Search Results (160)

Background: Multidrug-resistant tuberculosis (MDR-TB) remains a significant public health threat in Central Asia, where rising resistance to first-line anti-TB drugs challenges control efforts. As of 2024, the World Health Organization (WHO) reports that over 2.5% of new TB cases and 18% of previously treated cases are resistant to first-line TB drugs worldwide. Objectives: This integrative review synthesizes current evidence on MDR-TB in Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan, with a focus on infection control, diagnostic advancements, and evolving treatment strategies. Methods: A comprehensive literature search was conducted across five electronic databases: PubMed, Scopus, Web of Science, Embase, World Health Organization (WHO) Global Tuberculosis Database, and ClinicalTrials.gov. A total of 29 articles from Central Asian countries met the inclusion criteria. Results: Four main themes were identified: “genetic variability and resistance patterns of MDR-TB strains”; “barriers to effective treatment”; “diagnostic tools”, and “infection control strategies”. Conclusions: This review underscores the importance of comprehensive, multifactorial approaches in addressing drug-resistant TB in the region. The implementation of early diagnosis and all-oral treatment regimens has improved adherence in recent studies. Full article

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis complex (MTBC), remains a global health challenge and can lead to severe pulmonary and extrapulmonary complications. Multidrug-resistant TB (MDR-TB) poses additional challenges, requiring advanced diagnostic and treatment strategies. This study evaluates the BD MAX MDR-TB molecular test for a rapid diagnosis of MDR-TB, detecting resistance to rifampicin (RIF) and isoniazid (INH). The BD MAX MDR-TB test, utilizing real-time PCR, was used to analyze specimens collected from TB-suspected patients, identifying MTB DNA and mutations associated with rifampicin and isoniazid resistance. Results were compared with traditional drug susceptibility testing, and 79 out of 638 samples tested were positive for MTB DNA, with 65 showing a sufficient amount of genetic material for resistance gene identification. The BD MAX test showed a 100% correlation with phenotypic rifampicin resistance, though discrepancies were noted for isoniazid resistance, with a 93% concordance. The BD MAX MDR-TB test is an effective tool for a rapid diagnosis of MDR-TB, especially for rifampicin resistance. However, it may not detect certain mutations related to isoniazid resistance. Complementary tests like Xpert MTB/XDR or whole-genome sequencing could improve diagnostic accuracy and support more effective TB control strategies. Full article

Background and Objectives: Tuberculosis (TB) is one of the most common infectious diseases in developing countries. The resistance of the causative agent, Mycobacterium tuberculosis, to two or more first-line anti-TB drugs results in multidrug-resistant (MDR) TB, posing a serious challenge to the control of TB worldwide. This study was designed to determine the changes in drug resistance over time in TB strains isolated from patients in all departments of Uludağ University Hospital in western Türkiye. Materials and Methods: We retrospectively analyzed 104,598 clinical samples sent to our laboratory for the investigation of the presence of TB between 1996 and 2023. BACTEC 460 TB, BACTEC MGIT 960 culture systems and Löwenstein–Jensen medium were used for the culture of these samples. The susceptibility of M. tuberculosis complex strains grown in culture to isoniazid (INH) (0.1 μg/mL), rifampicin (RIF) (1.0 μg/mL), ethambutol (ETB) (5.0 μg/mL) and streptomycin (SM) (1.0 μg/mL) antibiotics was studied according to the manufacturer’s recommendation. Results: Out of 104,598 patient samples, 2752 (2.6%) were culture-positive, and the susceptibility test results of 1869 of these were analyzed. Of the isolates, 358 (19.2%) were found to be resistant to at least one first-line drug, i.e., INH, RIF, ETB, or SM. In addition, 2.9% were resistant to two or more first-line drugs. Conclusions: Drug susceptibility testing is essential to ensure the optimal treatment and control of drug-resistant TB strains. This study highlights the value of ongoing efforts to control tuberculosis drug resistance in the fight against this disease. Full article

Tuberculosis (TB) remains one of the leading causes of mortality worldwide, exacerbated by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains. In the pursuit of novel therapeutic strategies, thiazolidin-4-one derivatives have gained significant attention due to their structural diversity and broad-spectrum biological activities. This review provides a comprehensive summary of recent advances (2021–present) in the synthesis, structure–activity relationship (SAR), and mechanisms of action of thiazolidin-4-one derivatives as promising antitubercular agents. A detailed discussion of synthetic pathways is presented, including classical and multi-component reactions leading to various subclasses such as thiazolidine-2,4-diones, rhodanines, and pseudothiohydantoins. The SAR analysis highlights key functional groups that enhance antimycobacterial activity, such as halogen substitutions and heterocyclic linkers, while molecular docking and in vitro studies elucidate interactions with key Mtb targets including InhA, MmpL3, and DNA gyrase. Several compounds demonstrate potent inhibitory effects with MIC values lower than or comparable to first-line TB drugs, alongside favorable cytotoxicity profiles. These findings underscore the potential of thiazolidin-4-one scaffolds as a valuable platform for the development of next-generation antitubercular therapeutics. Full article

Background: Extrapulmonary tuberculosis (TB) presents significant diagnostic challenges, particularly in the context of multidrug-resistant (MDR) strains. This study assessed the utility of the WHO-recommended rapid molecular assays, originally validated for pulmonary TB, in diagnosing extrapulmonary TB and detecting the MDR Mycobacterium tuberculosis complex (MTBC). Materials and Methods: A total of 6274 clinical samples, including 4891 pulmonary and 1383 extrapulmonary samples, were analyzed between 2019 and 2022 using the BD MAX™ MDR-TB assay (BD MAX), the Xpert^® MTB/RIF assay (Xpert MTB/RIF), the Xpert^® MTB/XDR assay (Xpert MTB/XDR), FluoroType MTB, and phenotypic drug susceptibility testing (DST). Results: MTBC was detected in 426 samples using BD MAX (376 pulmonary and 50 extrapulmonary), of which 277 were culture-confirmed. Phenotypic testing confirmed 299 positive cultures on Löwenstein–Jensen (LJ) medium and 347 in BD BACTEC™ MGIT™ (BACTEC MGIT) mycobacterial growth indicator tube (BBL) liquid culture. BD MAX showed high sensitivity and specificity for extrapulmonary TB detection (93.1% and 98.4%, respectively). Resistance to isoniazid or rifampicin was identified in 11% of MTBC-positive cases, whereas 3.69% were confirmed as MDR-TB. The molecular assays effectively detected resistance-associated mutations (katG, inhA, and rpoB), with high concordance to phenotypic tests (DST) (κ = 0.69–0.89). Conclusions: This study demonstrates that molecular assays, although validated for pulmonary TB, are also reliable for extrapulmonary TB detection and drug resistance profiling. Their rapid turnaround and robust accuracy support broader implementation in routine diagnostics, especially for challenging extrapulmonary specimens where early detection is critical for targeted therapy. Full article

Tuberculosis (TB) is an infectious disease caused by bacteria that primarily target the lungs. The transmission of this disease occurs through the air in the form of droplet nuclei. Unfortunately, there has been an emergence of resistance to strains of such infections, such as multidrug- as well as extensively drug-resistant strains. Healthcare workers (HCWs) are particularly vulnerable to contracting TB due to their direct contact with patients. This study aims to evaluate the knowledge, attitude, and practices among Lebanese healthcare workers towards TB and its resistant forms, particularly multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). This study is a cross-sectional, descriptive, questionnaire-based research study that was conducted on HCWs in Lebanon. A total of 517 HCWs were included in this study. The findings displayed that 48.52% of HCWs had good knowledge of TB and MDR-TB/XDR-TB, 49.52% had average knowledge, and 2.13% had bad knowledge. Moreover, only 16.25% had a good attitude, 71.92% had an average attitude, and 11.8% had a bad attitude. Furthermore, only 14.7% had good practices, 54.74% had average practices, and 30.56% had bad practices. Having a history of testing for TB was found to be related to increased attitude. Also, the history of having TB-infected family members was found to be linked to both increased attitude and practice scores. Moreover, this study highlights the idea that high knowledge scores do not mean high attitude or high practices scores. On the same note, acceptable attitude scores do not inflict acceptable practice scores. The findings of this study showed that there is an overall good knowledge regarding TB, MDR-TB, and XDR-TB, average attitude, and average-to-bad practices. Gaps are seen in all sectors, even knowledge, especially with matters related to the diagnosis of MDR-TB/XDR-TB and its treatment duration. Also, the attitude section revealed a gap in the understanding of the modes of transmission of such an infection. Full article

Multidrug-resistant tuberculosis (MDR-TB) is a significant public health challenge globally, exacerbated by the limited efficacy of existing therapeutic approaches, prolonged treatment duration, and severe side effects. As drug resistance continues to emerge, innovative drug delivery systems and treatment strategies are critical to combating this crisis. This review highlights the molecular mechanisms underlying resistance to drugs in Mycobacterium tuberculosis, such as genetic mutation, efflux pump activity, and biofilm formation, contributing to the persistence and difficulty in eradicating MDR-TB. Current treatment options, including second-line drugs, offer limited effectiveness, prompting the need for innovation of advanced therapies and drug delivery systems. The progression in drug discovery has resulted in the approval of innovative therapeutics, including bedaquiline and delamanid, amongst other promising candidates under investigation. However, overcoming the limitations of traditional drug delivery remains a significant challenge. Nanotechnology has emerged as a promising solution, with nanoparticle-based drug delivery systems offering improved bioavailability and targeted and controlled release delivery, particularly for pulmonary targeting and intracellular delivery to macrophages. Furthermore, the development of inhalable formulations and the potential of nanomedicines to bypass drug resistance mechanisms presents a novel approach to enhancing drug efficacy. Moreover, adjunctive therapies, including immune modulation and host-directed therapies, are being explored to improve treatment outcomes. Immunotherapies, such as cytokine modulation and novel TB vaccines, offer complementary strategies to the use of antibiotics in combating MDR-TB. Personalized medicine approaches, leveraging genomic profiling of both the pathogen and the host, offer promise in optimizing treatment regimens and minimizing drug resistance. This review underscores the importance of multidisciplinary approaches, combining drug discovery, advanced delivery system development, and immune modulation to address the complexities of treating MDR-TB. Continued innovation, global collaboration, and improved diagnostics are essential to developing practical, accessible, and affordable treatments for MDR-TB. Full article

The clinical characteristics of multidrug-resistant tuberculosis (MDR-TB) patients with concurrent nontuberculous mycobacterial (NTM) infection present significant challenges to treatment. This study investigated the clinical characteristics of MDR-TB patients with concurrent NTM infection during treatment. A retrospective cohort study was conducted to collect the clinical data of MDR-TB patients who initiated treatment between January 2020 and December 2022. A total of 389 patients were analyzed, among which 111 patients who were lost to follow-up and 56 patients who missed etiological examination of tuberculosis during the visit period were excluded. A total of 222 patients with complete data were included in this study. The species identification method primarily employed molecular biology techniques, specifically the DNA microarray method and/or MPB64 antigen detection using the colloidal gold method. Patients whose sputum or bronchoalveolar lavage fluid cultures were positive and who were identified at least once as having NTM or as MPB64 negative were included in this study. Imaging data, comorbidities, pre-treatment infection, and nutritional indicators were analyzed during treatment. Among the 222 MDR-TB patients, no concurrent NTM cases were identified at the beginning of treatment. However, 19 cases (8.56%) were presumed to be NTM-positive during treatment, which appeared during anti-tuberculosis treatment from 2 to 12 months, averaging 6 (3, 12) months. Thirteen patients were only tested for MPB64, with five having two negative MPB64 tests. The symptoms of NTM-positive patients varied, and imaging findings were similar to those of MDR-TB but did not worsen. The emergence of presumed NTM-positive cases (8.56%) among MDR-TB patients during treatment highlights the need for monitoring, as symptoms and imaging findings may mimic MDR-TB without worsening. Early and repeated testing, including methods beyond MPB64, may be useful for more accurate diagnosis and tailored management. Full article

Background: Tuberculosis (TB) remains a leading cause of mortality worldwide, particularly in low- and middle-income countries. The rise of multidrug-resistant TB (MDR-TB) poses significant challenges to global health. This study reviews the experience of the largest pulmonology center in Serbia, a country with low MDR-TB incidence, focusing on TB prevalence, resistance detection, and treatment strategies between 2012 and 2021. Methods: We retrospectively analyzed a total of 1239 patients who were diagnosed and treated for TB in the period from 2012 to 2021 at University Clinical Center of Serbia. Results: Drug resistance was identified in 21 patients (1.7%), with the highest resistance to rifampicin (1.4%) and isoniazid (1.3%). Pyrazinamide and streptomycin resistance were detected in only a few cases. Patients with resistant TB were younger on average, though the difference was not statistically significant (46.4 ± 19.1 vs. 53.6 ± 18.4, p = 0.079). Prior TB history was more frequent in the resistant group, almost reaching statistical significance (4 vs. 82, p = 0.052). Conclusions: These findings underscore the critical importance of sustained surveillance, particularly of latent and drug-resistant TB forms, in alignment with the World Health Organization’s (WHO) TB control strategy to preserve Serbia’s low-incidence status. Moreover, given Serbia’s strategic location on a major migration route, there is an elevated risk of new TB cases emerging and potential shifts in TB-drug-resistance patterns developing in the future. Full article

Oxazolidinones, novel synthetic antibacterials, inhibit protein biosynthesis and show potent activity against Gram-positive bacteria, including Mycobacterium tuberculosis (MTB). In this study, we aimed to compare the in vitro activity of linezolid (LZD) and four oxazolidinones, including tedizolid (TZD), contezolid (CZD), sutezolid (SZD), and delpazolid (DZD), against multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) isolates from Hainan. We established their epidemiological cut-off values (ECOFFs) using ECOFFinder software and analyzed mutations in rrl (23S rRNA), rplC, rplD, mce3R, tsnR, Rv0545c, Rv0930, Rv3331, and Rv0890c genes to uncover potential mechanisms of oxazolidinone resistance. This study included 177 MTB isolates, comprising 67 MDR and 110 pre-XDR-TB isolates. Overall, SZD exhibited the strongest antibacterial activity against clinical MTB isolates, followed by TZD and LZD, with CZD and DZD showing equivalent but weaker activity (SZD_MIC50 = TZD_MIC50 < LZD_MIC50 < CZD_MIC50 = DZD_MIC50; SZD_MIC90 < TZD_MIC90 = LZD_MIC90 < CZD_MIC90 = DZD_MIC90). Significant differences in MIC distribution were observed for TZD (p < 0.0001), CZD (p < 0.01), SZD (p < 0.0001), and DZD (p < 0.0001) compared to LZD but not between MDR-TB and pre-XDR-TB isolates. We propose the following ECOFFs: SZD, 0.5 µg/mL; LZD, TZD, and CZD, 1.0 µg/mL; DZD, 2.0 µg/mL. No statistically significant differences in resistance rates were observed among these five drugs (p > 0.05). We found that eight MTB isolates (4.52% [8/177]) resisted these five oxazolidinones. Among these, only one isolate, M26, showed an amino acid substitution (Arg79His) in the protein encoded by the rplD gene, which conferred cross-resistance to TZD and CZD. Three distinct mutations were identified in the mce3R gene; notably, isolate P604 displayed two insertions that contributed to resistance against all five oxazolidinones. However, no significant correlation was observed between mutations in the rrl, rplC, rplD, mce3R, tsnR, Rv0545c, Rv0930, Rv3331, and Rv0890c genes with oxazolidinone resistance in the clinical MTB isolates tested. In summary, this study provides the first report on the resistance of MTB in Hainan to the five oxazolidinones (LZD, TZD, CZD, SZD, and DZD). In vitro susceptibility testing indicated that SZD exhibited the strongest antibacterial activity, followed by TZD and LZD, while CZD and DZD demonstrated comparable but weaker effectiveness. Mutations in rplD and mce3R were discovered, but further research is needed to clarify their role in conferring oxazolidinone resistance in MTB. Full article

Background: Treatment outcomes are critical measures of TB treatment success, especially in resource-limited settings where tuberculosis remains a major public health issue. This study evaluated the treatment outcomes of patients with drug-resistant tuberculosis (DR-TB), co-infected with human immunodeficiency virus (HIV), and the impact of nutritional status, as measured by body mass index (BMI), on these outcomes in rural areas of the Olivier Reginald Tambo District Municipality, Eastern Cape, South Africa. Methods: A retrospective review of 360 patient files from four TB clinics and one referral hospital was conducted between January 2018 and December 2020. Data collected included patient demographics, clinical characteristics, BMI (categorized as underweight, normal, overweight, or obese), HIV status, DR-TB type, and treatment outcomes. Statistical analyses assessed the association between BMI categories, HIV status, and treatment outcomes. A scatter plot was used to illustrate BMI trends as a continuous variable in relation to age, enabling an analysis of BMI distribution across different age groups. Additionally, bar charts were utilized to explore categorical relationships and patterns in BMI across these groups. Results: The majority of patients were co-infected with HIV and had DR-TB, with rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB) being the most prevalent forms. Treatment outcomes varied significantly by BMI category. Underweight patients had the lowest cure rates (23.2%), highlighting the adverse impact of malnutrition on DR-TB treatment success. Patients with normal BMI demonstrated higher cure rates (34.7%), while overweight and obese patients had moderate outcomes. HIV co-infection further reduced cure rates, with co-infected individuals showing poorer outcomes than HIV-negative patients. Gender disparities were also observed, with females achieving higher cure rates (39.1%) compared to males (31.4%). Weak trends linked BMI and DR-TB type, such as a higher prevalence of normal BMI among RR-TB cases. Conclusion: This study underscores the significant influence of nutritional status on DR-TB treatment outcomes, particularly among patients co-infected with HIV. Underweight patients face the greatest risk of poor outcomes, emphasizing the need for nutritional support as a critical component of DR-TB management. Comprehensive HIV care and gender-specific interventions are also essential to address disparities in treatment success. Tailored strategies focusing on these aspects can significantly enhance outcomes in high-burden, resource-limited settings. Full article

Background/Objectives: Tuberculosis (TB) is preventable and curable, but multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) pose significant challenges worldwide due to the limited treatment options, lengths of therapies, and high rates of treatment failure. The management of MDR-TB has been revolutionized by all oral anti-TB drug regimens that are likely to improve adherence and treatment outcomes. These regimes include bedaquiline (B), pretomanid (P), and linezolid (L) (BPaL), and moxifloxacin if resistance to fluoroquinolones is not detected (BPaLM). Based on the evidence generated by the TB-PRACTECAL and ZeNix randomized controlled trials, BPaL/BPaLM regimens are recommended over the currently recommended longer regimens in patients with MDR-TB or monoresistance to rifampin (RR). To our knowledge, no data are currently available on the implementation of BPaL/BPaLM regimens in Italy. Results: Seventeen patients completed the BPaL/BPaLM regimen, with a treatment success rate of 90% (17/19), consistent with the literature data. Eleven patients out of the nineteen retained in care (58%) complained about symptoms consistent with adverse events (AEs). No treatment interruption was necessary due to AEs. Methods: Here, we report the real-world experience of a tertiary referral hospital for TB in Italy, from 2022 to 2024, in the management, outcomes, and adverse drug reactions of a cohort of twenty-two MDR/RR patients treated with BPaL and BPaLM regimens. Conclusions: BPaL-containing regimens also serve as promising options for patients with RR/MDR-TB in terms of real-life experience, but further multicentric studies are required in Europe to confirm the efficacy of shorter regimens to eliminate MDR TB. Full article

Multidrug-resistant tuberculosis (MDR-TB) poses a significant global health threat, especially when it involves the central nervous system (CNS). Tuberculous meningitis (TBM), a severe manifestation of TB, is linked to high mortality rates and long-term neurological complications, further exacerbated by drug resistance and immune evasion mechanisms employed by Mycobacterium tuberculosis (Mtb). Although pulmonary TB remains the primary focus of research, MDR-TBM introduces unique challenges in diagnosis, treatment, and patient outcomes. The effectiveness of current treatments is frequently compromised by poor CNS penetration of anti-TB drugs and the necessity for prolonged therapy, which often involves considerable toxicity. This review explores the potential of cytokine-based adjunct immunotherapies for MDR-TBM, addressing the challenges of balancing pro-inflammatory and anti-inflammatory signals within the CNS. A central focus is the prospective role of glutathione, not only in reducing oxidative stress but also in enhancing host immune defenses against Mtb’s immune evasion strategies. Furthermore, the development of vaccines aimed at upregulating glutathione synthesis in macrophages represents a promising strategy to bolster the immune response and improve treatment outcomes. By integrating glutathione and innovative vaccine approaches into MDR-TBM management, this review proposes a comprehensive strategy that targets Mtb directly while supporting immune modulation, with the potential to enhance patient outcomes and reduce treatment related adverse effects. We underscore the urgent need for further research into adjunctive therapies and immunomodulatory strategies to more effectively combat MDR-TBM. Full article

Multidrug-resistant tuberculosis (MDR-TB) patients are treated with a standardised, short World Health Organization (WHO) regimen which includes clofazimine (CFZ) and bedaquiline (BDQ) antibiotics. These two antibiotics lead to the development of QT prolongation in patients, inhibiting potassium (K⁺) uptake by targeting the voltage-gated K⁺ (Kv)11.1 (hERG) channel of the cardiomyocytes (CMs). However, the involvement of these antibiotics to regulate other K⁺ transporters of the CMs, as potential mechanisms of QT prolongation, has not been explored. This study determined the effects of CFZ and BDQ on sodium, potassium–adenosine triphosphatase (Na⁺,K⁺-ATPase) activity of CMs using rat cardiomyocytes (RCMs). These cells were treated with varying concentrations of CFZ and BDQ individually and in combination (1.25–5 mg/L). Thereafter, Na⁺,K⁺-ATPase activity was determined, followed by intracellular adenosine triphosphate (ATP) quantification and cellular viability determination. Furthermore, molecular docking of antibiotics with Na⁺,K⁺-ATPase was determined. Both antibiotics demonstrated dose–response inhibition of Na⁺,K⁺-ATPase activity of the RCMs. The greatest inhibition was demonstrated by combinations of CFZ and BDQ, followed by BDQ alone and, lastly, CFZ. Neither antibiotic, either individually or in combination, demonstrated cytotoxicity. Molecular docking revealed an interaction of both antibiotics with Na⁺,K⁺-ATPase, with BDQ showing higher protein-binding affinity than CFZ. The inhibitory effects of CFZ and BDQ, individually and in combination, on the activity of Na⁺,K⁺-ATPase pump of the RCMs highlight the existence of additional mechanisms of QT prolongation by these antibiotics. Full article

Tuberculosis (TB) is one of the leading causes of death due to infectious disease. It is a treatable disease; however, conventional treatment requires a lengthy treatment regimen with severe side effects, resulting in poor compliance among TB patients. Intermittent drug use, the non-compliance of patients, and prescription errors, among other factors, have led to the emergence of multidrug-resistant TB, while the mismanagement of multidrug-resistant TB (MDR-TB) has eventually led to the development of extensively drug-resistant tuberculosis (XDR-TB). Thus, there is an urgent need for new drug development, but due to the enormous expenses and time required (up to 20 years) for new drug research and development, new therapeutic approaches to TB are required. Host-directed therapies (HDT) could be a most attractive strategy, as they target the host defense processes instead of the microbe and thereby may prevent the alarming rise of MDR- and XDR-TB. This paper reviews the progress in HDT for the treatment of TB using repurposed drugs which have been investigated in clinical trials (completed or ongoing) and plant-derived natural products that are in clinical or preclinical trial stages. Additionally, this review describes the existing challenges to the development and future research directions in the implementation of HDT. Full article