Antitubercular Drugs Research Articles

2D-QSAR and molecular docking study on nitrofuran analogues as antitubercular agents

<abstract><sec> <title>Background</title> <p>Resistance to most of the antitubercular drugs has been on rising trends due to the misuse of existing drugs. This has encouraged us to explore a novel scaffold that has the potential for quick antimicrobial action with minimum side effects. Nitrofurans have attracted us due to their extensive biological activities, such as antibacterial and antifungal activities.</p> </sec><sec> <title>Objective</title> <p>The antitubercular activities of 126 nitrofuran derivatives have been investigated by using indicator parameters and topological and structural fragment descriptors.</p> </sec><sec> <title>Methods</title> <p>The different quantitative structure activity relationship (QSAR) models have been created and validated by using two different methodologies: combinatorial protocol in multiple linear regression (CP-MLR) and partial least-squares (PLS) analysis.</p> </sec><sec> <title>Results</title> <p>The 16 descriptors identified in CP-MLR are from six different classes: Constitutional, Functional, Atom Centered Fragments, Topological, Galvez, and 2D autocorrelation. Indicator parameters and Dragon descriptors suggested that the presence of a furan ring substituted by nitro group is essential for antitubercular activity. Further descriptors from constitutional, and functional classes suggest that the number of double bonds, number of sulphur atoms and number of fragments like thiazole, morpholine and thiophene should be minimum, along with the positive influence of Kier-Hall electrotopological states (Ss) for improved activity. The ACF class descriptors, GALVEZ class descriptors, and 2D-AUTO descriptor GATS4p have also shown positive influence on the antitubercular activity. The TOPO class descriptor T(O…S) suggests that the minimum gap between sulphur and oxygen is favorable for activity.</p> </sec><sec> <title>Conclusions</title> <p>The models acknowledged in the study have explained the variance between 72 to 76% in the training set and in the prediction of the test set compounds. Also, compounds <bold>122</bold>, <bold>123</bold> and <bold>82</bold> were found to possess good binding affinity towards nitroreductase.</p> </sec></abstract>

A Study on Anti-Tubercular Drug Resistance Pattern in a Tertiary Care Hospital

Background: Tuberculosis is one of the oldest infectious diseases known to mankind. Archaeological evidences from ancient civilizations have shown the existence of tuberculosis in the prehistoric era. Even though effective chemotherapy for tuberculosis has been available for decades, tuberculosis still remains as a public health challenge all over the world. Over the years not only the medical implications but also the social and economic impact of tuberculosis has been enormous. AIM: To measure anti-tubercular drug resistance pattern at S.V.S. Medical College and Hospital, Mahabubnagar District. Material & Methods: Prospective hospital based observational study. The study was carried out in the Department of Pulmonary Medicine, S.V.S Medical College and Hospital, Enugonda, Mahbubnagar. Mar. 2021 – Feb. 2022. Patients with both Pulmonary and Extra pulmonary tuberculosis who were attending to the study facility. study consisted of 50 subjects. 1.Collection of samples (sputum, bronchial wash, pleural fluid, synovial fluid & lymph node tissue). 2. Staining method was done by Fluorescence microscopy staining procedure. 3.Grading of the slide as per WHO. 4. Culture & DST was done on L-J medium and Proportionate method. Results: Among the resistant cases, isolated R resistance was observed in 10 cases (33.3%), R with H was observed in 12 cases (40%), R with S was observed in 2 cases (6.66%), R with H, S & Lfx was observed in 2 cases (6.66%) and R with H & S was observed in 1 case (3.33%). Conclusion: The study demonstrates that levels of R, MDR & XDR are more than expected levels when compared with other studies conducted in India as per global DRS guidelines. In view of these results, Multidrug resistance continues to be a serious problem in Mahbubnagar District of TELANGANA. R resistance can be considered as a surrogate marker for MDR-TB. On the basis of these results, it is now necessary to conduct more DRS in much larger population.

A study on the mycobacterial burden and phenotypic drug resistance pattern with reference to the GeneXpert Cycle Threshold values in pulmonary tuberculosis

Introduction and aim. Tuberculosis (TB) remains a significant global health challenge. Early and accurate diagnosis is crucial to prevent further transmission. The present study aimed to correlate cycle threshold values with smear microscopy and culture positivity, and determine cut-off cycle threshold values for levels of smear grade and culture positivity. Material and methods. Forty presumptive cases of pulmonary TB were included and subjected to Ziehl- Neelsen stain, culture on Lowenstein Jensen media, CBNAAT and drug susceptibility testing for first line anti-tubercular drugs. Results. Our study predicts 3+, 2+, and 1+ sputum smear grade at a cut-off of Ct value ≤ 16.74, ≤19.68, and ≤ 22.32 respectively. A strong positive correlation was found between time to culture positivity and Ct value. A cut-off of Ct value ≤22.32 predicts culture positivity with a sensitivity of 92%, and a specificity of 67%. None of the isolates showed rifampicin resistance by 1% proportion method. Conclusion. Understanding the appropriate utilization of CBNAAT Ct values and their correlation with smear microscopy grade, culture, and drug susceptibility testing can assist clinicians in early identification and prompt initiation of appropriate treatment. This knowledge can contribute to the prevention of drug resistance, reduced transmission, and a decreased disease burden associated with TB.

Hepatoprotective effect of Pippali Ghrita, an Ayurvedic Formulation against Anti-Tubercular Drug Induced Hepatotoxicity in Wistar Rats

Combination chemotherapy of Isoniazid, Rifampicin, and Pyrazinamide is the preferred regimen for successful treatment of Tuberculosis (TB). The major complication of otherwise useful Anti-tubercular treatment (ATT) drugs is hepatic damage. There is lack of a definite effective treatment for the same in modern medicine. In view of this, the hepatoprotective activity of an Ayurvedic formulation, Pippali Ghrita (PG), was evaluated in anti-tubercular drug induced hepatotoxicity in Wistar rats. ATT drugs, viz., Isoniazid, Rifampicin, and Pyrazinamide were administered for 30 days to induce hepatotoxicity. Co-administration of PG in study group and Silymarin in standard control group was done for same duration. Hepatotoxicity was assessed on basis of ponderal parameters (body and liver weight) and biochemical parameters, viz., liver function parameters (Aspartate transaminase and Alanine transaminase), and oxidative stress parameters (Malondialdehyde and Superoxide dismutase). Results demonstrated significant increase in body weight and significant reduction in the liver weight, in study group and standard control group as compared to ATT control group. Likewise, significant reduction in liver function parameters and Malondialdehyde levels, with increase in Superoxide dismutase activity were observed, when compared to the ATT control group. The results indicated that co-administration of Pippali Ghrita for 30 days along with ATT prevented anti-tubercular drugs induced hepatotoxicity in Wistar rat model.

A dual-targeting succinate dehydrogenase and F1Fo-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M.tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the F1Fo-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M.tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M.tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.

Bronchiectasis with Trans Mediastinal Herniation of Left Upper Lobe in 3-Year-Old Child: A Case Report

BACKGROUND: Bronchiectasis is a disorder characterized by destruction of smooth muscle and elastic tissue due to inflammation which leads to permanent dilation of bronchi and bronchioles. It may develop in association with Cystic Fibrosis, a single severe episode or recurrent episodes of pneumonia and exposure to tuberculosis. The principal conditions associated with bronchiectasis are obstruction and infection. Infections primarily originate from issues with airway clearance, which cause bronchi and bronchioles to enlarge irreversibly. Vertical airways are notably affected, while distal bronchi and bronchioles are more severely affected. The degree of disease activity and chronicity may affect the histological findings. Childhood bronchiectasis can proceed to severe consequences including persistent bacterial bronchitis, in developing nations like India due to a lack of effective diagnosis and treatment as a result of poor health care infrastructure in the rural areas as well as limited awareness on the part of general public and health care professionals. THE CASE: A 3.5-year-old Indian boy presented with productive cough and cold for 8 days associated with low grade fever. Patient was admitted through Out Patient Department (OPD) due to respiratory distress and facial swelling. Clinical exam revealed presence of crepitation, wheeze and pectus carinatum. Patient has history of multiple hospital admissions due to pneumonia and respiratory distress. There is history of exposure to tuberculosis. His mother had been diagnosed with tuberculosis when the child was 3 months old. She received anti-tubercular drugs and is now cured. HRCT thorax reveals collapse of basal segment of right lung, trans-mediastinal space shift of left upper lobe and bi-lateral bronchiectatic changes which include unusually thickened enlarged airways exhibiting the characteristic tram-track appearance. Echocardiogram findings show thickened pericardium, mild pericardial collection and trace tricuspid valve regurgitation. The case is unique since it is quite rare for a young child to have such a severe form of bronchiectasis. CONCLUSION: Diagnosis can be done with the help of radiological and clinical examination. However, High Resolution Computed Tomography (HRCT) scan is the investigation of choice. Early management is a key factor in minimizing more serious complication like severe hemoptysis and cor pulmonale. Current treatment modalities include antibiotics, bronchodilators, anti-inflammatory drugs and chest physical therapy. Severe cases may require injectable antibiotics. Bronchiectasis was thought to be an orphan disease that seldom progressed to severe consequences, especially after the introduction of newer antimicrobials. There exist guidelines that advocate treatments for bronchiectasis, and reports of therapy have been shown to be linked with clinical success. However, such guidelines do not exist in India at present. This case is noteworthy as it portrays bronchiectasis in an Indian child that has proceeded to the severe complication of transmediastinal herniation, demonstrating that it is relatively common albeit under-diagnosed in developing countries. Though is an irreversible disease in adults, in children if detected early there is almost complete restoration of pulmonary function and adequate exercise tolerance. Early diagnosis with suitable pharmacological and non-pharmacological management is critical for a positive outcome and prevention of sequelae like persistent bacterial bronchitis.

Deciphering insights into the binding mechanism and plasticity of Telacebec with M. tuberculosis cytochrome bcc-aa3 supercomplex through an unbiased molecular dynamics simulation, free-energy analysis, and DFT study

The cytochrome bcc-aa3 supercomplex, a key component in the electron transport chain pathway involved in bacterial energy production and homeostasis, is a clinically validated target for tuberculosis (TB), leading to Telacebec (Q203). Telacebec is a potent candidate drug under Phase II clinical development for the treatment of drug-sensitive and drug-resistant TB. Recently, the cryo-electron microscopy structure of this supercomplex from Mycobacterium tuberculosis (Mtb) complexed with Q203 was resolved at 6.9 Å resolution (PDB ID: 7E1W). To understand the binding site (QP site) flexibility and Q203’s stability at the QP site of the Mtb cytochrome bcc complex, we conducted molecular dynamics (MD) simulation and free energy analysis on this complex in an explicit hydrated lipid bilayer environment for 500 ns. Through this study, the persistence of a range of direct and indirect interactions was observed over the course of the simulation. The significance of the interactions with His375, Tyr161, Ala178, Ala179, Ile183, His355, Leu356, and Thr313 is underlined. Electrostatic energy was the primary source of the net binding free energy, regardless of the important interacting residues. The overall binding free energy for Q203 was −112.84 ± 7.73 kcal/mol, of which the electrostatic and lipophilic energy contributions were −116.31 ± 1.14 and −21.32 ± 2.35 kcal/mol, respectively. Meanwhile, DFT calculations were utilized to elucidate Q203’s molecular properties. Overall, this study deciphers key insights into the cytochrome bcc-aa3 supercomplex with Q203 on the ground of molecular mechanics and quantum mechanics that may facilitate structure-based drug design and optimization for the discovery of the next-generation antitubercular drug(s). Communicated by Ramaswamy H. Sarma

Shortened Treatment Regimens for Drug Sensitive TB.

Tuberculosis (TB) has remained a global health challenge despite the availability of effective anti-tubercular drugs and various treatment strategies. Apart from the complications related to TB disease per se, adverse effects of antitubercular therapy (ATT) also contribute to morbidity. In addition to the adverse effects, the long duration of the treatment regimen also reduces the patient's acceptability of ATT. The available "short-course treatment regimens" are still relatively long, thereby adversely affecting treatment compliance. There is a need for effective, safe, short and intensive regimens for TB which can reduce the treatment cost and adverse effects, thereby improving its acceptance. With the emergence of new evidence, the World Health Organization (WHO) has recently endorsed 4 mo short duration ATT regimen for non-severe, drug-sensitive cases of tuberculosis. Even in severe forms of disease like tubercular meningitis (TBM), trials are underway evaluating efficacy and safety of shorter regimens. Inclusion of fluroquinolones and rifapentine help shorten the regimens. These shortened regimens, however, need more close monitoring for adverse effects and may need to be converted to longer course if there is inadequate clinical response. Thus, shorter regimens for pediatric TB are likely to not only decrease the burden on patients and healthcare but also improve compliance and lower the side effects of the drugs due to prolonged exposure. This article reviews the current evidence and the guidelines pertaining to the shortened, intensive regimens for drug-sensitive tuberculosis.

In Silico Drug Repurposing Studies for the Discovery of Novel Salicyl-AMP Ligase (MbtA)Inhibitors.

Tuberculosis (TB) continues to pose a global health challenge, exacerbated by the rise of drug-resistant strains. The development of new TB therapies is an arduous and time-consuming process. To expedite the discovery of effective treatments, computational structure-based drug repurposing has emerged as a promising strategy. From this perspective, conditionally essential targets present a valuable opportunity, and the mycobactin biosynthesis pathway stands out as a prime example highlighting the intricate response of Mycobacterium tuberculosis (Mtb) to changes in iron availability. This study focuses on the repurposing and revival of FDA-approved drugs (library) as potential inhibitors of MbtA, a crucial enzyme in mycobactin biosynthesis in Mtb conserved among all species of mycobacteria. The literature suggests this pathway to be associated with drug efflux pumps, which potentially contribute to drug resistance. This makes it a potential target for antitubercular drug discovery. Herein, we utilized cheminformatics and structure-based drug repurposing approaches, viz., molecular docking, dynamics, and PCA analysis, to decode the intermolecular interactions and binding affinity of the FDA-reported molecules against MbtA. Virtual screening revealed ten molecules with significant binding affinities and interactions with MbtA. These drugs, originally designed for different therapeutic indications (four antiviral, three anticancer, one CYP450 inhibitor, one ACE inhibitor, and one leukotriene antagonist), were repurposed as potential MbtA inhibitors. Furthermore, our study explores the binding modes and interactions between these drugs and MbtA, shedding light on the structural basis of their inhibitory potential. Principal component analysis highlighted significant motions in MbtA-bound ligands, emphasizing the stability of the top protein-ligand complexes (PLCs). This computational approach provides a swift and cost-effective method for identifying new MbtA inhibitors, which can subsequently undergo validation through experimental assays. This streamlined process is facilitated by the fact that these compounds are already FDA-approved and have established safety and efficacy profiles. This study has the potential to lay the groundwork for addressing the urgent global health challenge at hand, specifically in the context of combating antimicrobial resistance (AMR) and tuberculosis (TB).

CLINICAL PHARMACIST INTERVENTIONS ON MILIARY KOCH’S PATIENT WITH ANTITUBERCULAR THERAPY-INDUCED HEPATOTOXICITY AND PSYCHOSIS: A RARE CASE REPORT

Psychosis and hepatotoxicity are the dangerous side effects of the antitubercular drugs directly observed treatment short course (DOTS) therapy. Hematological spreading of tubercular bacteria in the lungs is also known as miliary tuberculosis. In this case study, 45-year-old man, weighing 55 kg was brought to the hospital with the chief complaints of vomiting (multiple episodes), fever, pain in abdomen, difficulty in breathing, mucoid cough, and disturbed sleep for the past 1 week. He had a known case of smear-positive pulmonary tuberculosis (in the past 1 month), but at that time, patient was not taking regular antitubercular treatment (ATT) medications (DOTS therapy). After 3th week of irregular antitubercular drug treatment, patient developed with the problems such as vomiting (multiple episodes), fever, pain in abdomen, difficulty in breathing, cough with expectorations, disturbed in sleep, and delirium. Pulmonologists had found the provisional and final diagnosis on the bases of subjective and objective observations miliary KOCH’S with antitubercular drugs induced hepatotoxicity and psychosis. Patients recovered from psychosis and hepatotoxicity withdrawn the first line ATT medication and tablet pyridoxine, antipsychotic medicines, and modified ATT were added in the therapy. Psychotic in a patient on ATT can be one of the complications of tablet isoniazid. As a clinical pharmacologist, we prevent and minimize drugs-induced complications and adverse drug reactions. Proper patients counseling and patients’ education are important for the better management of patients.

Tuberculosis manifesting as bilateral acute parotid swelling with unilateral lower motor neuron facial palsy: an unusual presentation

A 41-year-old female presented to the otorhinolaryngology department with a history of painful swelling over the bilateral parotid region, low-grade fever for the past one month and progressively worsening left-side facial weakness for the last 15 days. She had received multiple courses of antibiotics elsewhere, which did not result in any improvement except pain. She had no past history of any comorbidities or any previous history of tuberculosis. Examination revealed that she had a non-tender, circumscribed, solitary, 3×3 cm size, firm swelling over the bilateral parotid region. Clinical signs of grade V facial nerve palsy (House and Brackmann classification) were noted. There was a severe grade left lower motor neuron facial nerve palsy (left side) seen. There was no cervical lymphadenopathy. The rest of the head and neck examination was unremarkable. Fine needle aspiration cytology (FNAC) from the most prominent part of the swelling was suggestive of granulomatous inflammation. The patient was initially treated with intravenous antibiotics, supportive care and started on antitubercular drugs (once the diagnosis was established) under the National Tuberculosis Eradication Program (NTEP) to which she responded well and after three months of therapy, her swelling and facial weakness improved significantly. In addition to reporting a completely rare kind of presentation, this paper reviews relevant literature and stresses the need for a high degree of suspicion for tuberculous parotitis in a patient with bilateral parotid swelling. The use of fine needle aspiration is important so that this curable condition can be diagnosed early and medically treated. In this way, surgical intervention can be avoided and further complications can be prevented.

Diffuse Tenosynovial Giant Cell Tumor of the Wrist with Joint Destruction and Invasion

Abstract A 54-year-old man took antitubercular drugs for 1 year for right wrist pain, swelling, and restriction of movements, with no improvements. Magnetic resonance imaging wrist reported multiple nodules and soft-tissue mass with intraosseous erosions involving carpal bones, distal radius, and ulna. Resection of the mass, excision of the distal ulna, and wrist arthrodesis were done. The histopathology confirmed a diffuse tenosynovial giant cell tumor (TSGCT). No postoperative radiotherapy or systemic therapies were given. The patient remained symptom-free at 2 years of follow-up. Diffuse TSGCT with joint destruction and invasion of the wrist is rare. Therefore, a high index of suspicion is required before considering the most common infective etiologies in the wrist.

Nano vs Resistant Tuberculosis: Taking the Lung Route.

Tuberculosis (TB) is among the top 10 infectious diseases worldwide. It is categorized among the leading killer diseases that are the reason for the death of millions of people globally. Although a standardized treatment regimen is available, non-adherence to treatment has increased multi-drug resistance (MDR) and extensive drug-resistant (XDR) TB development. Another challenge is targeting the death of TB reservoirs in the alveoli via conventional treatment. TB Drug resistance may emerge as a futuristic restraint of TB with the scarcity of effective Anti-tubercular drugs. The paradigm change towards nano-targeted drug delivery systems is mostly due to the absence of effective therapy and increased TB infection recurrent episodes with MDR. The emerging field of nanotechnology gave an admirable opportunity to combat MDR and XDR via accurate diagnosis with effective treatment. The new strategies targeting the lung via the pulmonary route may overcome the new incidence of MDR and enhance patient compliance. Therefore, this review highlights the importance and recent research on pulmonary drug delivery with nanotechnology along with prevalence, the need for the development of nanotechnology, beneficial aspects of nanomedicine, safety concerns of nanocarriers, and clinical studies.

Early Blockage of Mycobacterium Tuberculosis Cell-wall Synthesis via EchA\6 Inhibition to Overcome Resistance Strain: Insights from Umbrella Sampling Simulations

Background: Tuberculosis (TB) has long been the major infectious cause of mortality, ranking higher than HIV/AIDS as the most common cause of death from a single infectious agent worldwide. The EchA6 target of mycobacteria plays a vital role in synthesizing an important component of the mycobacterial outer membrane. The failure of TB treatment has prompted the investigation of novel anti-tubercular drugs. Objective: This study was aimed at blockage of Mycobacterium tuberculosis cell-wall synthesis via EchA6 inhibition to overcome resistance strain. Methods: Over 3,000,000 compounds and GSK951A (positive control) were investigated as the inhibitors in this study. The GROMACS molecular dynamic package was used to analyze the protein- inhibitor complex's conformational changes under constant temperature and pressure. Also, umbrella sampling (US) was used for free binding energy (ΔG) calculation. Results: Four compounds were chosen for the docking investigation. According to the MD analysis, the studied inhibitors demonstrated good stability and flexibility. According to ∆G obtained from US, the ∆G of GSK951A, ZINC11815220, ZINC67770050, ZINC55048326, and ZINC89700914 were -6.14 kcal mol-1, -5.25 kcal mol-1, -10.19 kcal mol-1, -8.55 kcal mol-1, and -8.37 kcal mol-1, respectively. Conclusion: In conclusion, ZINC67770050 is recommended for further study in the laboratory. This investigation is an important starting point for discovering anti-tubercular drugs using EchA6 inhibition.

An insight on the prospect of quinazoline and quinazolinone derivatives as anti-tubercular agents.

Multiple potential drugs have been developed based on the heterocyclic molecules for the treatment of different symptoms. Among the existing heterocyclic molecules, quinazoline and quinazolinone derivatives have been found to exhibit extensive pharmacological and biological characteristics. One significant property of these molecules is their potency as anti-tubercular agents. Thus, both quinazoline and quinazolinone derivatives are modified using different functional groups as substituents for investigating their anti-tubercular activities. We present a summary of the reported anti-tubercular drugs, designed using quinazoline and quinazolinone derivatives, in this review.

Tuberculosis Diagnosis and Detection of Drug Resistance: A Comprehensive Updated Review

Tuberculosis (TB) is a significant public health challenge, especially in developing nations. Developing a TB eradication strategy is hampered by the global health concern of drug-resistant (DR) TB. Effective patient treatment, preventing TB transfer and avoiding the upsurge of DR strains depend primarily on the timely and accurate identification of DR TB. Due to inadequate sensitivity, the necessity of trained laboratory personnel, the sluggish growth pattern of Mycobacterium bacilli in culture, and the small number of bacilli that are usually found in extrapulmonary TB samples, TB diagnosis is still tricky in clinical practice. Although mycobacterial culture is the gold standard to identify TB and determine drug resistance, it takes 2 to 8 weeks to develop. Despite their high cost, nucleic acid amplification tests (NAATs) and whole-genome sequencing (WGS) are the commonly employed molecular-based methods for diagnosing and identifying TB. The WHO suggested the GeneXpert MTB/RIF to identify TB and detect resistance to rifampicin. In comparison, numerous molecular techniques were developed, including allele-specific PCR (MAS-PCR), solid-phase hybridization, real-time PCR (RT-PCR) and droplet digital PCR-based technique (DDPCR). This manuscript is intended to overview the current approaches for the phenotypic and genotypic diagnosis of TB disease and identifying resistance to antitubercular drugs depending on recently published articles, WHO and CDC reports, and commercially available diagnostic tools.

Treatment outcomes of multidrug resistant tuberculosis (MDR TB) treated with bedaquiline under programmatic management of drug resistant tuberculosis at a tertiary care hospital in Punjab, India

IntroductionMDR TB is a serious global concern which is hampering TB elimination goals badly. Standardized MDR TB regimen had high default rates, more side effects and poor treatment outcomes. Bedaquiline is a newer anti-tubercular drug which has made oral regimens possible for MDR TB. We aimed to study the outcomes of MDR TB patients treated with Bdq containing regimens. Methods155 patients of MDR TB on Bdq containing regimen enrolled at GMC, Patiala under NTEP from 2017 to 2020 were enrolled retrospectively. ResultsOut of 155 patients enrolled, 82 (52.9 %) were cured, 31 (20 %) completed treatment, 18 (11.6 %) defaulted, 22 (14.2 %) died and 2 (0.12 %) failed treatment. ConclusionBdq is well tolerated with very less side effects and has better outcomes as compared to standard MDR regimens which were followed earlier.

Marine-Fungi-Derived Gliotoxin Promotes Autophagy to Suppress Mycobacteria tuberculosis Infection in Macrophage.

The Mycobacterium tuberculosis (MTB) infection causes tuberculosis (TB) and has been a long-standing public-health threat. It is urgent that we discover novel antitubercular agents to manage the increased incidence of multidrug-resistant (MDR) or extensively drug-resistant (XDR) strains of MTB and tackle the adverse effects of the first- and second-line antitubercular drugs. We previously found that gliotoxin (1), 12, 13-dihydroxy-fumitremorgin C (2), and helvolic acid (3) from the cultures of a deep-sea-derived fungus, Aspergillus sp. SCSIO Ind09F01, showed direct anti-TB effects. As macrophages represent the first line of the host defense system against a mycobacteria infection, here we showed that the gliotoxin exerted potent anti-tuberculosis effects in human THP-1-derived macrophages and mouse-macrophage-leukemia cell line RAW 264.7, using CFU assay and laser confocal scanning microscope analysis. Mechanistically, gliotoxin apparently increased the ratio of LC3-II/LC3-I and Atg5 expression, but did not influence macrophage polarization, IL-1β, TNF-a, IL-10 production upon MTB infection, or ROS generation. Further study revealed that 3-MA could suppress gliotoxin-promoted autophagy and restore gliotoxin-inhibited MTB infection, indicating that gliotoxin-inhibited MTB infection can be treated through autophagy in macrophages. Therefore, we propose that marine fungi-derived gliotoxin holds the promise for the development of novel drugs for TB therapy.

Effect of Metformin on Plasma Exposure of Rifampicin, Isoniazid, and Pyrazinamide in Patients on Treatment for Pulmonary Tuberculosis.

To evaluate the effect of metformin on the plasma levels of rifampicin, isoniazid, and pyrazinamide in patients with drug-sensitive pulmonary tuberculosis being treated with first-line antituberculosis treatment (ATT) and to assess the influence of gene polymorphisms on the metabolic pathway of metformin and plasma levels of antitubercular drugs. Nondiabetic adults aged 18-60 years with pulmonary tuberculosis were randomized to either the standard ATT (ATT group) or ATT plus metformin (METRIF group) groups in a phase IIB clinical trial. An intensive pharmacokinetic study with blood collection at 0 hour (predosing), followed by 1, 2, 4, 6, 8, and 12 hours after dosing was conducted during the first month of treatment in a subset of 60 study participants after a minimum of 14 doses. Plasma concentrations of rifampicin, isoniazid, pyrazinamide, and metformin were measured by high-performance liquid chromatography using validated methods, and pharmacokinetic parameters and OCT1 and MATE1 gene polymorphisms were compared between the groups. Significant increases in the clearance of rifampicin, isoniazid, and pyrazinamide were observed in patients in the METRIF group (n = 29) compared with those in the ATT group (n = 31). The AA genotypes of the single-nucleotide polymorphism of rs2289669 ( MATE1 ) in the METRIF group showed a significantly decreased area under the concentration-time curve to the last observation point and increased clearance of rifampicin. Metformin altered rifampicin and isoniazid plasma concentrations in patients receiving antituberculosis treatment for pulmonary tuberculosis with little effect on sputum conversion at the end of treatment. Studies with larger sample sizes are needed to understand host drug-drug interactions.

1897. Therapeutic Drug Monitoring in CSF and Plasma in Tuberculous Meningitis:Correlation with Disease Outcome

Abstract Background Tuberculous meningitis (TBM) is a serious form of extra-pulmonary tuberculosis with significant morbidity and mortality. TBM patients are treated with pulmonary tuberculosis regimen, often requiring extension for 1 year or longer. Current study was designed to find any association of CSF and blood levels of anti-tubercular drugs with treatment response in patients with tuberculous meningitis using therapeutic drug monitoring. Pharmacokinetic Parameters of Rifampicin and Isoniazid in CSF and Plasma Methods A prospective observational study was conducted in a tertiary care institute in North India among clinic-radiologically and/or microbiologically diagnosed TBM patients. Plasma and CSF levels of anti TB drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) were determined using Liquid Chromatography Mass Spectrometry technology at 1 week and 1 month (follow up) after initiating treatment. The primary outcome assessed was association of drug levels with treatment response. The secondary outcomes assessed were association of drug levels with treatment duration/alteration, patient demographic profile, comorbidities and adverse effects. Patients were followed-up till treatment completion. Results A total of 40 patients with TBM were recruited. All received daily weight-based doses of anti TB drugs. Low Cmax of INH and rifampicin in plasma were observed in 60.5% & 42.1% of observations respectively. In CSF, low Cmax of INH and rifampicin were observed in 77.6% & 82.9% of observations respectively. The concentrations of INH (4 hours after drug intake) during follow up were significantly lower among patients with poor response, at 1 month (p=0.008) & 6 months (p=0.009). Similarly, low Cmax & CSF levels of INH at follow up sampling were significantly associated with poor response at 6 months of therapy (p= 0.022 & 0.042 respectively). Conclusion Low plasma and CSF concentrations of isoniazid were associated with a poor response to treatment in patients with TBM. Therapeutic drug monitoring can guide dose modification of ATT to achieve target concentrations in patients with TBM and facilitate optimal treatment outcomes. Higher dose INH can be considered in TBM treatment regimen for better outcome. Disclosures All Authors: No reported disclosures