Recent advances and challenges of revolutionizing drug-resistant tuberculosis treatment.

Tuberculosis (TB), an infectious disease induced by Mycobacterium tuberculosis, is one of the primary public health threats all over the world. Since the prevalence of first-line anti-TB agents, the morbidity and mortality issues of TB descended obviously. Nevertheless, the emergences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, the double prevalence of HIV-TB co-infection, and the insufficiency of plentiful health care have led to an increased incidence of TB. It is noted that current drugs for treating TB have proved unsustainable in the face of highly resistant strains. Fortunately, five categories of new drugs and candidates with new mechanisms of action have emerged in the field of anti-TB research after decades of stagnation in the progression of anti-TB drugs. In this paper, the research status of these promising anti-TB drugs and candidates are reviewed, emphasizing the challenges to be addressed for efficient development of future TB therapies.

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.

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.

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.

Laryngeal tuberculosis: about 04 cases.

The purpose of this study is to present epidemiological, clinical, radiological, histological characteristics and treatment of laryngeal tuberculosis. It is also aimed at making the point about diagnosis difficulties. This retrospective study was conducted over three years; it concerned 4 cases, 3 males and one female. The average age was 35 years. Three of the 4 cases have had a cervical CT scan. All patients have had a laryngoscopy with biopsy and anatomopathological study. The onset modes of the disease have been progressive for all the patients. Topographical study has shown two epiglottic locations, one at the vocal cords and the other one at the posterior commissure. The diagnosis was orientated in the 3 cases by the CT scan and confirmed by anatomopathological exam in all cases. All patients have received anti-TB drugs with good evolution. The laryngeal location of tuberculosis is unusual. The clinical picture is nonspecific, raising the issue of differential diagnosis with tumor pathology. Sectional imaging and CT scan can guide the diagnosis and a positive diagnosis is often discovered on the occasion of a tumor biopsy of a pseudo-tumor lesion. Treatment is based on anti-TB drugs.

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.

Direct Medical Expenses and Influencing Factors of MDR/RR-TB in Eastern China: Based on Data from Multi-Hospital Information Systems.

Background: Multidrug-resistant (MDR) and rifampicin-resistant (RR) tuberculosis (TB) is related to high healthcare costs. However, studies on direct healthcare expenditure in different settings remain inconclusive. Hence, we aimed to examine the direct medical expenses (DME) of patients with MDR/RR-TB and assessed which patient characteristics were associated with higher costs. Methods: DME was evaluated using records from the hospital information system in three cities with different economic levels in Zhejiang Province, Eastern China, matching with data (including socio-demographics, disease treatment status, etc.) collected in the Tuberculosis Management Information System. A logistic regression model was used to identify variables associated with higher costs. Results: Of 193 patients with MDR/RR-TB, the average DME was $10,491 (interquartile range (IQR) $4679-16,710), consisting of $2696 (IQR $1019-5100) out-of-pocket costs, medical reimbursement, and subsidies, accounting for 32%, 50.3% and 14%, respectively. A total of 74.2% and 56% of DME were for drugs and anti-TB drugs, respectively. Only 16.9% of the patients were treated with an all-oral regimen. Higher DME was significantly associated with local residents 7.29 (95% confidence interval (CI) [2.62-20.3]), hospitalization experience 7.63 (95% (CI) [2.54-22.95]), longer duration of treatment 6.63 (95% CI [2.27-19.35]), and lower health insurance reimbursement 5.65 (95% CI [1.90-16.79]). Conclusion: DME of patients with MDR/RR-TB was still significant, and domestic migrants, hospitalization, long treatment duration, and high health insurance rates increased the financial burden on MDR/RR-TB patients. Reasonable intervention programs should be developed to reduce the medical burden of patients with MDR/RR-TB, according to the DME and its component of MDR-TB patients, besides the economic status of their regions.

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.

Frequency of rifampicin-resistant mycobacterium tuberculosis by GeneXpert MTB/RIF assay and its correlates among 2605 probable tuberculosis patients in upper Egypt.

RATIONALE: GeneXpert MTB/RIF (Mycobacterium tuberculosis/rifampicin) assay is a method for detecting rifampicin resistance (RR-MTB) in suspected samples in less than 2 hours with high sensitivity and specificity yield. This study aimed to use the GeneXpert MTB/RIF assay to determine the frequency of RR-MTB and to study the possible influencing correlates associated with positive results. SUBJECTS AND METHODS: This is a retrospective cross-sectional study of patients who visited TB clinic in 5 years (2016-2021). According to the data sheet of the patients, all the collected specimens were divided into 2 parts one for diagnosis by Ziehl-Neelsen stain and the other part for GeneXpert analysis. GeneXpert was also used to look for evidence of RR. RESULTS: Out of the 2605 total samples screened, 718 (27.6%) tested positive for MTB on GeneXpert assay; of them 633 (88.4%) were sensitive to Rifampicin, 83 (11.6%) were resistant to Rifampicin and 2 cases were undetermined. Factors contributing to RR-MTB were: smoker/ex-smoker, with 2.5 times more risk (p = 0.013.0, p = 0.001); recurrence cases had a 4-fold increased risk (p < 0.001); patients with very low M. tuberculosis detected on the GeneXpert MTB/RIF test were 8 times more likely to have RR-TB (P = 0.004). CONCLUSION: This study disclosed a high-rate MTB in Egyptian probable TB cases. Smoking, recurrence and cases with a very low M. tuberculosis burden noticed on the GeneXpert MTB/RIF test had augmented risk of RR-TB.

Limited sampling strategies for therapeutic drug monitoring of anti-tuberculosis medications: A systematic review of their feasibility and clinical utility.

Therapeutic drug monitoring (TDM) is recommended for medications with high inter-individual variability, narrow therapeutic index drugs, possible drug-drug interactions, drug toxicity, and subtherapeutic concentrations, as well as to assess noncompliance. The area under the plasma concentration-time curve (AUC) is a significant pharmacokinetic parameter since it calculates the drug's total systematic exposure in the body. However, multiple blood samples from the patient are required to calculate the area under the curve, which is inconvenient for both the patient and the healthcare professional. To alleviate the issue, the limited sampling strategy (LSS) was devised, in which sampling is minimized while obtaining complete and precise findings to anticipate the area under the curve. One can reduce costs, labor, and discomfort for patients and healthcare workers by applying this limited sampling strategy. This article examines a systematic evaluation of all the limited sampling done in anti-tuberculosis (anti-TB) medications resulting from the literature search of several research papers. This article also briefly describes the two methodologies: Multiple regression analysis (MRA) and the Bayesian approach used to develop a limited sampling strategy model. Anti-TB medications have been found to have considerable inter-individual variability, and isoniazid has a narrow therapeutic index, both of which are criteria for therapeutic drug monitoring. To avoid multi-drug resistance and therapy failure, it is proposed that limited sampling strategy-based therapeutic drug monitoring of anti-TB medications be undertaken to generate an individualized dose regimen, particularly for individuals at high risk of treatment failure or delayed response.

Current therapeutic delivery approaches using nanocarriers for the treatment of tuberculosis disease.

Tuberculosis is a major health issue globally and a leading cause of death due to the infective microorganism Mycobacterium tuberculosis. Treatment of drug resistance tuberculosis requires longer treatment with multiple daily doses of drugs. Unfortunately, these drugs are often associated with poor patient compliance. In this situation, a need has been felt for the less toxic, shorter, and more effective treatment of the infected tuberculosis patients. Current research to develop novel anti-tubercular drugs shows hope for better management of the disease. Research on drug targeting and precise delivery of the old anti-tubercular drugs with the help of nanotechnology is promising for effective treatment. This review has discussed the status currently available treatments for tuberculosis patients infected with Mycobacterium alone or in comorbid conditions like diabetes, HIV and cancer. This review also highlighted the challenges in the current treatment and research on the novel anti-tubercular drugs to prevent multi-drug-resistant tuberculosis. It presents the research highlights on the targeted delivery of anti-tubercular drugs using different nanocarriers for preventing multi-drug resistant tuberculosis. Report has shown the importance and development of the research on nanocarriers mediated anti-tubercular delivery of the drugs to overcome the current challenges in tuberculosis treatment.

Need to reinvigorateTuberculosis research in India - A review of studies registered under clinical trial registry of India.

Tuberculosis (TB) is one of the most serious public health issues in India. According to the global TB report 2020, India accounts for about one-quarter of the global TB burden. Despite considerable advances in mandatory notification of all TB cases, incorporation of the national health programmes with general health services (National Health Mission), and national drug resistance surveillance and many other accomplishments, much more needs to be considered in India to significantly decrease TB incidence. Research is the foundation for medical breakthroughs. In this study, all Tuberculosis-related studies registered under Clinical Trial Registry of India from its inception in July 2007 to February 2021 were reviewed and analysed using the keyword ''Tuberculosis'' in the 'Trial Search' section. A total of 31,196 studies were registered in CTRI, with 180 studies (0.58%) being related to tuberculosis. Of these studies, 76 (42.2%) were interventional in nature. These consisted of evaluating different management or treatment TB (50%, n = 90), diagnostic studies (19.4%, n = 35) and studies related to screening and prevention of TB (7.8%, n = 14). Maximum studies were conducted to evaluate safety and efficacy of anti-TB drugs (10%, n = 18) and to evaluate efficacy of shortening of duration of treatment (8.9%, n = 16). The studies related to extra pulmonary TB, MDR TB and TB in special populations and sources of funding and locations of the study sites were also analysed. These indicate that only minimal TB-related researches are conducted in India. It is indispensable to promote tuberculosis research in India in order to eradicate this infectious disease.

Urinary excretion of metformin in diabetic patients with and without tuberculosis.

BACKGROUND: Patients with concurrent diabetes mellitus (DM) and tuberculosis (TB) pose an increased risk of treatment failure in TB and management of DM is complicated. Anti-diabetic and anti-TB drugs may interact with on another other when co-administered. The role of anti-TB drugs on the excretion of metformin in urine has not been studied. Therefore, we carried out a study in DM patients with and without TB to compare the percentage of metformin excreted in urine. METHODS: A total of 52 DMTB and 17 DM patients were recruited in this study from the Chennai Corporation Centres. DM and DM - TB patients were administered the prescribed anti-TB and anti-diabetic drugs (metformin (MET), glipizide (GLP),glimepiride (GLM),glibenclamide (GLB),rifampicin (RMP),isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). DM and DMTB patients received metformin (MET) alone and in combination with sulphonylureas as diabetic drugs. The urine samples were collected from 0 to 8 hours after drug administration. Urine MET excreted in DM and DMTB patients were estimated by high performance liquid chromatography (HPLC) and percent dose was calculated. RESULTS: The percent dose of MET excreted in urine in DMTB patients was significantly higher when compared to DM patients. There is significant difference in the percent dose of MET excreted among DM patients with and without sulphonylureas, values being 23.3 and 17.7% respectively (p = 0.044). CONCLUSION: This is the first study to report on the percent dose of MET excretion in urine in patients with DM and DMTB receiving MET along with anti-TB drugs.

Antimicrobial Peptides as Immunomodulators and Antimycobacterial Agents to Combat Mycobacterium tuberculosis: a Critical Review.

Tuberculosis (TB) is a devastating disease foisting a significantly high morbidity, prepotent in low- and middle-income developing countries. Evolution of drug resistance among Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has made the TB treatment more complicated. The protracted nature of present TB treatment, persistent and tolerant Mtb populations, interaction with antiretroviral therapy and existing toxicity concerned with conventional anti-TB drugs are the four major challenges inflicted with emergence of drug-resistant mycobacterial strains, and the standard medications are unable to combat these strains. These factors emphasize an exigency to develop new drugs to overcome these barriers in current TB therapy. With this regard, antimycobacterial peptides derived from various sources such as human cells, bacterial sources, mycobacteriophages, fungal, plant and animal sources could be considered as antituberculosis leads as most of these peptides are associated with dual advantages of having both bactericidal activity towards Mtb as well as immuno-regulatory property. Some of the peptides possess the additional advantage of interacting synergistically with antituberculosis medications too, thereby increasing their efficiency, underscoring the vigour of antimicrobial peptides (AMPs) as best possible alternative therapeutic candidates or adjuvants in TB treatment. Albeit the beneficiary features of these peptides, few obstacles allied with them like cytotoxicity and proteolytic degradation are matter of concerns too. In this review, we have focused on structural hallmarks, targeting mechanisms and specific structural aspects contributing to antimycobacterial activity and discovered natural and synthetic antimycobacterial peptides along with their sources, anti-TB, immuno-regulatory properties, merits and demerits and possible delivery methods of AMPs.

Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs: An evaluation of in vitro, in vivo methodologies and human studies.

There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited. One of the reasons could be differences in methodologies and outcome assessments that makes it difficult to compare the studies. In this paper we summarize most relevant in vitro, in vivo, in silico and human PKPD studies performed to optimize the drug dose and regimens for treatment of tuberculosis. The in vitro assessment focuses on MIC determination, static time-kill kinetics, and dynamic hollow fibre infection models to investigate acquisition of resistance and killing of Mycobacterium tuberculosis populations in various metabolic states. The in vivo assessment focuses on the various animal models, routes of infection, PK at the site of infection, PD read-outs, biomarkers and differences in treatment outcome evaluation (relapse and death). For human PKPD we focus on early bactericidal activity studies and inclusion of PK and therapeutic drug monitoring in clinical trials. Modelling and simulation approaches that are used to evaluate and link the different data types will be discussed. We also describe the concept of different studies, study design, importance of uniform reporting including microbiological and clinical outcome assessments, and modelling approaches. We aim to encourage researchers to consider methods of assessing and reporting PKPD of anti-tuberculosis drugs when designing studies. This will improve appropriate comparison between studies and accelerate the progress in the field.

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.

The Biological and Clinical Aspects of a Latent Tuberculosis Infection.

Tuberculosis (TB), caused by bacilli from the Mycobacterium tuberculosis complex, remains a serious global public health problem, representing one of the main causes of death from infectious diseases. About one quarter of the world's population is infected with Mtb and has a latent TB infection (LTBI). According to the World Health Organization (WHO), an LTBI is characterized by a lasting immune response to Mtb antigens without any TB symptoms. Current LTBI diagnoses and treatments are based on this simplified definition, although an LTBI involves a broad range of conditions, including when Mtb remains in the body in a persistent form and the immune response cannot be detected. The study of LTBIs has progressed in recent years; however, many biological and medical aspects of an LTBI are still under discussion. This review focuses on an LTBI as a broad spectrum of states, both of the human body, and of Mtb cells. The problems of phenotypic insusceptibility, diagnoses, chemoprophylaxis, and the necessity of treatment are discussed. We emphasize the complexity of an LTBI diagnosis and its treatment due to its ambiguous nature. We consider alternative ways of differentiating an LTBI from active TB, as well as predicting TB reactivation based on using mycobacterial "latency antigens" for interferon gamma release assay (IGRA) tests and the transcriptomic analysis of human blood cells.