Search Results (563)

Tuberculosis (TB) continues to be a significant public health challenge in Europe, despite a sustained decline in disease incidence over recent decades. This narrative review briefly traces the historical development of TB diagnosis and focuses on the evolution of TB control protocols from the early twentieth century to the present across Europe, through a longitudinal comparative analysis of its geographical regions. A literature search was conducted using publications, guidelines, and surveillance reports from the World Health Organization (WHO), the European Centre for Disease Prevention and Control (ECDC), and national public health authorities. The analysis follows a geographical framework encompassing Eastern, Western, Northern, and Southern Europe, reflecting historical, socioeconomic, and healthcare system differences. This study presents the transition from traditional diagnostic approaches based on clinical assessment, chest radiography, and smear microscopy to modern molecular and immunological techniques, including Xpert MTB/RIF assays and interferon-gamma release assays (IGRAs). Similarly, treatment strategies have evolved from sanatorium-based supportive care to standardized, evidence-based short-course regimens employing first- and second-line anti-TB drugs. However, marked regional differences remain in the implementation of contemporary protocols. Western and Northern European countries have largely adopted advanced diagnostic technologies and comprehensive surveillance systems and are approaching TB elimination targets. In contrast, Eastern Europe continues to bear a disproportionate disease burden, driven by multidrug-resistant TB, HIV co-infection, and socioeconomic disparities. TB control protocols in Southern Europe are progressively converging with those of Western Europe through the adoption of modern diagnostic approaches, standardized treatment regimens, and WHO-endorsed guidelines. The findings of this study underscore the need for greater harmonization of TB control protocols across Europe through an initiative coordinated by the ECDC/WHO. Accelerating progress toward TB elimination in the European Region will depend on expanding access to modern diagnostic technologies, implementing targeted interventions in high-burden settings, and strengthening cross-border collaboration through coordinated public health policies. Full article

Tuberculosis (TB) remains a major global health challenge, compounded by rising drug resistance. Traditional medicinal plants used for TB-related symptoms represent a valuable yet underexplored source of potential antimycobacterial agents. In this study, the phytochemical content and biological activities of Dombeya rotundifolia and Lippia javanica were evaluated, and antimycobacterial compounds were isolated through bioassay-guided fractionation. Plant leaves were collected, extracted with solvents of varying polarity, and screened for phenolics and flavonoids. Antioxidant activity was assessed using DPPH and ferric reducing power assays, antimycobacterial activity was tested against Mycobacterium smegmatis, anti-inflammatory activity was determined by the egg albumin denaturation method, and cytotoxicity was evaluated in THP-1 cells using the MTT assay. Extraction yields varied, with water extracts of L. javanica showing the highest yield and hexane extracts of D. rotundifolia the lowest. Both plants contained bioactive phytochemicals with measurable antioxidant activity, while acetone and dichloromethane extracts of D. rotundifolia displayed the strongest antimycobacterial activity with MIC values of 0.16 mg/mL. Cytotoxicity assays indicated moderate toxicity at higher extract concentrations. Bioassay-guided isolation led to the identification of two fatty acid fractions with tentative characterization, which showed notable antimycobacterial activity (MIC 0.25 mg/mL). These findings provide preliminary support for the ethnomedicinal use of D. rotundifolia in respiratory conditions traditionally associated with tuberculosis and suggest a potential contribution of its fatty acids to its observed antimycobacterial activity. Full article

This review synthesizes recent advances in WHO-endorsed NAATs for TB diagnosis and drug resistance detection. We examine the principles, genetic targets, diagnostic performance, implementation settings, and programmatic role of assays across the spectrum of technological complexity, from cartridge-based platforms to line probe assays and sequencing-based technologies. In addition, we highlight emerging molecular tools that show promise for future WHO endorsement and may further strengthen decentralized and near-patient testing. Low- and moderate-complexity assays such as Xpert^® MTB/RIF, Xpert^® Ultra, and Truenat^TM MTB/MTB Plus have emerged as essential frontline tools for TB diagnosis and rifampicin resistance detection, especially in decentralized settings. LPAs, including GenoType^® MTBDRplus and MTBDRsl, extend resistance profiling to isoniazid, fluoroquinolones, and second-line injectables, and remain valuable in intermediate and central laboratories. More recent developments, including Xpert^® XDR, Deeplex^® Myc-TB, AmPORE-TB^®, and TBseq^®, enable broader resistance detection and, in the case of targeted sequencing assays, comprehensive characterization of multidrug-resistant and extensively drug-resistant TB (MDR/XDR-TB). Emerging diagnostic innovations—such as CRISPR-based detection systems, streamlined isothermal amplification assays, and portable sequencing technologies—further expand the landscape and may complement existing WHO-endorsed platforms. Importantly, these technologies reduce delays in regimen selection, improve patient outcomes, and provide critical data for surveillance. Nevertheless, performance gaps for rare mutations, limited sensitivity in paucibacillary or extrapulmonary disease, infrastructure requirements, and cost remain barriers to universal adoption. The evolution of TB molecular diagnostics demonstrates a clear shift toward more rapid, accurate, and comprehensive resistance detection. No single assay is universally optimal, yet the combined portfolio, spanning rapid cartridge-based NAATs, LPAs, and next-generation sequencing, forms a complementary framework for improving diagnosis, optimizing treatment, and supporting global TB elimination strategies. Full article

Using Global Burden of Disease 2021 modeled estimates, we assessed the burden, temporal trends, and inequalities of pediatric all-form tuberculosis (TB) and multidrug-resistant TB (MDR-TB) from 1990 to 2021 across 204 countries and territories. Compared with all-form TB, pediatric MDR-TB showed a distinct and less favorable estimated trajectory. Although GBD-based estimates suggested overall declines in pediatric all-form TB incidence and mortality, the MDR-to-all-form ratio increased worldwide for both incidence and mortality, suggesting a growing proportional contribution of MDR-TB within the estimated pediatric TB burden. In 2021, pediatric MDR-TB remained concentrated in low- and low–middle-SDI settings, where modeled socioeconomic inequalities appeared to become more pronounced over time. Mortality relative to incidence was highest among children aged under 5 years, with particularly elevated and imprecise mortality-to-incidence ratios for MDR-TB. Sex disparities also evolved differently by disease type: they generally narrowed for all-form TB but were more heterogeneous and in some settings widened for MDR-TB. These GBD-based findings suggest that progress in overall pediatric TB control may not have translated evenly to drug-resistant disease and highlight the need for pediatric TB strategies that explicitly address drug resistance, early childhood vulnerability, and inequitable access to diagnosis and treatment. Due to the sparsity of global pediatric data, no independent external validation was performed; findings are based on internal sensitivity analyses of GBD estimates. Full article

Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea; however, its association with antituberculous therapy (ATT) remains underrecognized. This review examines the risk, mechanisms, and clinical implications of CDI in patients with active tuberculosis (TB). Although ATT is traditionally considered low risk, prolonged exposure, particularly to rifampicin, may lead to cumulative disruption of gut microbiota and loss of colonization resistance. A characteristic feature of CDI in this setting is delayed onset, typically occurring several weeks to months after ATT initiation, which complicates timely diagnosis. Rifampicin plays a dual role, contributing to microbiota alterations and selection of resistant strains, while potentially affecting the pharmacokinetics of co-administered drugs. CDI in TB patients is associated with increased morbidity and mortality, with reported mortality rates up to 9.9%. Fidaxomicin is preferred due to its microbiota-sparing effect and lower recurrence rates, although cost remains a major limitation in high TB-burden settings, since vancomycin is an appropriate alternative. Management requires an individualized approach that balances the risk of CDI recurrence against the necessity of maintaining effective TB therapy. Full article

Brucellosis and tuberculosis (TB) are chronic infectious diseases of international public health importance, with developing countries being most affected. The diagnosis of brucellosis and tuberculosis co-infection remains challenging because both diseases present with overlapping nonspecific clinical manifestations, such as prolonged fever, fatigue, and weight loss, and elicit similar cell-mediated immune and inflammatory responses, which can complicate differential diagnosis, particularly in endemic regions. Recently, it has been shown that chronic infections affect cell stress pathways such as oxidative stress and telomere function. The current literature review provides an overview of the relationship between brucellosis and TB at a molecular level, focusing on telomere biology, oxidative stress and the mechanisms of antimicrobial resistance. Due to chronic immune response in brucellosis and TB patients, an increase in reactive oxygen species (ROS) levels is observed, leading to DNA damage and subsequent telomere shortening and alteration of telomerase activity. These alterations might be responsible for immune senescence, weakened defense response and persistent infection. In addition, different methods of drug resistance have been discovered among brucellae and mycobacteria, such as mutation in target sites, efflux systems and intracellular persistence, making their eradication difficult. Finally, the potential role of telomere-related genes and biomarkers of oxidative stress in diagnosis and prognosis is also highlighted. Insights into these interrelated pathways would allow us to have a better understanding of host–pathogen interactions and hence offer a possible means of developing new strategies in the fight against co-infection by finding new biomarkers. Full article

(1) Background: Indonesia faces the dual challenge of a high tuberculosis (TB) burden and increasing drug resistance. Conventional molecular diagnostics frequently fail to detect isoniazid resistance and nontuberculous mycobacteria (NTM). This study evaluates a domestic multiplex Open PCR system in Medan, Indonesia. (2) Methods: From July to November 2025, 1569 sputum specimens from suspected TB patients were analysed using the Indigen MTB/NTM/DR-TB Real-time PCR Kit Gen 2. (3) Results: Mycobacterial DNA was detected in 421 specimens (26.8%). Among these, 396 (94.1%) were drug-susceptible TB, while 16 (3.8%) showed resistance, predominantly INH mono-resistance (n = 14; 0.89% of total). Additionally, 9 cases (2.1%) involved NTM or TB-NTM co-infections. Tertiary hospitals showed significantly higher positivity rates (33.5%) than primary care (18.9%; p < 0.001). TB status was significantly associated with male (p = 0.0052) and older age (p = 0.006), whereas resistance profiles and NTM distribution were consistent across all demographic groups (p > 0.80). (4) Conclusions: This study describes the implementation and diagnostic yield of a domestic multiplex Open PCR system in Medan, Indonesia. By bridging diagnostic gaps across a decentralized referral network, this facilitates rapid and targeted therapy. Integrating multiplex domestic innovations into national diagnostic algorithms is essential for achieving Indonesia’s TB elimination targets. Full article

Background/Objectives: Rifampicin-resistant tuberculosis (RR-TB) and HIV co-infection remain major contributors to morbidity and mortality, particularly in high-burden settings. HIV-related clinical factors, including viral suppression, CD4-defined immune status, HIV drug resistance, virological failure, and ART failure, may influence RR-TB treatment response; however, existing evidence remains fragmented. This systematic review and meta-analysis protocol aims to synthesize evidence on the impact of HIV viral suppression, immune status, and HIV drug resistance/ART resistance status on RR-TB treatment outcomes. Methods: This protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. Published peer-reviewed studies and relevant grey literature from January 2005 to December 2025 will be searched in PubMed/MEDLINE, Cochrane Library, Embase, Web of Science, ScienceDirect, EBSCOhost, PsycINFO, Google Scholar, and other relevant sources. No language restriction will be applied at the search stage. Where feasible, non-English records will be translated for title/abstract and full-text screening. Two reviewers will independently screen studies, extract data, and assess study quality, with disagreements resolved by a third reviewer. Study-level risk of bias will be assessed using design-appropriate tools, and the certainty of evidence for each outcome will be evaluated using GRADE. Results: Evidence will be synthesized narratively and, where studies are sufficiently homogeneous, quantitatively through meta-analysis. Outcomes of interest will include treatment success, treatment failure, mortality, treatment completion, microbiological cure, and adverse events. Subgroup analyses will be considered by viral suppression status, CD4-defined immune status, HIV drug resistance/ART resistance status, geographic region, and treatment regimen where data permit. Conclusions: This review will provide evidence on how HIV viral suppression, immune status, and HIV drug resistance/ART resistance influence RR-TB treatment outcomes. The findings may inform integrated TB/HIV care, clinical monitoring, and treatment strategies for individuals co-infected with HIV and RR-TB. Full article

Background/Objectives: Reactive oxygen species (ROS) are key effectors of innate immunity but can also contribute to inflammation and tissue injury when their production is dysregulated. Although antibiotics are primarily selected for their antimicrobial activity, prolonged treatment may also influence host immune responses. However, the effects of anti-tuberculosis drugs on ROS production across innate immune cell subsets have not been assessed, especially not for novel drugs currently used against multi drug-resistant (MDR) tuberculosis (TB). Methods: Whole blood from healthy donors was incubated with seven antimycobacterial drugs used against MDR TB at sub-therapeutic, therapeutic, and supra-therapeutic concentrations. ROS production was quantified by flow cytometry using dihydrorhodamine 123 (DHR-123) in neutrophils, classical monocytes, and eosinophils under unstimulated conditions or following stimulation with Escherichia coli, fMLP, or PMA. Results: Bedaquiline and clofazimine decreased ROS production in neutrophils and classical monocytes across multiple stimuli (median values of Rh-123⁺ classical monocytes after E. coli stimulation without BDQ was 30.8% versus 24.9% with 1 µg/mL BDQ (p < 0.05, therapeutic concentration) and 31.3% without CFZ versus 19.2% with 1 µg/mL CFZ (p < 0.01, therapeutic concentration) in the same conditions). In contrast, levofloxacin and linezolid showed no detectable impact on ROS production in any cell population. Pretomanid uniquely induced a reduction in ROS generation in eosinophils and classical monocytes while sparing neutrophil oxidative burst activity, distinguishing it from other antibiotics tested (34.1% decrease in Rh-123 MFI of eosinophils between the control and PA 3 µg/mL after fMLP stimulation, p < 0.01, therapeutic concentration). Conclusions: These findings demonstrate that first line drugs against MDR TB display heterogeneous and cell type-specific effects on innate immune oxidative responses. Such differential effects on host immunity may have implications for both antimicrobial efficacy and inflammation control during tuberculosis treatment. Full article

Tuberculosis (TB) treatment is severely hampered by the rise in multi-drug-resistant strains and the prevalence of drug-induced toxicities. Host-Directed Therapies (HDTs) have emerged as a promising strategy to overcome these challenges by modulating innate immunity and circumventing Mycobacterium tuberculosis (Mtb) evasion mechanisms. A hallmark of Mtb pathogenesis is the arrest of phagosome maturation and the induction of host cell necrosis over protective apoptosis. In this study, we investigated the potential HDT effects of α-Lipoic acid (α-LA), a well-known antioxidant and metabolic cofactor, within an in vitro model of Mtb-infected THP-1 macrophages. Our findings indicate that α-LA treatment modulates the macrophage redox state and selectively promotes apoptosis in infected cells without increasing necrotic lysis. Furthermore, α-LA administration led to a significant, dose-dependent restoration of phagolysosome acidification, effectively reversing the maturation blockade imposed by Mtb. Notably, this enhanced acidification inversely correlated with intracellular bacterial survival. These results suggest that α-LA might act as a multifaceted HDT agent capable of restoring both host-protective cell death and phagosomal microbicidal mechanisms. Given its established safety profile and its ability to complement standard anti-TB drugs like Bedaquiline (BDQ), α-LA represents a highly promising candidate for adjunct therapy to improve TB treatment outcomes and mitigate the impact of antibiotic resistance. Full article

Background/Objectives: Tuberculosis (TB) treatment adherence remains suboptimal globally, contributing to relapse, transmission, and drug-resistant TB. Adherence is a culturally embedded behavioral process shaped by psychological readiness, social relationships, and structural conditions. This study aimed to validate a culturally grounded counseling model integrating the Sunrise Model of transcultural nursing and the Information–Motivation–Behavioral Skills (IMB) framework for TB treatment adherence in Kupang City, Indonesia. Methods: A cross-sectional study enrolled 172 pulmonary TB patients across all 11 primary healthcare centers in Kupang City (June–September 2025). A validated questionnaire measuring eight transcultural determinants, culturally grounded counseling (mediator), and adherence (outcome) was developed through expert validation, cognitive interviewing, and pilot testing. Structural Equation Modeling–Partial Least Squares (SEM-PLS) tested structural and mediation relationships via bootstrapped indirect effects (p < 0.05). Results: Reliability (CR: 0.842–0.959; ρA: 0.791–0.957), convergent validity (AVE: 0.577–0.921), and discriminant validity (all HTMT < 0.85) were confirmed. The model showed strong explanatory power (R² = 0.649 for adherence; SRMR = 0.074). Culturally grounded counseling was positively associated with adherence (β = 0.245, p = 0.003) and statistically mediated five antecedent–adherence relationships, including full mediation for economic conditions. Cultural values and lifestyle showed the strongest counseling association (β = 0.345, p < 0.001). Conclusions: Cross-sectional evidence supports a culturally grounded counseling model for TB adherence in diverse settings. Causal conclusions require longitudinal and interventional validation. The model offers a foundation for nurse-led intervention development and multi-site validation. Full article

Background: Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis). Drug-resistant TB remains a major public health challenge and calls for new approaches to drug development. Targeted delivery of antibacterial agents using nanoscale carriers represents one such approach. A decisive factor for efficient targeting is the judicious selection of the carrier platform. Methods: In the present study, diamond nanoparticles were evaluated as a prospective vehicle for conveying anti-TB drugs to lung cells. Conventional and analytical transmission electron microscopy were used to analyze the localization of the nanodiamonds (NDs) in the lungs of M. tuberculosis-infected mice 30 days after nanoparticle administration and 44 days post-infection. Results: The study shows that the NDs co-localize with M. tuberculosis in foamy macrophages of the lung, residing in the same cellular compartments—phagosomes/phagolysosomes and lipid droplets. These in vivo results demonstrate a high degree of macrophage-specific accumulation of NDs relative to M. tuberculosis. Conclusions: Consequently, NDs can be considered a promising carrier for targeted delivery of anti-TB therapeutics to the lungs during TB-induced inflammation. Full article

Background: The success of modern drug-resistant tuberculosis (DR-TB) regimens increasingly depends on linezolid (LZD) and pretomanid (Pa), yet the emergence of resistance to these critical agents threatens to reverse recent treatment advances, with limited consolidated evidence available from high-burden settings such as South Africa. Objectives: To systematically review and meta-analyse South African data on LZD and Pa resistance, minimum inhibitory concentrations (MICs), resistance-associated mutations, and treatment outcomes. Eligibility Criteria: We included clinical trials, cohort studies, surveillance studies, and molecular investigations conducted in South Africa from 2013 onward that reported resistance prevalence, MIC data, genotypic mutations, or treatment outcomes related to LZD and/or Pa. Information Sources: PubMed, PubMed, Embase, Web of Science, and grey literature sources were searched from January 2013 to 31 December 2025 in accordance with PRISMA 2020 guidelines. Risk of Bias: Study quality was assessed using the Joanna Briggs Institute (JBI) cohort appraisal checklist. Included Studies: Seventeen studies representing provincial and national cohorts were included. Synthesis of Results: Random-effects meta-analysis was used to estimate pooled baseline resistance. Subgroup, sensitivity, and meta-regression analyses were performed. Results: Random-effects meta-analysis demonstrated a pooled baseline LZD resistance prevalence of 0.53% (95% CI: 0.01–1.83; I² = 81.1%) in routine South African cohorts, while substantially higher resistance (33%) was observed in treatment-failure populations. Baseline LZD MICs were typically 0.125–1.0 µg/mL, while elevated MICs (up to 8.0 µg/mL) were associated with rplC and rrl mutations, particularly rplC Cys154Arg. No confirmed phenotypic Pa resistance was identified across included South African cohorts, despite the detection of resistance-associated mutations in genomic surveillance studies. MIC values remained within the range of 0.016–1.0 µg/mL. Mutations in ddn, fbiA, fbiC, and fgd1 were reported in genomic studies. Treatment success rates ranged from 63.6% to 99% for LZD-containing regimens and approached 90% for Pa-based regimens. Limitations: Limited study numbers, heterogeneity in laboratory methods, and overrepresentation of certain provinces may affect generalizability. Conclusions: Baseline resistance to LZD and Pa in South Africa remains low, supporting continued programmatic use. Ongoing molecular surveillance is essential to detect resistance amplification and preserve regimen efficacy. Full article

Background: Pediatric tuberculosis (TB) remains a major global health concern, accounting for a substantial proportion of TB-related morbidity and mortality worldwide. Treatment in children is particularly challenging due to age-specific pharmacokinetics, difficulties in drug administration, poor palatability, and reliance on caregivers for adherence. Objectives: This narrative review aims to evaluate the advantages and limitations of fixed-dose combinations (FDCs) in the treatment of pediatric TB, with a focus on adherence, pharmacological considerations, clinical outcomes, and implementation challenges. Methods: A narrative review of the literature was conducted, including clinical studies, pharmacokinetic analyses, programmatic data, and international guidelines related to the use of FDCs in pediatric TB management. Results: Evidence indicates that pediatric FDCs significantly improve treatment adherence by reducing pill burden and simplifying dosing regimens. They also decrease the risk of medication errors and inadvertent monotherapy, thereby contributing to the prevention of drug resistance. The availability of dispersible, child-friendly formulations has enhanced acceptability and ease of administration. However, limitations persist, including reduced flexibility in dose individualization, challenges in identifying the causative agent in adverse drug reactions, and variable access across settings. Pharmacokinetic concerns, particularly regarding rifampicin exposure, have been addressed in newer WHO-recommended formulations. Conclusions: FDCs represent a critical advancement in pediatric TB management and are strongly supported by international guidelines. Further research is needed to optimize formulations, ensure equitable access, and evaluate long-term clinical outcomes in diverse pediatric populations. Full article

Background/Objectives: Multidrug-resistant tuberculosis (MDR-TB) remains a major public health challenge in the WHO European Region, which reports the highest global proportion of rifampicin-resistant and MDR-TB cases. Whole-genome sequencing (WGS) has emerged as a key tool for improving drug-resistance detection and supporting molecular surveillance. However, the level of genomic implementation across Central and Eastern Europe (CEE) remains insufficiently characterized. This scoping review aimed to evaluate the use of WGS for MDR-TB in CEE countries and to classify implementation maturity using a predefined framework (L0–L4). Methods: A structured search of PubMed/MEDLINE and Web of Science identified original studies published in English between 2015 and 2026 reporting genomic applications in MDR-TB across 13 predefined CEE countries. Data were extracted on sequencing approaches, resistance prediction, transmission analysis, monitoring of new or repurposed drugs, bioinformatic pipelines, and programmatic integration. Countries were categorized according to a five-level maturity model based on documented capacity, scope of application, and integration into national tuberculosis programs (NTPs). Results: Twenty-eight studies were included. WGS was used in 23/28 studies (82.1%), predominantly for genomic resistance prediction (25/28). Transmission analysis was reported in 19/28 studies, with heterogeneous single nucleotide polymorphism (SNP) thresholds and clustering methodologies. Monitoring of resistance to new or repurposed drugs was described in 8/28 studies. No country achieved Level L4 (formally integrated genomic surveillance). Four countries were classified as L3 and nine as L2, while no L0 or L1 settings were identified. Conclusions: Countries in Central and Eastern Europe demonstrate increasing operational use of WGS for MDR-TB, primarily driven by clinical resistance prediction. However, the lack of formal integration into national surveillance systems highlights a persistent gap between technological adoption and structured public health implementation. Strengthening programmatic integration and methodological standardization is essential for advancing genomic surveillance of MDR-TB in the region. Full article