The changing treatment landscape for MDR/XDR-TB — Can current clinical trials revolutionise and inform a brave new world?

Summary Tuberculosis (TB) along with acquired immune deficiency syndrome and malaria rank among the top three fatal infectious diseases which pose threat to global public health, especially in middle and low income countries. TB caused by Mycobacterium tuberculosis (Mtb) is an airborne infectious disease and one‐third of the world's population gets infected with TB leading to nearly 1·6 million deaths annually. TB drugs are administered in different combinations of four first‐line drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) which form the core of treatment regimens in the initial treatment phase of 6–9 months. Several reasons account for the failure of TB therapy such as (i) late diagnosis, (ii) lack of timely and proper administration of effective drugs, (iii) lower availability of less toxic, inexpensive and effective drugs, (iv) long treatment duration, (v) nonadherence to drug regimen and (vi) evolution of drug‐resistant TB strains. Drug‐resistant TB poses a significant challenge to TB therapy and control programs. In the background of worldwide emergence of 558 000 new TB cases with resistance to rifampicin in the year 2017 and of them, 82% becoming multidrug‐resistant TB (MDR‐TB), it is essential to continuously update the knowledge on the mechanisms and molecular basis for evolution of Mtb drug resistance. This narrative and traditional review summarizes the progress on the anti‐tubercular agents, their mode of action and drug resistance mechanisms in Mtb. The aim of this review is to provide recent updates on drug resistance mechanisms, newly developed/repurposed anti‐TB agents in pipeline and international recommendations to manage MDR‐TB. It is based on recent literature and WHO guidelines and aims to facilitate better understanding of drug resistance for effective TB therapy and clinical management.

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“…; Honeyborne et al . ). At least 85% of drug‐susceptible TB are successfully treated and reported regularly to WHO by the 194 Member States.…”

Section: Introductionmentioning

confidence: 97%

Recent updates on drug resistance in Mycobacterium tuberculosis

et al. 2019

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“…As a result, the number of patients eligible to receive bedaquiline-containing regimens would significantly increase. Encouraging results from studies currently underway on the use of bedaquiline in all-oral, shorter-course regimens for the treatment of rifampicin-resistant TB could result in an even greater use of bedaquiline in TB control programmes globally (2,3). However, solid surveillance of drug-resistance is needed to monitor the emergence of resistance to bedaquiline in patients during therapy.…”

Section: Manuscriptmentioning

confidence: 99%

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

Ghodousi

Rizvi²,

Baloch

et al. 2019

Preprint

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20We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential 21 culture isolates from 30 drug-resistant tuberculosis patients on bedaquiline-containing regimen were 22 tested for minimum inhibitory concentration (MIC) and whole genome sequencing. An increase in MICs 23 associated with cross-resistance to clofazimine and appearance of specific mutations was documented in 24 six cases. The study underlines that appropriate monitoring is mandatory for the introduction of new drugs. 25 26 27 93 strains collected from two patients reported as "failure" at the end of treatment (patient-4 MIC 0.25 94 mg·L −1 , eight fold higher than baseline and patient-5 MIC 0.125 mg·L −1 , four fold higher than baseline) 95 would have been categorised as susceptible. This finding indicates that monitoring MICs during treatment 96 could be a better predictor for failure than single testing at critical concentration. The genetic basis of 97 4 resistance to bedaquiline is still the subject of much uncertainty. WGS analysis in different studies showed 98 that bedaquiline-clofazimine cross resistance arises through mutations in Rv0678 (6,7,8) and pepQ (9). In 99 this study, we show that the increase of MIC to bedaquiline and clofazimine could be explained by 100 mutations emerging during therapy in Rv0678. As reported in table 1 we observed four different mutations 101 and three of these were previously reported as associated 102 to bedaquiline resistance in MTB clinical strains (8). We show that the same mutations are associated to 103 Clofazimine resistance. As a result, regimens that contain both drugs might have to be reconsidered when 104 these mutations are identified, to reduce the risk of failure for the patients and transmission of such strains 105 in the community. Altogether, these data show that resistance to bedaquiline emerges during treatment 106 and emphasize the importance of using MIC and whenever possible molecular based surveillance in 107 national programmes implementing bedaquiline for the treatment of MDR/XDR-TB to monitor the 108 emergence of resistance. Moreover, a classification of mutations associated to bedaquiline and clofazimine 109 resistance is crucial to lead future development of tools for fast detection of resistance. Introducing drugs 110 without proper diagnostics to monitor drug resistance may lead to amplification of hardly treatable cases. 111 112 Ethics approval 113 Ethical clearance was approved by the Institutional review board for HIV, TB and Malaria programme, 114 Pakistan.

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“…2 Drug-resistant TB presents an even greater challenge: MDR-TB regimens comprise second-line drugs that are associated with significant toxicity and can require up to two years to complete, while XDR-TB, which is resistant to both first- and second-line drugs, demands bespoke combinations of nonstandard antibiotics for extended periods, often under close clinical management. 5 There is some positive news, though: global efforts to address the urgent need for new antimycobacterial agents have gained momentum through the development of a TB drug pipeline. 6 Excitingly, two new TB drugs, delamanid 7 and bedaquiline, 8 have recently secured regulatory approval for use in the treatment of drug-resistant TB 9 with bedaquiline showing promise in treatment-shortening regimens for MDR-TB.…”

Section: Introductionmentioning

confidence: 99%

“…6 Excitingly, two new TB drugs, delamanid 7 and bedaquiline, 8 have recently secured regulatory approval for use in the treatment of drug-resistant TB 9 with bedaquiline showing promise in treatment-shortening regimens for MDR-TB. 5 Moreover, there are other new and repurposed drugs and regimens in clinical development that offer some hope, 5,6 but the challenge remains formidable.…”

Section: Introductionmentioning

confidence: 99%

Harnessing Biological Insight to Accelerate Tuberculosis Drug Discovery

2019

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Conspectus Tuberculosis (TB) is the leading cause of mortality globally resulting from an infectious disease, killing almost 1.6 million people annually and accounting for approximately 30% of deaths attributed to antimicrobial resistance (AMR). This despite the widespread administration of a neonatal vaccine, and the availability of an effective combination drug therapy against the causative agent, Mycobacterium tuberculosis (Mtb). Instead, TB prevalence worldwide is characterized by high-burden regions in which co-epidemics, such as HIV, and social and economic factors, undermine efforts to control TB. These elements additionally ensure conditions that favor the emergence of drug-resistant Mtb strains, which further threaten prospects for future TB control. To address this challenge, significant resources have been invested in developing a TB drug pipeline, an initiative given impetus by the recent regulatory approval of two new anti-TB drugs. However, both drugs have been reserved for drug-resistant disease, and the seeming inevitability of new resistance plus the recognized need to shorten the duration of chemotherapy demands continual replenishment of the pipeline with high-quality “hits” with novel mechanisms of action. This represents a massive challenge, which has been undermined by key gaps in our understanding of Mtb physiology and metabolism, especially during host infection. Whereas drug discovery for other bacterial infections can rely on predictive in vitro assays and animal models, for Mtb, inherent metabolic flexibility and uncertainties about the nutrients available to infecting bacilli in different host (micro)environments instead requires educated predictions or demonstrations of efficacy in animal models of arguable relevance to human disease. Even microbiological methods for enumeration of viable mycobacterial cells are fraught with complication. Our research has focused on elucidating those aspects of mycobacterial metabolism that contribute to the robustness of the bacillus to host immunological defenses and applied antibiotics and that, possibly, drive the emergence of drug resistance. This work has identified a handful of metabolic pathways that appear vulnerable to antibiotic targeting. Those highlighted, here, include the inter-related functions of pantothenate and coenzyme A biosynthesis and recycling and nucleotide metabolism—the last of which reinforces our view that DNA metabolism constitutes an under-explored area for new TB drug development. Although nonessential functions have traditionally been deprioritized for antibiotic development, a common theme emerging from this work is that these very functions might represent attractive targets because of the potential to cripple mechanisms critical to bacillary survival under stress (for example, the Rel Mtb -dependent stringent response) or to adaptability under unfavorable, potentially lethal, conditions including antibiotic therapy (for example, ...

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The changing treatment landscape for MDR/XDR-TB — Can current clinical trials revolutionise and inform a brave new world?

Cited by 20 publications

References 21 publications

Recent updates on drug resistance in Mycobacterium tuberculosis

Recent updates on drug resistance in Mycobacterium tuberculosis

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

Harnessing Biological Insight to Accelerate Tuberculosis Drug Discovery

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