05）。两组患者不良事件发生率均为100%,不同起始剂量患者QTc间期延长、骨髓抑制、周围神经炎、视神经炎的发生率差异无统计学意义（P>0.05）,但利奈唑胺起始剂量1 200 mg/d患者中因不良事件需调整利奈唑胺治疗的比例为73.9%（17/23）,高于起始剂量600 mg/d的46.4%（13/28）（P=0.047）。其中,利奈唑胺起始剂量1 200 mg/d组中因不良事件中断使用利奈唑胺的比例为65.2%（15/23）,高于利奈唑胺起始剂量600 mg/d组中的25.0%（7/28）（P=0.004）。结论 利奈唑胺起始剂量600 mg/d与起始剂量 1 200 mg/d联合贝达喹啉治疗耐多药结核病的疗效相当,但起始剂量600 mg/d耐受性更好。建议在使用利奈唑胺联合贝达喹啉治疗耐多药结核病时,剂量可优先选择600 mg/d。     

超高效液相色谱-串联质谱法测定大鼠血浆及组织中贝达喹啉浓度及其药动学考察

目的:建立超高效液相色谱-串联质谱(UPLC-MS/MS)法测定SD大鼠血液及组织中贝达喹啉的浓度,研究其在大鼠体内的药动学及组织分布.方法:采用UPLC-MS/MS联用技术,测定大鼠血液及组织中贝达喹啉的药物浓度,并利用DAS软件及非房室模型统计矩方法计算药动学参数.结果:贝达喹啉线性范围为0.1～500 ng·mL...     

贝达喹啉治疗结核病的研究进展

结核病依然是全球重大公共卫生问题。耐多药和广泛耐药结核病的出现与蔓延是结核病控制面临的一大挑战。目前WHO推荐用于治疗耐药结核病的化疗药物存在种类少、疗效欠佳、不良反应多、疗程长等不足,因此,开发新型作用机制的抗结核药势在必行。贝达喹啉,靶点为分枝杆菌ATP合成酶,具有作用机制新颖、耐药率、半衰期长、特异性高、抗菌活性强、缩短耐多药结核病疗程,安全性良好等优点,但是同时也存在难以解释的高致死率等缺陷。本文主要从抗菌及耐药机制、药代动力学、抗菌活性、临床试验、安全性方面综述贝达喹啉治疗结核病的研究进展。     

atpE Mutation in Mycobacterium tuberculosis Not Always Predictive of Bedaquiline Treatment Failure

We report the emergence of an atpE mutation in a clinical Mycobacterium tuberculosis strain. Genotypic and phenotypic bedaquiline susceptibility testing displayed variable results over time and ultimately were not predictive of treatment outcome. This observation highlights the limits of current genotypic and phenotypic methods for detection of bedaquiline resistance.     

Dose-ranging activity of the newly registered antituberculosis drug bedaquiline (TMC207)

Evaluation of: Diacon AH, Dawson R, Von Groote-Bidlingmaier F et al. Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis. Antimicrob. Agents Chemother. 57(5), 2199–2203 (2013).

During the past decade considerable efforts have been made to develop and register new anti-TB drugs, making them available for patients in need. Bedaquiline (BDQ), approved by the US FDA in December 2012, is the first new anti-TB drug available for treatment of this disease since rifampicin became available in 1967. BDQ has the peculiarity of being a drug with a very long half-life and potent antimicrobial activity that becomes noticeable only after the first 4 days of treatment. Consequently, Diacon et al. have conducted a 14-day dose-ranging study aimed at assessing the early bactericidal activity of BDQ in TB patients who received loading doses of the drug during the first 2 days of treatment. The loading doses partially overcame the delayed antimicrobial activity only in patients treated daily with as much as 400 mg.     

Recent controversies about MDR and XDR‐TB: Global implementation of the WHO shorter MDR‐TB regimen and bedaquiline for all with MDR‐TB?

Tuberculosis (TB) is now the biggest infectious disease killer worldwide. Although the estimated incidence of TB has marginally declined over several years, it is out of control in some regions including in Africa. The advent of multidrug‐resistant TB (MDR‐TB) and extensively drug‐resistant TB (XDR‐TB) threatens to further destabilize control in several regions of the world. Drug‐resistant TB constitutes a significant threat because it underpins almost 25% of global TB mortality, is associated with high morbidity, is a threat to healthcare workers and is unsustainably costly to treat. The advent of highly resistant TB with emerging bacillary resistance to newer drugs has raised further concern. Encouragingly, in addition to preventative strategies, several interventions have recently been introduced to curb the drug‐resistant TB epidemic, including newer molecular diagnostic tools, new (bedaquiline and delamanid) and repurposed (linezolid and clofazimine) drugs and shorter and individualized treatment regimens. However, there are several controversies that surround the use of new drugs and regimens, including whether, how and to what extent they should be used, and who specifically should be treated so that outcomes are optimally improved without amplifying the burden of drug resistance, and other potential drawbacks, thus sustaining effectiveness of the new drugs. The equipoise surrounding these controversies is discussed and some recommendations are provided.     

重庆市耐多药结核分枝杆菌对贝达喹啉和德拉马尼的药物敏感性研究

目的分析重庆市耐多药结核分枝杆菌(multidrug-resistant Mycobacterium tuberculosis,MDR-TB)对贝达喹啉(bedaquiline,Bdq)和德拉马尼(delamanid,Dlm)的药物敏感性,以期为临床上Bdq和Dlm的合理使用提供参考。方法收集2017年11月至2018年11月间经重庆市公共卫生医疗救治中心鉴定为MDR-TB的菌株,采用微孔板法测定Bdq和Dlm的最低抑菌浓度(minimum inhibitory concentration, MIC),并对相关结果进行分析。结果所收集的111例MDR-TB临床分离株进行Bdq的药敏检测结果显示, MIC₅₀和MIC₉₀分别为0.016 mg/L和0.125 mg/L;109例MDR-TB菌株的Dlm药敏结果显示,MIC₅₀和MIC₉₀分别为0.016 mg/L和0.063 mg/L。各有5株菌株对Bdq和Dlm耐药,耐药率分别为4.50%和4.59%。不同耐药情况分组对Bdq和Dlm的耐药率与MDR...