Emergence Of Multidrug-resistant Tuberculosis Research Articles

Trend of pulmonary tuberculosis and rifampicin-resistance among tuberculosis presumptive patients in Central Tigray, Ethiopia; 2018 -2023: a six-year retrospective study

BackgroundTuberculosis (TB) is a major public health concern in the developing countries. Moreover, the emergence of multidrug-resistant tuberculosis is challenging. However, there are no organized data on the trends of pulmonary tuberculosis and rifampicin-resistant Mycobacterium tuberculosis in the study area.MethodsA retrospective cross-sectional study was conducted to fill the information gap in Central Tigray at St. Mary General Hospital between 2018 and 2023. Data were collected from the GeneXpert™ tuberculosis registration logbooks using standard checklists and analyzed using Statistical Package for Social Science version 22. After performing logistic regression, a p-value < 0.05 with a corresponding 95% confidence interval was considered statistically significant. Moreover, chi square test for trend was performed to assess the percentage of annual detection of pulmonary tuberculosis and rifampicin-resistant Mycobacterium tuberculosis during the study years.ResultPresumptive pulmonary tuberculosis patients with complete data (n = 3696) were included in the study. The overall prevalence of pulmonary tuberculosis was 11.7%, of which 8.1% were resistant to rifampicin. The study revealed that the incidence of pulmonary tuberculosis has been increasing, mainly in the recent four years. Likewise, an increase in rifampicin-resistant Mycobacterium tuberculosis was observed with considerable fluctuations. Age, human immunodeficiency virus infection, and presumptive rifampicin-resistant Mycobacterium tuberculosis infection were significantly associated with the presence of pulmonary tuberculosis. Moreover, pulmonary tuberculosis was more prevalent among participants in the productive-age group.ConclusionAlthough there have been fluctuations, an increasing of pulmonary tuberculosis and rifampicin-resistant Mycobacterium tuberculosis has been observed in recent years. Hence, prevention and treatment strategies for tuberculosis should be strengthened to alleviate the burden of pulmonary tuberculosis and rifampicin-resistant Mycobacterium tuberculosis in the study area.

Risk factors associated with multidrug-resistant tuberculosis in areas with a moderate tuberculosis burden.

The emergence of multidrug-resistant tuberculosis (MDR-TB) or rifampicin-resistant (RR) TB poses a significant challenge for TB control initiatives on a global scale. This study's aim was to estimate the incidence of MDR-/RR-TB and identify the risk factors associated with their incidence in four provinces in northern Iran. Drug susceptibility testing was conducted using the proportion method on Lowenstein-Jensen media. The demographic and clinical data were collected from the Iranian TB registry. Among 1083 individuals diagnosed with TB, 27 (2.5%) were identified as having MDR-/RR-TB, while 73 cases (6.7%) were any drug resistant (ADR). The statistical analysis revealed a significant association between marital status and MDR-/RR-TB (p=0.003). In addition, significant associations were observed between ADR-TB and gender (p=0.035) and previous treatment for TB (p=0.02). Our findings provide important information on the drug resistance pattern of Mycobacterium tuberculosis strains, as well as risk factors in northern Iran. Given the identified risk factors, creative approaches to promote treatment adherence in TB patients, particularly divorced/widowed women and individuals with a previous history of TB treatment, are required.

Advancements in Artificial Intelligence for the Diagnosis of Multidrug Resistance and Extensively Drug-Resistant Tuberculosis: A Comprehensive Review.

Tuberculosis (TB) remains a significant global health concern, particularly with the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). Traditional methods for diagnosing drug resistance in TB are time-consuming and often lack accuracy, leading to delays in appropriate treatment initiation and exacerbating the spread of drug-resistant strains. In recent years, artificial intelligence (AI) techniques have shown promise in revolutionizing TB diagnosis, offering rapid and accurate identification of drug-resistant strains. This comprehensive review explores the latest advancements in AI applications for the diagnosis of MDR-TB and XDR-TB. We discuss the various AI algorithms and methodologies employed, including machine learning, deep learning, and ensemble techniques, and their comparative performances in TB diagnosis. Furthermore, we examine the integration of AI with novel diagnostic modalities such as whole-genome sequencing, molecular assays, and radiological imaging, enhancing the accuracy and efficiency of TB diagnosis. Challenges and limitations surrounding the implementation of AI in TB diagnosis, such as data availability, algorithm interpretability, and regulatory considerations, are also addressed. Finally, we highlight future directions and opportunities for the integration of AI into routine clinical practice for combating drug-resistant TB, ultimately contributing to improved patient outcomes and enhanced global TB control efforts.

Silent epidemic of silicotuberculosis in India and emergence of multidrug-resistant tuberculosis?

ObjectivesIndia's projected silica-dust-exposed workers will be 52 million at the end of 2025. The elimination of tuberculosis (TB) is also targeted in India by 2025. Scientists in India have already pointed out that unless silicosis is controlled, the said elimination will be difficult to achieve. Methods and ResultsThis study provides evidence of an increasing incidence of tuberculosis (TB) including multidrug-resistant TB (MDR-TB) with mortality owing to treatment failure among the silica dust-exposed workers compared to their unexposed counterpart. It was also observed that TB as well as MDR-TB were directly proportional to the dose and/or duration of silica dust exposure (progression of silica-dust induced lung damage). This means the occurrence of both TB and MDR-TB is lowest in the unexposed group, moderate in the radiologically negative but silica dust-exposed group (subradiological silicosis owing to moderate exposure), and highest in the radiologically confirmed silicotic workers (maximally exposed group). Because India has a huge burden of silicosis cases, the said cases are vulnerable to pulmonary TB, including MDR-TB. The study indicates there will be an emergence of MDR-TB among the silica dust-exposed workers unless appropriate intervention measures are initiated with immediate effect. Failure to do so, it will probably lead to a silent epidemic of silicotuberculosis in India shortly. ConclusionsIt is important to have tools to detect silicosis cases quickly and at an early stage to identify a vulnerable population and adopt an effective intervention measure.

An Exploratory Review of the Potential of Lytic Proteins and Bacteriophages for the Treatment of Tuberculosis.

Tuberculosis (TB) is a highly prevalent infectious disease that causes more than 1.5 million deaths a year. More than 25% of TB deaths occur in Africa, and TB is South Africa's leading cause of death, with about 89,000 people dying of it yearly. The emergence of multidrug-resistant TB (MDR-TB) poses a significant threat to health security and could reverse the positive gains already made in the fight against TB. Antibiotic treatments are available, but side effects and the alarming increase in the prevalence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) will compromise the control of the spread and treatment of the disease. A promising option is to employ specialized enzymes encoded by bacteriophages, which destroy bacterial cell membranes and walls to treat tuberculosis. Phage therapy against bacteria is a known treatment that is now reemerging with lytic proteins. These proteins provide an alternative means to treat infectious diseases where conventional antibiotic regimens do not meet the requirements. This review explores and discusses the potential of lytic protein therapy as an antimicrobial strategy against M. tuberculosis and multidrug-resistant tuberculosis.

Empowering care: Unleashing pharmaceutical care to confront MDR-TB transmission risks-A prospective interventional study

IntroductionAccording to recent NTEP report it was estimated that in India the MDR-TB cases were 9.1/lakh population. Patients undergoing the pulmonary TB are known to cause MDR-TB due to multi drug resistance. Early identification of risk elements in Multidrug resistant-TB patients is crucial to managing and preventing the disease. ObjectiveTo evaluate risk variables that contribute to cause Multidrug resistant tuberculosis and to providing patient counselling to TB patients regarding risk factors. Methodology: A Prospective interventional study to assess the various Risk factors involved in cause of Multi drug resistance tuberculosis. This study was conducted for period of 09 months. The study is conducted with standard validated questionnaires which are prepared to assess the risk factors among Multidrug resistant-TB patients. Study site includes the tertiary care hospitals in Belagavi. ResultOverall, 120 Multidrug resistant tuberculosis patients were recruited from the district tuberculosis centre, Belagavi District, Karnataka. India. Most patients (47.50%) were aged 25–44 years. Of the 120 MDR-TB patients, 67.50% are male and 32.5% are female. Of 120 MDR-TB patients, 7.50% are HIV positive. As part of the study, smoking (26.67%), chewing tobacco (50%), and alcohol consumption (33.33%) were found to be other major risk factors. 24.17% of patients had a family history of tuberculosis, of which 5% had contact with an infected person as a source of infection. ConclusionThis study documented various risk variables involved in the emergence of Multidrug resistant TB. This research also highlighted the significance of pharmaceutical care in the effective management of multidrug-resistant tuberculosis (MDR-TB). This study identified risk variables that contribute to MDR-TB and helped educate tuberculosis patients about these risk factors.

Risk factors for treatment failure in multidrug resistant tuberculosis in Tunisia: An analytic study.

The emergence of multidrug resistant tuberculosis (MDR-TB) is a threat to global public health. The aim of our study was to determine risk factors for treatment failure in MDR-TB. Retrospective study conducted between January 2000 and March 2019 including patients with MDR-TB. Characteristics of patients with therapeutic failure were compared to cured ones. Logistic regression analysis was used to identify risk factors for treatment failure. Our study included 140 patients aged of 42±13 years (18-80). Fifty-seven percent of patients had treatment success and 12% had treatment failure. In multivariate logistic regression analysis, treatment failure was associated with age over 45 years (OR=1.05; 95%CI, 1.024-7.736;p=0.014), primary education level and illiteracy (OR=5.022; 95%CI, 1.316-19.161;p=0,018), history of incarceration (OR=3.291; 95%CI, 1.291-21.083;p=0.016), undernutrition (OR=4.544; 95%CI, 2.304-54.231;p=0,027), extensive TB (OR=6.406; 95%CI, 1.761-23.922; p=0.038), initial high grade positive smears (OR=1.210; 95%CI, 1.187-32.657; p=0.045), positive smear culture at 90 days of treatment (OR=6.871, 95%CI, 3.824-23.541; p=0.003), poor adherence (OR=6.110; 95%CI, 2.740-12.450; p=0.021) and occurrence of psychiatric adverse events (OR=3.644 95%CI, 2.560- 27.268; p=0.041). Therapeutic education, nutritional and psychological support and close follow-up are strongly recommended to optimize the prognosis of MDR-TB.

BacPROTACs targeting Clp protease: a promising strategy for anti-mycobacterial drug discovery.

Tuberculosis (TB) has claimed more lives over the course of two millennia than any other infectious disease worldwide. In 2021, the World Health Organization (WHO) estimated that 10.6 million people were diagnosed with TB, resulting in the deaths of 1.4 million HIV-negative individuals. The emergence of multidrug-resistant TB (MDR-TB), defined as resistance to at least rifampicin (RIF) and isoniazid (INH), and extensively drug-resistant TB (XDR-TB), poses the primary challenge to overcome in the coming years. We have recently conducted an extensive analysis of investments and research endeavours in the field, with the overarching objective of achieving the established milestone of TB eradication by the year 2030. Over the past several years, there has been notable progress in advancing a multitude of promising compounds, each possessing distinct mechanisms of action, into clinical phases of development. However, it is worth noting that strains of mycobacteria resistant to current antitubercular drugs have already emerged for some of these compounds The exploration of the innovative Proteolytic Target Chimeras (PROTACs) protein degradation approach has emerged as a viable avenue for the discovery of novel antimicrobials. While the ubiquitin system is exclusive to eukaryotic cells, certain bacteria use a similar degradation system that relies on the recognition of phosphorylated arginine residues (pArg) by the ClpC:ClpP (ClpCP) protease, thereby leading to protein degradation. In this opinion article, we have described and analized the advances in the use of PROTACs that leverage bacterial proteolytic machinery (BacPROTACs) to design new antitubercular agents. Scope Statement. The development of novel pharmaceuticals for tuberculosis treatment is deemed urgently necessary due to the emergence of resistant strains. In this context, the introduction of new technologies capable of alleviating the disease and attaining the objectives outlined by the World Health Organization is imperative. Among the innovative strategies, the degradation of proteins that are crucial for the survival of the bacillus holds promise for generating new medications, particularly those that are effective at treating latent (non-replicating) Mycobacterium tuberculosis. Within this perspective, we present the advancements and obstacles encountered in the exploration of new BacPROTAC compounds, with the intention of encouraging research and illuminating challenges associated with the implementation of BacPROTACs to address to the global tuberculosis crisis.

Identification of potential mutations associated with multidrug resistance among isolates of Mycobacterium tuberculosis in Malaysia by in silico screening

The emergence of multidrug resistance tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis (MTB) adaptation to survive in the presence of antibiotic, that were contributed by mutations in the MDR-associated genes. Previous research has indicated that the gene expression knockdown of fhaA leads to an accumulation of peptidoglycan (PG) precursors at the bacillary septum and poles, which suggest a possible deficiency in PG biosynthesis. Consequently, the cell wall becomes resistant to antibiotics, leading to multidrug resistance (MDR). In this study, bioinformatics analyses were performed on MDR-TB isolates from 24 clinical samples to search for novel mutations that contribute to antibiotic resistance. We found out a potential deletion of nucleotides encoding 6 amino acids in all 12 samples, particularly in fhaA gene (RV0020c). Our subsequent structural analysis shows that the deletion is at the position 243-248, causing conformational change of the native FhaA protein. We postulated that the deletion will potentially cause the loss of its binding affinity to MviN (precursor) and STPK (protein kinase), resulting in the inhibition and blockage of the peptidoglycan polymerization, causing MDR in MTB. In the future, experimental validation is necessitated to substantiate the association of these mutations with MDR.

Mycobacterial FtsZ and inhibitors: a promising target for the anti-tubercular drug development.

The emergence of multidrug-resistant tuberculosis (MDR-TB) strains has rendered many anti-TB drugs ineffective. Consequently, there is an urgent need to identify new drug targets against Mycobacterium tuberculosis (Mtb). Filament Forming Temperature Sensitive Gene Z (FtsZ), a member of the cytoskeletal protein family, plays a vital role in cell division by forming a cytokinetic ring at the cell's center and coordinating the division machinery. When FtsZ is depleted, cells are unable to divide and instead elongate into filamentous structures that eventually undergo lysis. Since the inactivation of FtsZ or alterations in its assembly impede the formation of the Z-ring and septum, FtsZ shows promise as a target for the development of anti-mycobacterial drugs. This review not only discusses the potential role of FtsZ as a promising pharmacological target for anti-tuberculosis therapies but also explores the structural and functional aspects of the mycobacterial protein FtsZ in cell division. Additionally, it reviews various inhibitors of Mtb FtsZ. By understanding the importance of FtsZ in cell division, researchers can explore strategies to disrupt its function, impeding the growth and proliferation of Mtb. Furthermore, the investigation of different inhibitors that target Mtb FtsZ expands the potential for developing effective treatments against tuberculosis.

The impact of diabetes mellitus on the emergence of multi-drug resistant tuberculosis and treatment failure in TB-diabetes comorbid patients: a systematic review and meta-analysis.

The existence of Type 2 Diabetes Mellitus (DM) in tuberculosis (TB) patients is very dangerous for the health of patients. One of the major concerns is the emergence of MDR-TB in such patients. It is suspected that the development of MDR-TB further worsens the treatment outcomes of TB such as treatment failure and thus, causes disease progression. To investigate the impact of DM on the Emergence of MDR-TB and Treatment Failure in TB-DM comorbid patients. The PubMed database was systematically searched until April 03, 2022 (date last searched). Thirty studies met the inclusion criteria and were included in this study after a proper selection process. Tuberculosis-Diabetes Mellitus patients were at higher risk to develop MDR-TB as compared to TB-non-DM patients (HR 0.81, 95% CI: 0.60-0.96, p < 0.001). Heterogeneity observed among included studies was moderate (I2 = 38%). No significant change was observed in the results after sub-group analysis by study design (HR 0.81, 95% CI: 0.61-0.96, p < 0.000). In the case of treatment failure, TB-DM patients were at higher risk to experience treatment failure rates as compared to TB-non-DM patients (HR 0.46, 95% CI: 0.27-0.67, p < 0.001). The results showed that DM had a significant impact on the emergence of MDR-TB in TB-diabetes comorbid patients as compared to TB-non-DM patients. DM enhanced the risk of TB treatment failure rates in TB-diabetes patients as compared to TB-non-DM patients. Our study highlights the need for earlier screening of MDR-TB, thorough MDR-TB monitoring, and designing proper and effective treatment strategies to prevent disease progression.

Cost-Effectiveness Analysis of the Optimal Control Strategies for Multidrug-Resistant Tuberculosis Transmission in Ethiopia

Despite the recent progress of global control efforts, tuberculosis (TB) remains a significant public health threat worldwide, especially in developing countries, including Ethiopia. Furthermore, the emergence of multidrug-resistant tuberculosis (MDR-TB) has further complicated the situation. This study aims at identifying the most effective strategies for combating MDR-TB in Ethiopia. We first present a compartmental model of MDR-TB transmission dynamics in Ethiopia. The model is shown to have positive solutions, and the stability of the equilibrium points is analyzed. Then, we extend the model by incorporating time-dependent control variables. These control variables are vaccination, distancing, and treatment for DS-TB and MDR-TB. Finally, the optimality system is numerically simulated by considering different combinations of the strategies, and their cost effectiveness is analysed. Our finding shows that, among single control strategies, the successful treatment of drug-susceptible tuberculosis (DS-TB) is the most effective control factor for eliminating MDR-TB transmission in Ethiopia. Furthermore, within the six dual control strategies, the combination of distancing and successful treatment of DS-TB is less costly and more effective than other strategies. Finally, out of the triple control strategies, the combination of distancing, successful treatment for DS-TB, and treatment for MDR-TB is the most efficient strategy for curbing the MDR-TB disease in Ethiopia. Thus, to reduce MDR-TB efficiently, it is recommended that authorities focus on treating MDR-TB, effective treatment of DS-TB, and promoting social distancing through public health education and awareness programs.

Discovery of novel reversible inhibitor of DprE1 based on benzomorpholine for the treatment of tuberculosis.

About a quarter of the world's population is infected with Mycobacterium tuberculosis, equivalent to about two billion people. With the emergence of multidrug-resistant tuberculosis, those existing anti-tuberculosis drugs no longer meet the demand for cure anymore; there is an urgent need for the development of new anti-tuberculosis drugs. Decaprenylphosphoryl-β-D-ribose 2´-epimerase (DprE1) has been proven to be a potential antimycobacterial target, and several inhibitors have entered clinical trial. Herein, we designed and synthesized a series of compounds based on the indole and benzomorpholine by using the strategy of scaffold hopping. The preferred compound B18 showed strong antimycobacterial activity in H37Rv and drug-resistant clinical isolates. In addition, compound B18 did not exhibit antimycobacterial efficacy against other species of strains. Subsequently, the target of B18 was identified as DprE1 by analyzing spontaneous compound-resistant mutation data, and a docking study was performed to illustrate the binding mode between B18 and DprE1. In general, compound B18 is compatible to current DprE1 inhibitors, even higher phosphodiesterase 6C selectivity and plasma protein binding rate, which represent a new type of effective reversible DprE1 inhibitor. IMPORTANCE Drug therapy remains the cornerstone of tuberculosis (TB) treatment, yet first-line anti-tuberculosis drugs are associated with significant adverse effects that can compromise patient outcomes. Moreover, prolonged and widespread use has led to an alarming rise in drug-resistant strains of Mycobacterium tuberculosis, including multidrug-resistant [MDR-tuberculosis (TB)] and extensively drug-resistant (XDR-TB) forms. Urgent action is needed to develop novel anti-tuberculosis agents capable of overcoming these challenges. We report that compound B18, a decaprenylphosphoryl-β-D-ribose 2´-epimerase inhibitor with a benzomorpholine backbone, exhibits potent activity against not only the non-pathogenic strain H37Ra, but also the pathogenic strain H37Rv and clinical MDR and XDR strains. Preliminary druggability studies indicate that B18 possesses high safety and acceptable pharmacokinetic properties, rendering it a promising candidate for further development as a novel anti-tuberculosis agent.

Rv1453 is associated with clofazimine resistance in Mycobacterium tuberculosis.

Clofazimine (CFZ) has been repurposed for treating tuberculosis (TB), especially multidrug-resistant tuberculosis (MDR-TB). However, the mechanisms of resistance to clofazimine are poorly understood. We previously reported a mutation located in the intergenic region of Rv1453 that was linked to resistance to CFZ and demonstrated that an Rv1453 knockout resulted in an increased minimum inhibitory concentration (MIC) of CFZ. The current study aims to go back and describe in detail how the mutation was identified and further explore its association with CFZ resistance by testing additional 30 isolates. We investigated MICs of clofazimine against 100 clinical strains isolated from MDR-TB patients by microplate alamarBlue assay. Whole-genome sequencing (WGS) was performed on 11 clofazimine-resistant and 7 clofazimine-susceptible strains, including H37Rv. Among the 11 clofazimine-resistant mutants subjected to WGS, the rate of mutation in the intergenic region of the Rv1453 gene was 55% (6/11) in clofazimine-resistant strains. Among another 30 clofazimine-resistant clinical isolates, 27 had mutations in the intergenic region of the Rv1453 gene. A mutation in the Rv1453 gene associated with clofazimine resistance was identified, which shed light on the mechanisms of action and resistance of clofazimine. IMPORTANCE Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis, especially the emergence of multidrug-resistant tuberculosis (MDR-TB) brings great distress to humans. Clofazimine (CFZ) plays an important role in the treatment of MDR-TB. To understand the underlying mechanism of clofazimine resistance better, in this study, we review and detail the findings of the mutation of intergenic region of Rv1453 and find additional evidence that this mutation is related to clofazimine resistance in 30 additional isolates. The significance of our research is to contribute to a comprehensive understanding of clofazimine-resistant mechanisms, which is critical for reducing the emergence of resistance and for anti-TB drug discovery.

Thioglycolic acid-capped gold nanoparticle/cytochrome P450-2E1 electrochemical biosensor for isoniazid

Tuberculosis (TB) is one of the deadliest diseases in Africa and it is classified as a serious global health problem. A new threat associated with the disease is the emergence of multidrug-resistant TB (MDR-TB), which results from improper dose or non-compliance with a treatment regime. It is, therefore, important to determine a patient’s rate of TB drug metabolism at a point-of-care, in order to enable appropriate dose prescription. This work presents a novel enzymatic nanobiosensor for real-time determination of isoniazid (INH), which is a highly prescribed drug for TB treatment. The nanobiosensor consists of a cytochrome P450-2E1 (CYP2E1) isoenzyme covalently attached to a screen printed or disk gold electrode (Au), functionalized with thioglycolic acid-capped gold nanoparticle (TGA-AuNP). The nanomaterial was green-synthesized with banana peel extract (BPE) as the reducing agent. It exhibited an ultraviolet-visible spectroscopy (UV–Vis) signature absorption band for AuNP at 536 nm and a direct bandgap energy (Eg) value of 2.00 eV. Fourier transform infra-red spectroscopy (FTIR) was used to confirm the reduction of Au3+ to Au0. High-resolution transmission electron microscopy (HR-TEM) and high-resolution scanning electron microscopy (HR-SEM) studies indicated that TGA-AuNPs were polydisperse and exhibited spherical morphology. Bovine serum albumin (BSA) and CYP2E1 were attached to the TGA-AuNPs-modified Au electrode using glutaraldehyde (Glu) as binder, to form the nanobiosensor (BSA/CYP2E1/Glu/TGA-AuNPs/Au). Differential pulse voltammetric (DPV) responses of the nanobiosensor for INH were determined in 10 mM phosphate buffer (pH 7.4). The limit of detection (LOD) and the limit of quantification (LOQ) values of the nanobiosensor were 0.0556 μM INH and 0.1683 μM INH, respectively.

Mapping Research Trends of Medications for Multidrug-Resistant Pulmonary Tuberculosis Based on the Co-Occurrence of Specific Semantic Types in the MeSH Tree: A Bibliometric and Visualization-Based Analysis of PubMed Literature (1966-2020).

Before the COVID-19 pandemic, tuberculosis is the leading cause of death from a single infectious agent worldwide for the past 30 years. Progress in the control of tuberculosis has been undermined by the emergence of multidrug-resistant tuberculosis. The aim of the study is to reveal the trends of research on medications for multidrug-resistant pulmonary tuberculosis (MDR-PTB) through a novel method of bibliometrics that co-occurs specific semantic Medical Subject Headings (MeSH). PubMed was used to identify the original publications related to medications for MDR-PTB. An R package for text mining of PubMed, pubMR, was adopted to extract data and construct the co-occurrence matrix-specific semantic types. Biclustering analysis of high-frequency MeSH term co-occurrence matrix was performed by gCLUTO. Scientific knowledge maps were constructed by VOSviewer to create overlay visualization and density visualization. Burst detection was performed by CiteSpace to identify the future research hotspots. Two hundred and eight substances (chemical, drug, protein) and 147 diseases related to MDR-PTB were extracted to form a specific semantic co-occurrence matrix. MeSH terms with frequency greater than or equal to six were selected to construct high-frequency co-occurrence matrix (42 × 20) of specific semantic types contains 42 substances and 20 diseases. Biclustering analysis divided the medications for MDR-PTB into five clusters and reflected the characteristics of drug composition. The overlay map indicated the average age gradients of 42 high-frequency drugs. Fifteen top keywords and 37 top terms with the strongest citation bursts were detected. This study evaluated the literatures related to MDR-PTB drug therapy, providing a co-occurrence matrix model based on the specific semantic types and a new attempt for text knowledge mining. Compared with the macro knowledge structure or hot spot analysis, this method may have a wider scope of application and a more in-depth degree of analysis.

Effects of Bedaquiline Combined with Fluoroquinolone and/or Clofazimine on QT Interval in Patients with Multidrug-Resistant Tuberculosis: a Retrospective Study.

With the application of bedaquiline (Bdq), the success rate of multidrug-resistant tuberculosis (MDR-TB) treatment has been significantly improved; however, the cardiac safety of the patients during treatment cannot be ignored. Hence, this study compared the effects of bedaquiline alone and bedaquiline combined with fluoroquinolones (FQs) and/or clofazimine (CFZ) on the QT interval. This single-center retrospective cohort study analyzed the clinical data of MDR-TB patients treated with bedaquiline for 24 weeks from January 2020 to May 2021 in Xi'an Chest Hospital and compared the changes in QTcF between the two groups. Eighty-five patients were included in the study and grouped by types of anti-TB drugs affecting the QT interval they used. Group A included bedaquiline (n = 33), and group B included bedaquiline in combination with fluoroquinolones and/or clofazimine (n = 52). Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 2.4% (2/85) experienced a postbaseline QTcF of ≥500 ms, and 24.7% (21/85) had at least one change of QTcF of ≥60 ms from baseline. In group A, 9.1% (3/33) had at least one ΔQTcF of >60 ms, as did 34.6% (18/52) of group B. Multivariate Cox regression analysis showed that the adjusted risk of QT prolongation was 4.82 times higher in group B (95% confidence interval [CI], 1.406 to 16.488). Bedaquiline combined with other anti-TB drugs affecting QT interval significantly increased the incidence of grade 3 or 4 QT prolongation; however, no serious ventricular arrhythmia and permanent drug withdrawal occurred. The use of bedaquiline combined with fluoroquinolone and/or clofazimine is an independent risk factor affecting QT interval. IMPORTANCE Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis. The emergence of MDR-TB is caused by an organism that is resistant to at least isoniazid and rifampin and is currently considered the major challenge for the global control of TB. Bedaquiline is the first new TB drug in 50 years with a unique mechanism of action, strong anti-M. tuberculosis activity. Yet unexplained excess deaths in the bedaquiline arms have been found in some phase II clinical trials; thus, the FDA has issued a "boxed warning." However, the cardiac safety of the patients during treatment cannot be ignored. Accordingly, further investigations are needed to establish whether bedaquiline combined with clofazimine, fluoroquinolones, or anti-TB drugs affecting the QT interval in a long-course or short-course treatment increases the risk of QT prolongation.

Novel Benzylamine Derivatives: Synthesis, Anti-Mycobacterium Tuberculosis Evaluation and Predicted ADMET Properties

Background: Tuberculosis (TB), a disease caused by the bacillus bacteria Mycobacterium tuberculosis is one of the major contributors of ill health in the world. TB is ranked in the top 10 causes of death globally and it is the leading killer associated with a single infectious agent. According to the World Health Organization (WHO), global number of deaths associated with TB have been slowly declining with 1.3 million in reported 2016 and 2017, and 1.2 million reported in 2018 and 2019. Objective: The synthesis, characterisation, biological evaluations, and the prediction of ADMET properties of the novel benzylamine derivatives. Methods: Commercially available reagents and solvents were purchased from Sigma Aldrich and Merck (South Africa). All chemicals were used as received, unless otherwise stated. The synthesised crude compounds were purified by flash silica gel column chromatography (5 – 30% ethyl acetate in hexane). The successful formation and purity of the synthesised compounds was confirmed by NMR, HRMS and melting point. Results: The respective organic compounds were synthesised by treating 3-ethoxysalcyladehyde, 5-bromo-3-ethoxysalcyladehyde, 5-chloro-3-ethoxysalcyladehyde with various aromatic amines and the products were obtained in good to excellent yields. The 1H and 13C NMR spectra of all the products showed the appearance of the methylene signals ranging from 3.88 – 4.68 ppm and 42.25 – 52.57 ppm respectively. Additionally, most compounds showed anti-Mycobacterium tuberculosis activity that ranged between 20 and 28 µM. Conclusion: A total of 36 compounds were synthesised and successfully biologically evaluated against Mycobacterium tuberculosis (Mtb) H37RV strain. All compounds showed activity against Mtb at concentrations of &gt; 20 µM &lt; 28 µM with the exception of compound one that was active against Mtb at higher concentration (MIC90 &gt; 125 µM).

Challenges and the Way forward in Diagnosis and Treatment of Tuberculosis Infection.

Globally, it is estimated that one-quarter of the world's population is latently infected with Mycobacterium tuberculosis (Mtb), also known as latent tuberculosis infection (LTBI). Recently, this condition has been referred to as tuberculosis infection (TBI), considering the dynamic spectrum of the infection, as 5-10% of the latently infected population will develop active TB (ATB). The chances of TBI development increase due to close contact with index TB patients. The emergence of multidrug-resistant TB (MDR-TB) and the risk of development of latent MDR-TB has further complicated the situation. Detection of TBI is challenging as the infected individual does not present symptoms. Currently, there is no gold standard for TBI diagnosis, and the only screening tests are tuberculin skin test (TST) and interferon gamma release assays (IGRAs). However, these tests have several limitations, including the inability to differentiate between ATB and TBI, false-positive results in BCG-vaccinated individuals (only for TST), false-negative results in children, elderly, and immunocompromised patients, and the inability to predict the progression to ATB, among others. Thus, new host markers and Mtb-specific antigens are being tested to develop new diagnostic methods. Besides screening, TBI therapy is a key intervention for TB control. However, the long-course treatment and associated side effects result in non-adherence to the treatment. Additionally, the latent MDR strains are not susceptible to the current TBI treatments, which add an additional challenge. This review discusses the current situation of TBI, as well as the challenges and efforts involved in its control.

Social Determinants and Risk Factors Associated with Multi-Drug Resistant Tuberculosis Among Tuberculosis Patients in Tamilnadu – A Case-Control Study

Introduction: The emergence of Multi-drug Resistant Tuberculosis (MDR- TB) is a challenge for global control and prevention mainly in developing countries. Socio-economic conditions, social vulnerability, and behavioral factors to be considered as risk factors in identifying MDR-TB. The objective of the study was to identify independent risk factors of MDR-TB among Tuberculosis patients. Methods: An unmatched Case-control study was conducted from January 2021 to June 2021 among tuberculosis (TB) patients registered under RNTCP in Kanchipuram district during the study period. ‘Cases’ were consecutive MDR TB patients aged 15 and older, diagnosed with MDR-TB. ‘Controls’ were patients aged 15 and older, diagnosed with drug susceptible TB. Data was collected using pretested semi-structured questionnaire with face-to- face interview. Univariate and multi-variate analysis were used to identify associated determinants of MDR-TB. Results: A total of 80 subjects, 20 cases and 60 controls (1:3) were recruited. Mean age of ‘cases’ was 32±9.3 years, and for controls was 31± 8.3 years. Multiple logistic regression analysis identified five significant risk factors for the occurrence of MDR TB as follows: passive smoking [OR = 8.449, 95% CI (6.791–30.27)], overcrowding [OR= 2.062,95% CI (1.004-4.005)], low socio-economic status [OR=11.362,95% CI (10.312-35.174)] and previous TB treatment [OR =13.72 with 95% CI (8.599-35.118)]. Inadequate ventilation [OR=4.6434(.217-13.906)] Conclusion: To reduce the burden of drug-resistance, these risk factors can be used as screening tool in identifying individuals with MDR-TB in resource limited settings.