Revolutionizing control strategies against Mycobacterium tuberculosis infection through selected targeting of lipid metabolism.

Lipid species play a critical role in the growth and virulence expression of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). During Mtb infection, foamy macrophages accumulate lipids in granulomas, providing metabolic adaptation and survival strategies for Mtb against multiple stresses. Host-derived lipid species, including triacylglycerol and cholesterol, can also contribute to the development of drug-tolerant Mtb, leading to reduced efficacy of antibiotics targeting the bacterial cell wall or transcription. Transcriptional and metabolic analyses indicate that lipid metabolism-associated factors of Mtb are highly regulated by antibiotics and ultimately affect treatment outcomes. Despite the well-known association between major antibiotics and lipid metabolites in TB treatment, a comprehensive understanding of how altered lipid metabolites in both host and Mtb influence treatment outcomes in a drug-specific manner is necessary to overcome drug tolerance. The current review explores the controversies and correlations between lipids and drug efficacy in various Mtb infection models and proposes novel approaches to enhance the efficacy of anti-TB drugs. Moreover, the review provides insights into the efficacious control of Mtb infection by elucidating the impact of lipids on drug efficacy. This review aims to improve the effectiveness of current anti-TB drugs and facilitate the development of innovative therapeutic strategies against Mtb infection by making reverse use of Mtb-favoring lipid species.

Yield & accuracy of Gastric Lavage in non-expectorating adults with Suspected Pulmonary Tuberculosis.

Objective: To determine the yield of Gastric lavage (GL) in non-expectorating adults with suspected Pulmonary Tuberculosis (PTB) and accuracy of GL-AFB smear with GL-GeneXpert (GXP) by taking AFB culture as gold standard. Methods: Cross-sectional study on suspected PTB patients was done at Ojha Institute of Chest Diseases during period 16th July 2020 till 15th January 2021. Adult patients of either gender suspected to have PTB and not expectorating were included. GL was performed and sent for AFB smear, GXP and AFB culture. Odds ratio, sensitivity and specificity were calculated. Results: After informed written consent, 206 patients, mean age was 38.17 ±17.30 years were inducted, including 89 (43.2%) males and 117 (56.8%) females. Gene Xpert, AFB smear & AFB culture were positive in 83(40%), 50 (24%) & 72 (35%) respectively in GL samples. Odds of PTB were 3.95 times higher among patients with ≤1 month of duration of symptoms (aOR 3.95, 95% CI 1.82-8.57, p-value 0.001), 6.24 times higher among patients with weight loss (aOR 6.24, 95% CI 3.03-12.84, p-value <0.001), and 4.22 times higher among patients with cavitation (aOR 4.22, 95% CI 1.99-8.93, p-value <0.001). GL-AFB smear showed sensitivity 63.89%, specificity 97.01%, positive predicted value 92%, negative predicted value 83.3%, and overall diagnostic accuracy 85.4%. Whereas GL-GXP showed sensitivity 94.4%, specificity 88.81%, positive predicted value 81.93%, negative predicted value 96.75%, and overall diagnostic accuracy 90.78%. Conclusion: Yield of GL significant to detect PTB in suspected cases who are not expectorating. GL-GXP diagnostic accuracy and sensitivity is higher than GL-AFB smear.

Determinants of stock-outs of first line anti-tuberculosis drugs: the case of public health facilities of Addis Ababa city administration health bureau, Addis Ababa, Ethiopia.

BACKGROUND: The health sectors success has been determined by consistent and reasonably priced health commodities supply. Despite possible death from the disease, Tuberculosis (TB) can be prevented with early diagnosis and appropriate treatment for which enough, effective, and qualified medicines need to be available. However, studies revealed stock of anti-TB drugs in health facilities. Here we present the recent finding on determinants of stock out of Anti-TB drug at public health facilities of Addis Ababa. OBJECTIVE: This study aimed to identify determinants of stock outs of first line anti TB drugs at public health facilities under Addis Ababa City Administration Health Bureau. METHOD: Mixed study design were employed. A total of 106 facilities were included in the sampling frame and data were collected from the study population such as drug store managers of health facilities providing TB treatment using semi structured questionnaire and through in-depth interview with Addis Ababa hubs of the Ethiopian Pharmaceuticals Supply Agency (EPSA), Addis Ababa City Administration Health Bureau and selected heads of pharmacy departments of health facilities from May 1-30, 2020 considering one year back retrospective data from March 20,2019 to March 20,2020. Structured record review of data from Logistics Management Information System (LMIS) tools having TB drugs was done using structured observation checklist. Data were entered, cleaned, and analyzed using SPSS Version 20. Both descriptive and multiple logistic regression analysis were performed. RESULT: 52(62.7%) of health facilities encountered stock out for at least one of these drugs during the past 1 year. Rifampicin 75 mg + Isoniazid 50 mg (RH 75/50 mg) were most stocked out first line anti-TB drug from 33(39.8%) of facilities with 17 mean stocks out days while Rifampicin 75 mg + Isoniazid 50 mg + Pyrazinamide 150 mg (RHZ 75/50/150 mg) were the least first line anti-TB drug stocked out from facilities with mean 5 days of stock out. Delayed supply of anti TB drug from EPSA, delivery of reduced quantity of anti TB drugs by EPSA and stocked out of anti TB Drugs at EPSA were significant determinate factors of stock out of first line anti-TB drug from facilities with 95%CI of 10.34(2.167-49.329), 11.452(2.183-60.079) and 5.646(1.240-25.707) respectively. CONCLUSION: Above median of health facilities encountered stock out of first line anti-TB drug in Addis Ababa. Delayed supply of anti TB drug from EPSA, delivery of reduced quantity of anti TB drugs by EPSA and stocked out of anti TB Drugs at EPSA were significant determinate factor of stocked out of first line anti-TB drug from facilities. EPSA and other responsible bodies shall work collaboratively to improve their service and ensure availability of adequate amount of Anti TB drug in health facilities.

Drug resistance patterns, treatment outcomes and factors affecting unfavourable treatment outcomes among extensively drug resistant tuberculosis patients in Pakistan; a multicentre record review.

Background: Extensively drug resistant tuberculosis (XDR-TB) is considered as a major threat to global health. This study aimed to analyse the treatment outcomes and identify the factors significantly associated with unfavourable treatment outcomes among XDR-TB patients. Methods: We conducted a retrospective observational study at 10 Programmatic Management Units of the National Tuberculosis Control Program of Pakistan. The Electronic Nominal Recording Reporting System records were used to collect data of all eligible XDR-TB patients registered at the study sites between March 2012 and August 2018. Treatment outcomes were analysed as per the standard criteria. Factors associated with unfavourable treatment outcomes were analysed by using multivariate binary logistic regression analysis. Results: Out of the total 184 patients, 59 (32.1%) completed their treatment successfully. Whereby, 83 patients (45.1%) died, 24 (13%) had treatment failure, and 11 (6%) were lost to follow-up. Treatment outcomes were not evaluated in 7 (3.8%) patients. Factors significantly associated with unfavourable treatment outcomes included; conventional therapy with bedaquiline, unfavourable interim treatment outcomes and occurrence of adverse drug events (negative association). Conclusion: Treatment success rate in the study cohort was sub-optimal (i.e., <75%). The poor success rate and high mortality are concerning, and requires immediate attention of the program managers and clinicians.

Targeting Non-Replicating Mycobacterium tuberculosis and Latent Infection: Alternatives and Perspectives (Mini-Review).

Latent tuberculosis infection (LTBI) represents a major challenge to curing TB disease. Current guidelines for LTBI management include only three older drugs and their combinations-isoniazid and rifamycins (rifampicin and rifapentine). These available control strategies have little impact on latent TB elimination, and new specific therapeutics are urgently needed. In the present mini-review, we highlight some of the alternatives that may potentially be included in LTBI treatment recommendations and a list of early-stage prospective small molecules that act on drug targets specific for Mycobacterium tuberculosis latency.

Molecular characterization and antimicrobial resistance profiles of Mycobacterium tuberculosis complex in environmental substrates from three dairy farms in Eastern Cape, South Africa.

This study analysed 330 environmental substrates from three dairy farms for the occurrence, drug resistance and the genetic mutations of MTBC (Mycobacterium tuberculosis complex) in Eastern Cape, South Africa using PCR, while the Genotype MTBDRplus assay was used for drug susceptibility and genetic mutations analyses. About 17% (55/330) of the samples were positive for MTBC at 16.7% (water), 13.3% (soil) and 20% (hayfeed). Isoniazid resistance was detected in 47.3% (26/55) of the samples while 16.4% (9/55) were multidrug-resistant. Genetic mutations were detected on the rpoB gene (resistance to rifampicin) with frequencies ranging from 53.6% (D516V) to 21.4% (H526D), while mutations on the katG and inhA genes (resistance to isoniazid) ranged between 14.3% and 80%. Incidents of diverse genetic mutations in the environmental matrices suggest possible resistance to other anti-TB drugs not assayed in this study and emphasizes the need for continuous monitoring of drug resistance patterns for timely detection and control of new clonal groups of MTBC.

Incidence of adverse reactions caused by first-line anti-tuberculosis drugs and treatment outcome of pulmonary tuberculosis patients in Morocco.

PURPOSE: The treatment of tuberculosis is associated with a high incidence of adverse reactions with different degrees of severity. The aim of this study was to determine the incidence of adverse reactions caused by first-line anti-tuberculosis drugs and to evaluate the treatment outcome of TB patients in a large region of Morocco. METHODS: It is a multi-centric observational cohort study conducted from January 01, 2014 to January 01, 2016. A questionnaire was established for data collection from clinical charts of TB patients. The study was carried out in all the 18 centers located in the Rabat-Salé-Kénitra region of Morocco where tuberculosis is treated. Adverse reactions are evaluated from the start of TB treatment until its end by a specialist clinician. The treatment outcomes are evaluated, and the definitions and classifications of these outcomes are defined according to World Health Organization guidelines. RESULTS: Among a total number of 2532 patients treated for TB, the average age is 37.3 ± 16.4 years, 10.0% of patients produced adverse reactions. 7.4% of adverse reactions are gastrointestinal, 3.7% are cutaneous, 2.0% are hepatic, 1.14% are articular, 1.07% are immunoallergic, 0.7% are neuropsychiatric, and 0.1% are ocular. The treatment outcome of TB patients is 79.1% rate for successful treatment and 15.6% for unsuccessful treatment. CONCLUSION: Adverse reactions caused by anti-TB drugs are frequent among patients with TB. These ADRs must be followed up by a closer monitoring during anti-TB treatment period. Treatment success outcome in our study is slightly lower than the success rate target of WHO of at least 85%.

SURVEY OF ANTITUBERCULOSIS DRUG ADMINISTRATION AND ADVERSE EFFECTS IN ELEPHANTS IN NORTH AMERICA.

Tuberculosis, caused by Mycobacterium tuberculosis, is a disease causing morbidity and mortality in captive elephants (Elephas maximus and Loxodonta africana) as well as free-ranging individuals. Elephants in North America diagnosed with tuberculosis are often treated with antituberculosis drugs, unlike livestock species, which has necessitated the development of treatment guidelines adapted from recommendations for humans. There are few published reports describing empirical treatment, which may be complicated by poor patient compliance, interruptions in drug administration, and adverse effects. A survey of elephants in North America was conducted to compile information on treatment protocols, including drugs, dosages, routes of administration, serum drug concentrations, and adverse effects of antituberculosis treatment. Responses were received regarding 182 elephants, 12 of which were treated prophylactically or therapeutically with antituberculosis drugs. Treatment protocols varied among elephants, and included various combinations of isoniazid, rifampin, pyrazinamide, ethambutol, enrofloxacin, levofloxacin, and ethionamide. Serum drug concentrations also varied considerably among and within individuals. Facility staff reported 5 elephants (out of 7 treated elephants with responses) that exhibited clinical signs that may have been associated with antituberculosis drugs or treatment procedures. Anorexia, decreased water intake, constipation, depression, ataxia, limb paresis, and tremors were among the signs observed. Most adverse effects were reported to be moderate or severe, resulting in interruption of the treatment. The results from this survey provide veterinarians and elephant managers with valuable historical data to make informed clinical management decisions regarding antituberculosis therapy in elephants.

Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations.

Optimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by a one-compartment model and that for INH and EMB by a two-compartment model. Plasma maximum concentration (Cmax) and AUC targets were based on published results for children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except for N-acetyltransferase 2 non-slow acetylators (rapid and intermediate acetylators) in the lower-weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.).

Risk factors for the occurrence of multidrug-resistant tuberculosis among patients undergoing multidrug-resistant tuberculosis treatment in East Shoa, Ethiopia.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is resistant to the two main first-line anti-tuberculosis drugs: rifampicin and isoniazid. It is a major threat to public health worldwide. The objective of this study was to assess the potential risk factors for multidrug-resistant tuberculosis among patients undergoing MDR-TB treatment at two community hospitals in Ethiopia. METHODS: A case-control study design was conducted from February 1, 2016, to April 29, 2016. TB-positive patients with MDR-TB and non-MDR-TB were considered as cases and controls, respectively. A total of 219 study participants were included in the study. An interviewer-administered structured questionnaire was used to collect primary data from the patients, and a checklist was used to collect data from the clinical records. Bivariate and multivariate logistic regression analyses were used to assess the potential risk factors for the occurrence of MDR-TB. RESULTS: The odds of developing MDR-TB were higher in patients previously treated with anti-TB drugs (odds ratio [OR] = 6.1, 95%CI: 2.92-12.62, P < 0.001), those with a history of contact with known TB patients (OR = 2.1, 95%CI: 1.04-4.43, P < 0.001), those living in a rural setting (OR = 5.6, 95%CI: 2.14-14.46, P = 0.001), those with a history of alcohol consumption (OR = 4.3, 95%CI: 2.29-10.49, P < 0.001) and those without a job (OR = 2.4, 95%CI: 1.06-5.42, P = 0.001). CONCLUSIONS: The study revealed that contact with known TB patients, previous TB treatment, residence area, lack of a job, and alcohol consumption were potential risk factors for the occurrence of MDR-TB. Enhancing public health education, intensifying directly observed therapy programmes for all TB patients and designing control strategies are recommended.

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection.

Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC0-8), maximum concentration (Cmax), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores (P < 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC0-8 values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC0-8 for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.).

Assessments of serum copper and zinc concentration, and the Cu/Zn ratio determination in patients with multidrug resistant pulmonary tuberculosis (MDR-TB) in Côte d'Ivoire.

BACKGROUND: In Côte d'Ivoire, multidrug-resistant tuberculosis (MDR-TB) is a serious public health problem with a prevalence estimated at 2.5% in 2006. Zinc and copper are essential Trace element needed to strengthen the immune system and also useful in the fight against tuberculosis. The Cu / Zn ratio is a good indicator of oxidative stress. The principal aim of this study was to evaluate the serum concentration of some trace element and determine the Cu / Zn ratio in patients with multidrug resistant pulmonary tuberculosis (MDR-TB) before and after second line treatment of TB. METHODS: Blood samples were obtained from 100 MDR-TB patients after confirmation of their status through the microscopic and molecular diagnosis of resistance to Isoniazid and Rifampicin by GeneXpert. The concentration level of zinc and copper were determined using flame air / acetylene atomic absorption spectrometer (AAS) Type Varian Spectr AA-20 Victoria, Australlia. RESULTS: A significant decrease in zinc levels (P < 0.05) and an increased Cu / Zn ratio (P < 0.05) was observed in MDR-TB patients compared to controls TB free. During treatment a significant reduction in Cu / Zn ratio (P < 0.05) was observed compared to the initial result. CONCLUSIONS: The decrease in serum zinc level and the high Cu / Zn ratio could explain the immune system dysfunction and the high level of oxidative stress in patients with MDR-TB. Therefore the evaluation of the zinc and copper status could represent essential parameters in monitoring of TB second line treatment for better treatment management.

Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes.

Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring.

INTRODUCTION: Tuberculosis (TB) remains one of the world's deadliest communicable diseases. Although cure rates of the standard four-drug (rifampicin, isoniazid, pyrazinamide, ethambutol) treatment schedule can be as high as 95-98 % under clinical trial conditions, success rates may be much lower in less well resourced countries. Unsuccessful treatment with these first-line anti-TB drugs may lead to the development of multidrug resistant and extensively drug resistant TB. The intrinsic interindividual variability in the pharmacokinetics (PK) of the first-line anti-TB drugs is further exacerbated by co-morbidities such as HIV infection and diabetes. METHODS: Therapeutic drug monitoring has been proposed in an attempt to optimize treatment outcome and reduce the development of drug resistance. Several studies have shown that maximum plasma concentrations (C max), especially of rifampicin and isoniazid, are well below the proposed target C max concentrations in a substantial fraction of patients being treated with the standard four-drug treatment schedule, even though treatment's success rate in these studies was typically at least 85 %. DISCUSSION: The proposed target C max concentrations are based on the concentrations of these agents achieved in healthy volunteers and patients receiving the standard doses. Estimation of C max based on one or two sampling times may not have the necessary accuracy since absorption rate, especially for rifampicin, may be highly variable. In addition, minimum inhibitory concentration (MIC) variability should be taken into account to set clinically meaningful susceptibility breakpoints. Clearly, there is a need to better define the key target PK and pharmacodynamic (PD) parameters for therapeutic drug monitoring (TDM) of the first-line anti-TB drugs to be efficacious, C max (or area under the curve (AUC)) and C max/MIC (or AUC/MIC). CONCLUSION: Although TDM of first-line anti-TB drugs has been successfully used in a limited number of specialized centers to improve treatment outcome in slow responders, a better characterization of the target PK and/or PK/PD parameters is in our opinion necessary to make it cost-effective.

Detection of mutations associated with isoniazid resistance in multidrug-resistant Mycobacterium tuberculosis clinical isolates.

OBJECTIVES: To determine the prevalence of isoniazid resistance-conferring mutations among multidrug-resistant (MDR) isolates of Mycobacterium tuberculosis from Poland. METHODS: Nine genetic loci, including structural genes (katG, inhA, ahpC, kasA, ndh, nat and mshA) and regulatory regions (i.e. the mabA-inhA promoter and oxyR-ahpC intergenic region) of 50 MDR M. tuberculosis isolates collected throughout Poland were PCR-amplified in their entirety and screened for mutations by direct sequencing methodology. RESULTS: Forty-six (92%) MDR M. tuberculosis isolates had mutations in the katG gene, and the katG Ser315Thr substitution predominated (72%). Eight (16%) isolates (six with a mutated katG allele) had mutations in the inhA promoter region and two such isolates also had single inhA structural gene mutations. Mutations in the oxyR-ahpC locus were found in five (10%) isolates, of which all but one had at least one additional mutation in katG. Mutations in the remaining genetic loci (kasA, ndh, nat and mshA) were detected in 12 (24%), 4 (8%), 5 (10%) and 17 (34%) MDR isolates, respectively. All non-synonymous mutants for these genes harboured mutations in katG. One isolate had no mutations in any of the analysed loci. CONCLUSIONS: This study accentuates the usefulness of katG and inhA promoter mutations as predictive markers of isoniazid resistance. Testing only for katG 315 and inhA -15 mutations would detect isoniazid resistance in 84% of the MDR M. tuberculosis sample. This percentage would increase to 96% if the sequence analysis was extended to the entire katG gene. Analysis of the remaining genetic loci did not contribute greatly to the identification of isoniazid resistance.

Comprehensive Therapeutic Approaches to Tuberculous Meningitis: Pharmacokinetics, Combined Dosing, and Advanced Intrathecal Therapies.

Tuberculous meningitis (TBM) presents a critical neurologic emergency characterized by high mortality and morbidity rates, necessitating immediate therapeutic intervention, often ahead of definitive microbiological and molecular diagnoses. The primary hurdle in effective TBM treatment is the blood-brain barrier (BBB), which significantly restricts the delivery of anti-tuberculous medications to the central nervous system (CNS), leading to subtherapeutic drug levels and poor treatment outcomes. The standard regimen for initial TBM treatment frequently falls short, followed by adverse side effects, vasculitis, and hydrocephalus, driving the condition toward a refractory state. To overcome this obstacle, intrathecal (IT) sustained release of anti-TB medication emerges as a promising approach. This method enables a steady, uninterrupted, and prolonged release of medication directly into the cerebrospinal fluid (CSF), thus preventing systemic side effects by limiting drug exposure to the rest of the body. Our review diligently investigates the existing literature and treatment methodologies, aiming to highlight their shortcomings. As part of our enhanced strategy for sustained IT anti-TB delivery, we particularly seek to explore the utilization of nanoparticle-infused hydrogels containing isoniazid (INH) and rifampicin (RIF), alongside osmotic pump usage, as innovative treatments for TBM. This comprehensive review delineates an optimized framework for the management of TBM, including an integrated approach that combines pharmacokinetic insights, concomitant drug administration strategies, and the latest advancements in IT and intraventricular (IVT) therapy for CNS infections. By proposing a multifaceted treatment strategy, this analysis aims to enhance the clinical outcomes for TBM patients, highlighting the critical role of targeted drug delivery in overcoming the formidable challenges presented by the blood-brain barrier and the complex pathophysiology of TBM.

Metabolic Rewiring of Mycobacterium tuberculosis upon Drug Treatment and Antibiotics Resistance.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge, further compounded by the issue of antimicrobial resistance (AMR). AMR is a result of several system-level molecular rearrangements enabling bacteria to evolve with better survival capacities: metabolic rewiring is one of them. In this review, we present a detailed analysis of the metabolic rewiring of Mtb in response to anti-TB drugs and elucidate the dynamic mechanisms of bacterial metabolism contributing to drug efficacy and resistance. We have discussed the current state of AMR, its role in the prevalence of the disease, and the limitations of current anti-TB drug regimens. Further, the concept of metabolic rewiring is defined, underscoring its relevance in understanding drug resistance and the biotransformation of drugs by Mtb. The review proceeds to discuss the metabolic adaptations of Mtb to drug treatment, and the pleiotropic effects of anti-TB drugs on Mtb metabolism. Next, the association between metabolic changes and antimycobacterial resistance, including intrinsic and acquired drug resistance, is discussed. The review concludes by summarizing the challenges of anti-TB treatment from a metabolic viewpoint, justifying the need for this discussion in the context of novel drug discovery, repositioning, and repurposing to control AMR in TB.

Confronting Tuberculosis: A Synthetic Quinoline-Isonicotinic Acid Hydrazide Hybrid Compound as a Potent Lead Molecule Against Mycobacterium tuberculosis.

The current tuberculosis (TB) treatment is challenged by a complex first-line treatment for drug-sensitive (DS) TB. Additionally, the prevalence of multidrug (MDR)- and extensively drug (XDR)-resistant TB necessitates the search for new drug prototypes. We synthesized and screened 30 hybrid compounds containing aminopyridine and 2-chloro-3-formyl quinoline to arrive at a compound with potent antimycobacterial activity, UH-NIP-16. Subsequently, antimycobacterial activity against DS and MDR Mycobacterium tuberculosis (M.tb) strains were performed. It demonstrated an MIC50 value of 1.86 ± 0.21 µM for laboratory pathogenic M.tb strain H37Rv and 3.045 ± 0.813 µM for a clinical M.tb strain CDC1551. UH-NIP-16 also decreased the MIC50 values of streptomycin, isoniazid, ethambutol, and bedaquiline to about 45, 55, 68, and 76%, respectively, when used in combination, potentiating their activities. The molecule was active against a clinical MDR M.tb strain. Cytotoxicity on PBMCs from healthy donors and on human cell lines was found to be negligible. Further, blind docking of UH-NIP-16 using Auto Dock Vina and MGL tools onto diverse M.tb proteins showed high binding affinities with multiple M.tb proteins, the top five targets being metabolically critical proteins CelA1, DevS, MmaA4, lysine acetyltransferase, and immunity factor for tuberculosis necrotizing toxin. These bindings were confirmed by fluorescence spectroscopy using a representative protein, MmaA4. Envisaging that a pathogen will have a lower probability of developing resistance to a hybrid molecule with multiple targets, we propose that UH-NIP-16 can be further developed as a lead molecule with the bacteriostatic potential against M.tb, both alone and in combination with first-line drugs.

Investigating the Impact of First-Line Anti-Tuberculosis Drugs Encapsulated in a Eugenol-Based Nanoemulsion on Human Serum Albumin.

BACKGROUND: Eugenol exhibits broad-spectrum antibacterial and anti-inflammatory properties. However, cytotoxicity at high concentrations limits the full utilization of eugenol-based drug complexes. Formulations of multidrug-loaded eugenol-based nanoemulsions have reduced cytotoxicity; however, it remains crucial to understand how these eugenol complexes interact with primary human carrier proteins to design and develop therapeutic alternatives. Consequently, this study primarily aims to investigate the impact on Human Serum Albumin (HSA) when it interacts with eugenol-based complexes loaded with first-line anti-tuberculosis drugs. METHODS: This study used various spectroscopic such as UV-visible spectroscopy, Fluorescence spectroscopy, Fourier-transform infrared spectroscopy and computational methods such as molecular docking and 100 ns molecular simulation to understand the impact of eugenol-based first-line anti-tuberculosis drug-loaded nanoemulsions on HSA structure. RESULTS: The binding of the HSA protein and eugenol-based complexes was studied using UV-visible spectroscopic analysis. Minor changes in the fluorophores of the protein further confirmed binding upon interaction with the complexes. The Fourier-transform infrared spectra showed no significant changes in protein structure upon interaction with eugenol-based multidrug-loaded nanoemulsions, suggesting that this complex is safe for internal administration. Unlike eugenol or first-line anti-tuberculosis alone, molecular docking revealed the strength of the binding interactions between the complexes and the protein through hydrogen bonds. The docked complexes were subjected to a 100 ns molecular dynamics simulation, which strongly supported the conclusion that the structure and stability of the protein were not compromised by the interaction. CONCLUSIONS: From the results we could comprehend that the eugenol (EUG)-drug complex showed greater stability in HSA protein structure when compared to HSA interacting with isoniazid (INH), rifampicin (RIF), pyrazinamide (PYR), or ethambutol (ETH) alone or with EUG alone. Thus, inferring the potential of EUG-based drug-loaded formulations for a safer and efficient therapeutic use.

Polymerase Chain Reaction (PCR) Profiling of Extensively Drug-Resistant (XDR) Pathogenic Bacteria in Pulmonary Tuberculosis Patients.

Introduction Pulmonary tuberculosis (TB) remains a global health concern, exacerbated by the emergence of extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. This study employs advanced molecular techniques, specifically polymerase chain reaction (PCR) profiling, to comprehensively characterize the genetic landscape of XDR pathogenic bacteria in patients diagnosed with pulmonary TB. The objective of the study is to elucidate the genes that are associated with drug resistance in pulmonary TB strains through the application of PCR and analyze specific genetic loci that contribute to the development of resistance against multiple drugs. Materials and methods A total of 116 clinical samples suspected of TB were collected from the tertiary healthcare setting of Saveetha Medical College and Hospitals for the identification of MTB, which includes sputum (n = 35), nasal swabs (n = 17), blood (n = 44), and bronchoalveolar lavage (BAL) (n = 20). The collected specimens were processed and subjected to DNA extraction. As per the protocol, reconstitution of the DNA pellet was carried out. The reconstituted DNA was stored at -20 °C for the PCR assay. From the obtained positive sample specimens, XDR pulmonary TB specimens were focused on the targeted genes, specifically the rpoB gene for rifampicin resistance, inhA, and katG gene for thepromoter region for isoniazid resistance. Results Out of a total of 116 samples obtained, 53 tested positive for pulmonary TB, indicative of a mycobacterial infection. Among these positive cases, 43 patients underwent treatment at a tertiary healthcare facility. Subsequently, a PCR assay was performed with the extracted DNA for the target genes rpoB, inhA, and katG. Specifically, 22 sputum samples exhibited gene expression for rpoB, inhA, and katG, while nine nasal swabs showed expression of the rpoB and inhA genes. Additionally, rpoB gene expression was detected in seven blood specimens, and both rpoB and inhA genes were expressed in five BAL samples. Conclusion The swift diagnosis and efficient treatment of XDR-TB can be facilitated by employing advanced and rapid molecular tests and oral medication regimens. Utilizing both newly developed and repurposed anti-TB drugs like pretomanid, bedaquiline, linezolid, and ethionamide. Adhering to these current recommendations holds promise for managing XDR-TB effectively. Nevertheless, it is significant to conduct well-designed clinical trials and studies to further evaluate the efficacy of new agents and shorter treatment regimens, thus ensuring continuous improvement in the management of this challenging condition.