Search Results (116)

Background: Treatment adherence and outcomes for drug-resistant tuberculosis (DR-TB) continue to be subpar in rural South Africa, where structural health system limitations, comorbid conditions, and diverse resistance patterns make clinical management more challenging. This study aimed to assess how demographic, clinical, and programmatic factors, including a Community Engagement–Clinical Governance (CE–CG) implementation period, affect DR-TB treatment outcomes using explanatory predictive modeling. Methods: A retrospective cohort study was conducted using routine program data from 694 DR-TB patients. A complete-case analysis was performed for multivariable modeling (n = 282). Logistic regression and decision tree models were used to examine the relationships between treatment success and selected predictors, including age, sex, treatment regimen, resistance phenotype, comorbidities, and the CE–CG implementation period. Model discrimination and performance were evaluated using receiver operating characteristic (ROC) curves, pseudo-R² statistics, likelihood ratio tests, and multicollinearity diagnostics. Results: The cohort had a mean age of 40.7 years, and 58.8% of patients were male. Overall treatment success was 59.9%. Severe resistance phenotypes were rare (1.7%) but clinically significant. Comparative analysis showed no notable demographic or outcome differences between included and excluded patients, indicating minimal selection bias. In adjusted models, treatment initiation during the CE–CG implementation period was significantly linked to lower odds of treatment success (adjusted odds ratio [aOR] = 0.443; 95% CI: 0.240–0.818; p = 0.009). Severe resistance phenotypes were strongly negatively associated with treatment success (aOR = 0.303; p = 0.056). Logistic regression models had limited discriminatory ability (AUC: 0.523–0.548), while the decision tree model showed modest improvement (AUC: 0.626). Overall, the model’s explanatory power was limited (pseudo-R² = 0.029), although no evidence of multicollinearity was found. Conclusions: Programmatic implementation periods and resistance severity were important factors associated with treatment outcomes in this rural DR-TB cohort. Although model discrimination was modest and explanatory power was limited, the findings provide useful insights into structural and programmatic vulnerabilities that affect treatment success in real-world settings. Strengthening clinical governance, improving routine program documentation, and incorporating more granular adherence, social, and governance indicators into routine data systems may improve both program evaluation and future predictive modeling. Full article

Background: Bedaquiline (BDQ) resistance poses a serious threat to its long-term efficacy, particularly in high-burden settings like South Africa, where data remain scattered and largely non-synthesized. Objective: This study aimed to estimate the trends of BDQ resistance in drug resistant tuberculosis (DR-TB), characterize associated resistance mechanisms, and evaluate implications for treatment outcomes in South Africa. Eligibility criteria: We included primary studies reporting BDQ resistance, resistance mechanisms, minimum inhibitory concentrations (MICs), or treatment outcomes among patients with MDR- or XDR-TB treated with BDQ-containing regimens in South Africa. Information sources: PubMed, Web of Science, and Embase were searched for studies published between January 2016 and July 2024. Risk of bias: Study quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Synthesis of results: Random-effects meta-analysis with Freeman–Tukey double-arcsine transformation was used to estimate pooled BDQ resistance prevalence. Heterogeneity, sensitivity analyses, and publication bias were assessed. Results: Twenty-eight studies were included. The pooled prevalence of BDQ resistance was 6.0% (95% CI: 4.1–7.9%; I² = 62%). Treatment success averaged 63.5%, and culture conversion reached 84.1%. Resistance-associated mutations were most frequently reported in Rv0678, followed by atpE and pepQ, often associated with elevated MICs (≥2–4 μg/mL). Evidence of small-study effects was observed (Egger’s test, p = 0.0012). A pooled prevalence estimate was calculated; however, evidence of small-study effects suggests that estimates should be interpreted cautiously. Limitations: Heterogeneity in study design, outcome definitions, and resistance testing methods limited comparability across studies. Conclusions: Bedaquiline remains effective for DR-TB treatment in South Africa; however, emerging resistance and its molecular drivers pose a growing threat to regimen sustainability, including BPaL. Strengthened surveillance and standardized resistance testing are urgently needed. Full article

Background: Drug-resistant tuberculosis (DR-TB) remains a major public health challenge in South Africa, particularly in rural settings with high HIV co-infection rates. Understanding predictors of treatment response among people living with HIV is essential for improving clinical management and programmatic outcomes. This study aimed to identify socio-demographic and clinical predictors of treatment outcomes among HIV-positive individuals diagnosed with multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR-TB) in rural Eastern Cape Province, South Africa. Methods: A retrospective cohort study was conducted using routinely collected clinical records of DR-TB patients initiated on treatment between January 2020 and December 2024 at two public healthcare facilities. A total of 239 patients with complete treatment outcome data were included. Treatment outcomes were classified as favourable (cured or treatment completed) or unfavourable (death, treatment failure, or loss to follow-up). Descriptive statistics were used to summarise patient characteristics, while univariate and multivariable logistic regression analyses were performed to identify factors associated with treatment outcomes. Results: Most participants were aged ≤ 39 years (58%), male (60%), unemployed (90%), and without income (80%). MDR-TB accounted for 40% of cases, rifampicin-resistant-TB (RR-TB) for 53%, and XDR-TB for 7.1%. Multivariable analysis showed that XDR-TB was the strongest independent predictor of unfavourable treatment outcome (AOR = 0.18; 95% CI: 0.06–0.58; p = 0.004). Income status was also significantly associated with outcome, with participants reporting some incomes having lower odds of favourable outcomes (AOR = 0.46; 95% CI: 0.23–0.92; p = 0.036). The model demonstrated modest predictive performance (AUC = 0.67). Conclusions: These findings highlight the dominant influence of resistance phenotype, particularly XDR-TB, on treatment prognosis among HIV-positive DR-TB patients in rural Eastern Cape. Integrating early resistance profiling, intensified clinical management of XDR-TB, and socioeconomic support mechanisms may improve treatment outcomes in high-burden rural settings. Full article

Drug-resistant tuberculosis (DR-TB) represents a major public health threat, particularly in the prisons of Latin America and the Caribbean, where rates are up to 40 times higher than those observed in the general population. These facilities act as community amplifiers due to overcrowding, poor ventilation, diagnostic delays, and treatment discontinuity. This study offers a critical reflection on the magnitude, determinants, and implications of DR-TB in regional penitentiary contexts. A reflective analytical review was conducted in PubMed, Scopus, Web of Science, SciELO, and LILACS, complemented by WHO and PAHO reports, prioritising studies from 2019 to 2024. The findings reveal MDR-TB and pre-extensively drug-resistant (pre-XDR) outbreaks in Peru, Paraguay, and the Dominican Republic, as well as community transmission linked to prisons in Brazil and Colombia. Persistent gaps remain in systematic screening, drug susceptibility testing coverage, and post-release follow-up. Scientific production continues to be uneven and predominantly biomedical, with limited consideration of social and human rights determinants. DR-TB in prisons reflects the structural deficiencies of health and justice systems; its control requires intersectoral policies, genomic surveillance, and strategies that ensure early diagnosis, treatment continuity, and dignified detention conditions. Full article

Rapid and accurate detection of drug-resistant tuberculosis (DR-TB) is critical for effective treatment and containment. The Xpert^® MTB/XDR (GXXDR) assay is designed to detect Mycobacterium tuberculosis complex (MTBC) and resistance to isoniazid and second-line anti-TB drugs directly from clinical specimens. We evaluated the clinical performance of GXXDR using 61 MTBC-positive specimens with available phenotypic drug susceptibility testing results. GXXDR results were compared to a phenotypic drug susceptibility test (pDST) and whole-genome sequencing (WGS) to assess sensitivity, specificity, and concordance. Resistance to isoniazid, fluoroquinolones, amikacin, capreomycin, and ethionamide was analyzed. Sensitivity comparisons between GXXDR, WGS, pDST, and manufacturer data were performed using Fisher’s exact and Tango tests. GXXDR demonstrated a high specificity for most drugs and a strong sensitivity for isoniazid (93.8%) and fluoroquinolone (92.3%), consistent with manufacturer reports. In contrast, the sensitivity for amikacin (58.3%), capreomycin (35.7%), and ethionamide (27.3%) was significantly lower than stated by the manufacturer (91.9%, 84.0% and 64.7%, respectively), likely due to resistance mutations outside the assay’s target regions. Sensitivity concordance of GXXDR with WGS was high for all drugs, except ethionamide. The GXXDR assay enables rapid and reliable detection of isoniazid and fluoroquinolone resistance in clinical settings, though sensitivity for certain second-line drugs may be affected by regional genetic diversity. These findings underscore the importance of integrating local epidemiological data to optimize molecular diagnostics for DR-TB. Full article

In the last three decades, 2-oxazolidinones have emerged as an important class of inhibitors of bacterial protein synthesis, effective in the treatment of multidrug-resistant (MDR) bacterial infections. From a public health perspective, the importance of 2-oxazolidinones is related to the treatment of tuberculosis (TB), primarily MDR-TB and extensively drug-resistant XDR-TB. Linezolid, the first oxazolidinone antibiotic approved by FDA, is still used in therapy despite common adverse events, such as myelosuppression and serotonergic toxicity, as well as the increasing percentage of linezolid-resistant bacteria (Staphylococcus aureus, enterococci and methicillin-resistant S. aureus). Tedizolid phosphate was the second commercially available oxazolidinone antibiotic approved, followed by other oxazolidinones (contezolid, radezolid, ranbezolid, sutezolid, delpazolid, cadazolid, TBI-233 and MK-7762) that are in clinical study. Contezolid is approved in China and cadazolid has entered phase III clinical trials. This comprehensive review intends to provide an overview of the compounds belonging to this class already in use in therapy and/or clinical studies and to portray the most significant and recent outcomes regarding new oxazolidinones under study. Three literature databases, i.e., PubMed/MEDLINE, Google Scholar and Scopus, were used for the literature search, particularly focusing on the last five years, and screened using different keywords. The design of new drugs belonging to this class may be of considerable interest to researchers and clinicians, contributing to the discovery of new antibiotics that retain antibacterial activity but have fewer side effects. Full article

Background: To effectively manage tuberculosis (TB), it is essential to address the high incidence of the disease, as multidrug-resistant pulmonary TB (MDR-PTB) remains a significant concern to halt pre-extensive drug-resistant (pre-XDR) recrudescence. The objective of the current study was to examine and compare MDR-PTB patterns among adult PTB patients (>12 years) in Bangladesh’s urban and rural areas who had newly diagnosed and previously treated PTB. Methods: A total of 430 newly diagnosed and previously treated adult patients with PTB were randomly recruited during two study periods: the 1st period, from May 2010 to December 2010 (eight months), and the 2nd period, from January 2014 to January 2015 (thirteen months). Only the drug-resistant (DR) patients were included in the final analysis. Mycobacteriological tests, i.e., smear microscopy, culture, drug susceptibility testing (proportion method of Canetti), line-probe assay, and GeneXpert MTB/RIF were performed. Logistic regression analysis was used to determine the strength of associations between treatment outcomes and predictor variables. Results: Of the newly diagnosed patients, 156 cases were negative and drug-sensitive (DS) at diagnosis, and 274 patients exhibited various DR patterns. During the 1st period, MDR-PTB was 26% among newly diagnosed patients, while the proportion was 31% among previously treated patients in the 2nd period. The majority of MDR-PTB belonged to the age group of ≤45 years. Male patients consistently revealed a higher proportion of MDR-PTB compared to females in both the newly diagnosed and previously treated groups. Conclusion: The proportion of MDR-PTB was higher among the previously treated patients than among newly diagnosed patients. Regardless of demographic characteristics, a significant proportion of patients showed DR, particularly in previously treated groups, indicating a substantial burden of MDR-PTB. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health burden, particularly due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Rifampicin, a frontline anti-TB drug that inhibits RNA polymerase, has been central to therapy, but rpoB mutations compromise its efficacy. This highlights the need for Rifampicin analogues that target alternative enzymes to sustain therapeutic effectiveness. In this study, a structure-based computational approach was employed to screen Rifampicin analogues against enoylacyl carrier protein reductase (InhA), a validated enzyme in the biosynthesis of mycolic acids. A library of 399 analogues was retrieved from SwissSimilarity and evaluated using ADMET analysis, with the best candidates showing favourable pharmacokinetic profiles and compliance with Lipinski’s Rule of Five. Molecular docking identified ZINC000013629834 (−10.90 kcal/mol) and ZINC000253411694 (−10.36 kcal/mol) as superior to Rifampicin (−9.05 kcal/mol), with ILE21, SER20, and THR196 consistently stabilizing interactions. Molecular dynamics simulations confirmed the stability of the complexes, with RMSD values of 0.167 nm, 0.175 nm, and 0.297 nm for ZINC000013629834, ZINC000253411694, and Rifampicin, respectively. MM/PBSA analysis showed comparable binding free energies. These findings suggest that optimized Rifampicin analogues targeting InhA may overcome rpoB-associated resistance and serve as promising leads for next-generation anti-TB drug development. Full article

Background: Tuberculosis remains a major global public health challenge, particularly among children. This study aims to provide a comprehensive assessment of the global, regional, and national burden of tuberculosis among children (0–14 years) using data from the Global Burden of Disease (GBD) 2021 study. Methods: Data on the incidence of tuberculosis (drug-susceptible, MDR-TB, and XDR-TB), as well as disability-adjusted life years (DALYs), among children aged 0–14 years in 204 countries and territories from 1990 to 2021 were obtained from the GBD 2021 study. Estimated annual percentage changes (EAPCs) in age-standardised incidence rates (ASIRs) and DALY rate were calculated overall and stratified by age, sex, and sociodemographic index (SDI) to quantify temporal trends. Spearman correlation analyses were performed to assess associations between tuberculosis burden and SDI. Results: In 2021, there were an estimated 759,300 new tuberculosis cases (ASIR: 37.7 per 100,000 population) among children globally, including 32,515 cases of MDR-TB (ASIR: 1.6) and 1193 cases of XDR-TB (ASIR: 0.1). Both global ASIR and DALY rate exhibited a declining trend from 1990 to 2021, with EAPC of −2.61% (95%CI: −2.74 to −2.47) and −4.38% (−4.61 to −4.14), respectively. From 1990 to 2021, High-income North America was the only GBD region with an increasing ASIR for tuberculosis (EAPC = 1.12, 95% CI: 0.61 to 1.64). From 1990 to 2021, there was no significant change in ASIR of MDR-TB (EAPC = 1.18, 95% CI: −0.16 to 2.54). However, eight of the 21 GBD regions exhibited increasing trends in the ASIR of MDR-TB, with the largest increase observed in Oceania (11.99, 10.49 to 13.52), followed by Central Asia (9.76, 6.48 to 13.13) and South Asia (5.71, 3.10 to 8.38). A strong negative correlation was observed between tuberculosis burden and SDI, with the highest disease burden concentrated in low-SDI regions. Conclusions: Achieving elimination targets will require stronger diagnostics and treatment for childhood tuberculosis, alongside reduced transmission, improved infection detection, and preventive therapy for exposed children, especially those under 5 years. Full article

Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), remains a leading global threat, escalated now by the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. In search of a novel anti-tubercular agent with a distinct mechanism of action, this study explores deep-sea marine metabolites as potential inhibitors of the F₄₂₀-dependent oxidoreductase Rv1155, a redox enzyme essential for M. tb survival. A total of 2773 marine-derived compounds curated from the CMNPD, Reaxys, and MarinLit databases were screened using an integrated CADD workflow combining molecular docking, in-silico ADMET profiling, and molecular dynamics (MD) simulations. Docking identified 68 metabolites with strong affinity (−10.98 to −15.95 kcal/mol) for the Rv1155 binding pocket, and from which three compounds, Upenamide (CMNPD_22964), Aspyronol (Compound_1749), and Fiscpropionate F (Compound_1796), were shortlisted as hit candidates. Among these, Upenamide displayed the strongest binding (ΔG = −28.56 kcal/mol) with stable RMSD and hydrogen bond persistence during 100 ns MD simulation, while Aspyronol demonstrated a promising ADMET profile comparable to the native cofactor F₄₂₀₂. MM-GBSA analysis further confirmed the strong binding strength (ΔG _bind = −24.77 to −34.07 kcal/mol) for all three hit candidates. These findings confirm the strong and stable interaction of selected deep-sea marine metabolites with Rv1155. This validated screening pipeline established here provides a cost-effective framework for future experimental validation and expansion to additional F₄₂₀-related drug targets in M. tb. Full article

National Tuberculosis Reference Laboratories (NTRLs) are central to tuberculosis (TB) control programs. Between 2018 and 2024, the Republic of Congo, a country of 6 million inhabitants, achieved a transformative strengthening of its TB diagnostic system, coordinated by the NTRL. Strategic investments, supported mainly by international partners, enabled a substantial decentralization of services, expanding the diagnostic network from 38 to 113 diagnostic and testing centers and increasing GeneXpert sites from 3 to 31. The expansion of the diagnostic network and specimen referral system was associated with a reduced structural gap in diagnostic coverage by extending access to GeneXpert testing to a larger number of peripheral and previously underserved centers. Critically, the establishment of a BSL-3 laboratory and the deployment of advanced assays like Xpert MTB/XDR ended the reliance on overseas testing by introducing in-country capacity for multidrug-resistant and pre-extensively drug-resistant TB detection. These systemic improvements were associated with significant positive outcomes, including an annual molecular testing surging from 11,609 in 2022 to over 27,000 in 2024 and bacteriological confirmation rates rising from 34 to 73%. This comprehensive laboratory systems strengthening, which also facilitated cross-programmatic initiatives like HIV and Mpox testing integration, underscores how sustained investment in infrastructure, logistics, and quality management is fundamental to improving case detection, surveillance, and progress toward the WHO End TB Strategy milestones. Full article

Tuberculosis (TB) remains a leading infectious killer, increasingly complicated by multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease; current regimens, although effective, are prolonged, toxic, and often fail to reach intracellular bacilli in heterogeneous lung lesions. This narrative review synthesizes how next-generation antimycobacterial strategies can be translated “from molecule to patient” by coupling potent therapeutics with delivery platforms tailored to the lesion microenvironment. We survey emerging small-molecule classes, including decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1) inhibitors, mycobacterial membrane protein large 3 (MmpL3) inhibitors, and respiratory chain blockers, alongside optimized uses of established agents and host-directed therapies (HDTs). These are mapped to inhalable and nanocarrier systems that improve intralesional exposure, macrophage uptake, and targeted release while reducing systemic toxicity. Particular emphasis is placed on pulmonary dry powder inhalers (DPIs) and aerosols for direct lung targeting, stimuli-responsive carriers that trigger release through pH, redox, or enzymatic cues, and long-acting depots or implants that shift daily dosing to monthly or quarterly schedules to enhance adherence, safety, and access. We also outline translational enablers, including model-informed pharmacokinetic/pharmacodynamic (PK/PD) integration, device formulation co-design, manufacturability, regulatory quality frameworks, and patient-centered implementation. Overall, aligning stronger drugs with smart delivery platforms offers a practical pathway to shorter, safer, and more easily completed TB therapy, improving both individual outcomes and public health impact. Full article

Drug-resistant tuberculosis (DR-TB) threatens global TB control. We investigated the prevalence and molecular characteristics of second-line drug resistance among rifampicin (RIF)- and/or isoniazid (INH)-resistant Mycobacterium tuberculosis complex (MTBC) isolates in São Paulo, Brazil, using the MTBDRsl v. 2.0 line-probe assay. MTBC isolates RIF- and/or INH-resistant by GenoType MTBDRplus or phenotypic testing (2019–2021) were subsequently tested by MTBDRsl for fluoroquinolone (FQ) and injectable drugs (capreomycin, amikacin, kanamycin) resistance. Isolates with inferred mutations underwent Sanger sequencing. Of 13,557 isolates, 728 (5.4%) were RIF- and/or INH-resistant (297 INH-R, 235 RIF-R, 196 MDR). Among them, 623 (85.6%) were tested by MTBDRsl; 582 (93.4%) showed no additional resistance, while 41 (6.6%) carried mutations. FQ resistance was detected in 38 isolates (92.7%), mostly in gyrA (n = 35). Three isolates with gyrB mutations were wild-type by sequencing. Two MDR isolates harbored the rrs a1401g mutation, and one also harbored gyrA D94G. Sequencing confirmed resistance in 38 of 41 isolates. Most MDR strains with second-line mutations (n = 32/33; 97%) were pre-XDR. Affected patients were predominantly male (68.4%), with pulmonary TB (92.1%), and unfavorable outcomes (39.5%). Second-line resistance prevalence was low overall, but FQ resistance was high among MDR isolates. Findings support integrating molecular and sequencing-based tools for accurate detection and management of DR-TB. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be a leading cause of morbidity and mortality in Mexico, with more than 20,000 new cases annually and a rising proportion of drug-resistant strains. This work addresses the molecular epidemiology of TB in the Mexican context, emphasizing its role in understanding transmission, genetic diversity, and resistance mechanisms. To achieve this, we reviewed molecular typing approaches including spoligotyping, Mycobacterial Interspersed Repetitive Unit–Variable Number Tandem Repeat (MIRU-VNTR) analysis, and whole-genome sequencing (WGS), which have been applied to characterize circulating lineages and identify drug-resistance-associated mutations. The results indicate that the Euro-American lineage (L4) predominates across the country, although significant regional variation exists, with Haarlem, LAM, T, and X sub lineages dominating in different states, and occasional detection of Asian (L2) and Indo-Oceanic (L1) lineages. Key resistance mutations were identified in katG, rpoB, pncA, and gyrA, contributing to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, particularly in border and marginalized regions. These findings highlight how social factors, such as migration, urban overcrowding, and comorbidities including diabetes and HIV, influence transmission dynamics. We conclude that integrating molecular tools with epidemiological surveillance is crucial for strengthening public health strategies and guiding interventions tailored to Mexico’s heterogeneous TB burden. Full article

For drug-susceptible TB, the WHO-endorsed first-line regimen (isoniazid, rifampicin, ethambutol, pyrazinamide) remains the global reference. Therapy must always be tailored to drug susceptibility, especially in MDR- and XDR-TB. HIV-associated mycobacterial infections—including Mycobacterium tuberculosis (TB), disseminated Mycobacterium avium complex (MAC), and Mycobacterium leprae (M. leprae)—remain leading causes of morbidity and mortality in people living with HIV (PLWH). TB continues to account for the highest burden of AIDS-related deaths worldwide, while MAC and leprosy complicate care in advanced immunosuppression. This review synthesizes current evidence on epidemiology, clinical features, and management challenges of HIV–mycobacterial co-infections. We discuss drug-susceptible and drug-resistant TB therapies, drug–drug interactions with antiretroviral therapy (ART), and the clinical impact of immune reconstitution inflammatory syndrome (IRIS). Beyond established regimens, we highlight host-directed strategies such as metformin, glutathione augmentation, mTOR modulation, and vitamin D; immunotherapies including interferon-γ, GM-CSF, and IL-7; and therapeutic vaccines (M72/AS01E, MTBVAC, VPM1002) as promising adjuncts. Distinct from guideline-focused overviews, this review emphasizes non-tuberculous mycobacterial disease (NTM, including MAC) and leprosy in PLWH and synthesizes host-directed and adjunctive strategies with their translational prospects, including ART compatibility and IRIS. By integrating TB, NTM, and leprosy across the HIV care continuum, we highlight opportunities not treated in detail elsewhere—particularly HDT-enabled approaches and implementation considerations in PLWH. Full article