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PloS One 2024To analyze the results of proficiency testing for anti-tuberculosis drug susceptibility testing (DST) in China. Number of laboratory participating the proficiency...
To analyze the results of proficiency testing for anti-tuberculosis drug susceptibility testing (DST) in China. Number of laboratory participating the proficiency testing performed DST, and the sensitivity, specificity, reproducibility, and accordance rate were calculated from data of 13 rounds proficiency testing results for DST from 2008 to 2021. A total of 30 and 20 strains of Mycobacterium tuberculosis with known susceptibility results were sent to each laboratory in 2008 to 2019, 2020 and 2021, respectively. The number of participating laboratories ranged from 30 in 2009 to 546 in 2021. L-J DST was the predominant method. The specificity presented relatively higher than sensitivity. Improvement of specificity were observed for all drugs through the years, while sensitivity did not show improvement for amikacin and capreomycin. Accordance rate of pyrazinamide and kanamycin and reproducibility of capreomycin and pyrazinamide were not significantly improved through the years. Most of the participating laboratories significantly improved the quality of their DST through the consecutive rounds of proficiency testing except for second-line injectable drugs and pyrazinamide. The results highlight the importance of developing novel and/or improving existing methods for phenotypic DST for certain drugs.
Topics: Mycobacterium tuberculosis; Microbial Sensitivity Tests; China; Antitubercular Agents; Humans; Laboratory Proficiency Testing; Reproducibility of Results; Phenotype; Amikacin; Pyrazinamide
PubMed: 38809914
DOI: 10.1371/journal.pone.0304265 -
Microbiology Spectrum Jul 2024The host immune responses play a pivotal role in the establishment of long-term memory responses, which effectively aids in infection clearance. However, the prevailing...
The host immune responses play a pivotal role in the establishment of long-term memory responses, which effectively aids in infection clearance. However, the prevailing anti-tuberculosis therapy, while aiming to combat tuberculosis (TB), also debilitates innate and adaptive immune components of the host. In this study, we explored how the front-line anti-TB drugs impact the host immune cells by modulating multiple signaling pathways and subsequently leading to disease relapse. Administration of these drugs led to a reduction in innate immune activation and also the cytokines required to trigger protective T cell responses. Moreover, these drugs led to activation-induced cell death in the mycobacterial-specific T cell leading to a reduced killing capacity. Furthermore, these drugs stalled the T cell differentiation into memory subsets by modulating the activation of STAT3, STAT4, FOXO1, and NFκB transcription factors and hampering the Th1 and Th17-mediated long-term host protective memory responses. These findings suggest the urgent need to augment directly observed treatment, short-course (DOTS) therapy with immunomodulatory agents to mitigate the adverse effects linked to the treatment.IMPORTANCEAs a central component of TB eradication initiatives, directly observed treatment, short-course (DOTS) therapy imparts immune-dampening effects during the course of treatment. This approach undermines the host immune system by delaying the activation process and lowering the immune response. In our investigation, we have unveiled the impact of DOTS on specific immune cell populations. Notably, the signaling pathways involving STAT3 and STAT4 critical for memory responses and NFκβ associated with pro-inflammation were substantially declined due to the therapy. Consequently, these drugs exhibit limited effectiveness in preventing recurrence of the disease. These observations highlight the imperative integration of immunomodulators to manage TB infection.
Topics: Antitubercular Agents; Tuberculosis; Mycobacterium tuberculosis; Humans; Animals; Mice; Cytokines; Immunity, Innate; Recurrence; Signal Transduction; Immunologic Memory; Female; Mice, Inbred C57BL; Th1 Cells; Th17 Cells
PubMed: 38809023
DOI: 10.1128/spectrum.00412-24 -
Jornal Brasileiro de Pneumologia :... May 2024
Topics: Brazil; Humans; Tuberculosis; Antitubercular Agents; Tuberculosis, Pulmonary
PubMed: 38808837
DOI: 10.36416/1806-3756/e20240121 -
Scientific Reports May 2024Tuberculosis (TB) continues to be a global health crisis, necessitating urgent interventions to address drug resistance and improve treatment efficacy. In this study, we...
Tuberculosis (TB) continues to be a global health crisis, necessitating urgent interventions to address drug resistance and improve treatment efficacy. In this study, we validate lumazine synthase (RibH), a vital enzyme in the riboflavin biosynthetic pathway, as a potential drug target against Mycobacterium tuberculosis (M. tb) using a CRISPRi-based conditional gene knockdown strategy. We employ a high-throughput molecular docking approach to screen ~ 600,000 compounds targeting RibH. Through in vitro screening of 55 shortlisted compounds, we discover 3 compounds that exhibit potent antimycobacterial activity. These compounds also reduce intracellular burden of M. tb during macrophage infection and prevent the resuscitation of the nutrient-starved persister bacteria. Moreover, these three compounds enhance the bactericidal effect of first-line anti-TB drugs, isoniazid and rifampicin. Corroborating with the in silico predicted high docking scores along with favourable ADME and toxicity profiles, all three compounds demonstrate binding affinity towards purified lumazine synthase enzyme in vitro, in addition these compounds exhibit riboflavin displacement in an in vitro assay with purified lumazine synthase indicative of specificity of these compounds to the active site. Further, treatment of M. tb with these compounds indicate reduced production of flavin adenine dinucleotide (FAD), the ultimate end product of the riboflavin biosynthetic pathway suggesting the action of these drugs on riboflavin biosynthesis. These compounds also show acceptable safety profile in mammalian cells, with a high selective index. Hence, our study validates RibH as an important drug target against M. tb and identifies potent antimycobacterial agents.
Topics: Mycobacterium tuberculosis; Antitubercular Agents; Molecular Docking Simulation; Multienzyme Complexes; Drug Discovery; Bacterial Proteins; Humans; Tuberculosis; Microbial Sensitivity Tests; Animals
PubMed: 38806590
DOI: 10.1038/s41598-024-63051-6 -
BMC Infectious Diseases May 2024Hepatitis B virus (HBV) infection can cause liver failure, while individuals with Acquired Immunodeficiency Virus Disease (AIDS) are highly susceptible to various...
BACKGROUND
Hepatitis B virus (HBV) infection can cause liver failure, while individuals with Acquired Immunodeficiency Virus Disease (AIDS) are highly susceptible to various opportunistic infections, which can occur concurrently. The treatment process is further complicated by the potential occurrence of immune reconstitution inflammatory syndrome (IRIS), which presents significant challenges and contributes to elevated mortality rates.
CASE PRESENTATION
The 50-year-old male with a history of chronic hepatitis B and untreated human immunodeficiency virus (HIV) infection presented to the hospital with a mild cough and expectoration, revealing multi-drug resistant pulmonary tuberculosis (MDR-PTB), which was confirmed by XpertMTB/RIF PCR testing and tuberculosis culture of bronchoalveolar lavage fluid (BALF). The patient was treated with a regimen consisting of linezolid, moxifloxacin, cycloserine, pyrazinamide, and ethambutol for tuberculosis, as well as a combination of bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) for HBV and HIV viral suppression. After three months of treatment, the patient discontinued all medications, leading to hepatitis B virus reactivation and subsequent liver failure. During the subsequent treatment for AIDS, HBV, and drug-resistant tuberculosis, the patient developed disseminated cryptococcal disease. The patient's condition worsened during treatment with liposomal amphotericin B and fluconazole, which was ultimately attributed to IRIS. Fortunately, the patient achieved successful recovery after appropriate management.
CONCLUSION
Enhancing medical compliance is crucial for AIDS patients, particularly those co-infected with HBV, to prevent HBV reactivation and subsequent liver failure. Furthermore, conducting a comprehensive assessment of potential infections in patients before resuming antiviral therapy is essential to prevent the occurrence of IRIS. Early intervention plays a pivotal role in improving survival rates.
Topics: Humans; Male; Middle Aged; Cryptococcosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Liver Failure; Acquired Immunodeficiency Syndrome; Hepatitis B, Chronic; Coinfection; Antitubercular Agents; HIV Infections; AIDS-Related Opportunistic Infections
PubMed: 38802753
DOI: 10.1186/s12879-024-09431-9 -
BMC Infectious Diseases May 2024Tuberculosis (TB) causes over 1 million deaths annually. Providing effective treatment is a key strategy for reducing TB deaths. In this study, we identified factors...
INTRODUCTION
Tuberculosis (TB) causes over 1 million deaths annually. Providing effective treatment is a key strategy for reducing TB deaths. In this study, we identified factors associated with unsuccessful treatment outcomes among individuals treated for TB in Brazil.
METHODS
We obtained data on individuals treated for TB between 2015 and 2018 from Brazil's National Disease Notification System (SINAN). We excluded patients with a history of prior TB disease or with diagnosed TB drug resistance. We extracted information on patient-level factors potentially associated with unsuccessful treatment, including demographic and social factors, comorbid health conditions, health-related behaviors, health system level at which care was provided, use of directly observed therapy (DOT), and clinical examination results. We categorized treatment outcomes as successful (cure, completed) or unsuccessful (death, regimen failure, loss to follow-up). We fit multivariate logistic regression models to identify factors associated with unsuccessful treatment.
RESULTS
Among 259,484 individuals treated for drug susceptible TB, 19.7% experienced an unsuccessful treatment outcome (death during treatment 7.8%, regimen failure 0.1%, loss to follow-up 11.9%). The odds of unsuccessful treatment were higher with older age (adjusted odds ratio (aOR) 2.90 [95% confidence interval: 2.62-3.21] for 85-100-year-olds vs. 25-34-year-olds), male sex (aOR 1.28 [1.25-1.32], vs. female sex), Black race (aOR 1.23 [1.19-1.28], vs. White race), no education (aOR 2.03 [1.91-2.17], vs. complete high school education), HIV infection (aOR 2.72 [2.63-2.81], vs. no HIV infection), illicit drug use (aOR 1.95 [1.88-2.01], vs. no illicit drug use), alcohol consumption (aOR 1.46 [1.41-1.50], vs. no alcohol consumption), smoking (aOR 1.20 [1.16-1.23], vs. non-smoking), homelessness (aOR 3.12 [2.95-3.31], vs. no homelessness), and immigrant status (aOR 1.27 [1.11-1.45], vs. non-immigrants). Treatment was more likely to be unsuccessful for individuals treated in tertiary care (aOR 2.20 [2.14-2.27], vs. primary care), and for patients not receiving DOT (aOR 2.35 [2.29-2.41], vs. receiving DOT).
CONCLUSION
The risk of unsuccessful TB treatment varied systematically according to individual and service-related factors. Concentrating clinical attention on individuals with a high risk of poor treatment outcomes could improve the overall effectiveness of TB treatment in Brazil.
Topics: Humans; Brazil; Male; Female; Adult; Middle Aged; Antitubercular Agents; Treatment Failure; Young Adult; Adolescent; Tuberculosis; Aged; Directly Observed Therapy; Child; Child, Preschool; Risk Factors; Infant; HIV Infections; Treatment Outcome; Aged, 80 and over
PubMed: 38802744
DOI: 10.1186/s12879-024-09417-7 -
Tuberculosis (Edinburgh, Scotland) Jul 2024To assess the validity of Xpert Tuberculosis Fingerstick score for monitoring treatment response and analyze factors influencing its performance.
OBJECTIVE
To assess the validity of Xpert Tuberculosis Fingerstick score for monitoring treatment response and analyze factors influencing its performance.
METHODS
122 adults with pulmonary tuberculosis were recruited and stratified into three cohorts: Diabetic-drug-susceptible-TB (DM-TB), Non-diabetic-drug-susceptible-TB (NDM-TB) and Non-diabetic Multidrug-resistant TB (MDR-TB). Fingerstick blood specimens were tested at treatment initiation (M0) and the end of the first (M1), second (M2), and sixth month (M6) to generate a TB-score.
RESULTS
The TB-score in all participants yielded an AUC of 0.707 (95% CI: 0.579-0.834) at M2 when its performance was evaluated against sputum culture conversion. In all non-diabetes patients, the AUC reached 0.88 (95% CI: 0.756-1.000) with an optimal cut-off value of 1.95 at which sensitivity was 90.0% (95% CI: 59.6-98.2%) and specificity was 81.3% (95% CI: 70.0-88.9%). The mean TB score was higher in patients with low bacterial loads (n = 31) than those with high bacterial loads (n = 91) at M0, M1, M2, and M6, and was higher in non-cavitary patients (n = 71) than those with cavitary lesions (n = 51) at M0, M1, and M2.
CONCLUSION
Xpert TB-score shows promising predictive value for culture conversion in non-diabetic TB patients. Sputum bacterial load and lung cavitation status have an influence on the value of TB score.
Topics: Humans; Tuberculosis, Pulmonary; Male; Female; Adult; Middle Aged; Antitubercular Agents; Mycobacterium tuberculosis; Sputum; Predictive Value of Tests; Drug Monitoring; Treatment Outcome; Reproducibility of Results; Aged; Tuberculosis, Multidrug-Resistant; Time Factors; Biomarkers; Gene Expression Profiling; Young Adult
PubMed: 38801793
DOI: 10.1016/j.tube.2024.102521 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Facile access to some novel biologically relevant dihydrotriazolopyrimidine carboxylic acid-derived amide analogues using NMI/SOCl, and aromatic and aliphatic primary...
Facile access to some novel biologically relevant dihydrotriazolopyrimidine carboxylic acid-derived amide analogues using NMI/SOCl, and aromatic and aliphatic primary and secondary amines, is reported herein. The role of -methylimidazole (NMI) as the base and sulfuryl chloride (SOCl) as the coupling reagent has been effectively realized in accessing these molecules in good to excellent yields. The feasibility of the developed protocol has also been extended to the gram-scale synthesis of -benzylbenzamide in a 75% yield from benzoic acid and benzyl amine. The newly synthesized compounds were tested via in vitro anti-inflammatory and anti-tubercular activity studies. The compounds and were found to be the most active anti-inflammatory agents, whereas and were found to exhibit promising anti-tubercular potency when compared to other synthesized molecules. The structure-activity relationship (SAR) studies revealed the importance of the presence of electron-donating functionalities in enhancing the anti-inflammatory potential of the newly synthesized molecules. However, the presence of electron-withdrawing substituents was found to be significant for improving their anti-tubercular potency.
PubMed: 38794119
DOI: 10.3390/ph17050548 -
Viruses May 2024The coexistence of HIV infection and latent tuberculosis infection (LTBI) presents a significant public health concern due to the increased risk of tuberculosis (TB)... (Observational Study)
Observational Study
BACKGROUND
The coexistence of HIV infection and latent tuberculosis infection (LTBI) presents a significant public health concern due to the increased risk of tuberculosis (TB) reactivation and progression to active disease. The multicenter observational cohort study, TUBHIVIT, conducted in Italy from 2017 to 2023, aimed to assess the prevalence of LTBI among people living with HIV (PLHIV) and their outcomes following LTBI screening and therapy initiation.
METHODS
We performed a prospective study in five referral centers for HIV care in Italy. PLHIV who consented Tto participate underwent QuantiFERON-TB Gold Plus and clinical, microbiological, and radiological assessments to exclude subclinical tuberculosis, as opportune. PLHIV diagnosed with LTBI who started chemoprophylaxis were followed until the end of therapy.
RESULTS
A total of 1105 PLHIV were screened for LTBI using the QuantiFERON-TB Gold Plus test, revealing a prevalence of 3.4% of positive results (38/1105). Non-Italy-born individuals exhibited a significantly higher likelihood of testing positive. Thirty-one were diagnosed with LTBI, 1 showed active subclinical TB, and 6 were lost to follow-up before discriminating between latent and active TB. Among the PLHIV diagnosed with LTBI, 83.9% (26/31) started chemoprophylaxis. Most individuals received 6-9 months of isoniazid-based therapy. Of the 26 PLHIV commencing chemoprophylaxis, 18 (69.2%) completed the therapy, while 3 discontinued it and 5 were still on treatment at the time of the analysis. Adverse events were observed in two cases, while in one case the patient refused to continue the treatment.
Topics: Humans; Latent Tuberculosis; Italy; Male; Female; Adult; HIV Infections; Prospective Studies; Middle Aged; Mass Screening; Prevalence; Antitubercular Agents; Isoniazid; Coinfection
PubMed: 38793658
DOI: 10.3390/v16050777 -
Viruses Apr 2024Chronic immune activation in tuberculosis (TB) associated with human immunodeficiency virus (HIV) infection (HIV/TB) modifies their clinical course. We prospectively...
Chronic immune activation in tuberculosis (TB) associated with human immunodeficiency virus (HIV) infection (HIV/TB) modifies their clinical course. We prospectively measured osteopontin (OPN), full-length galectin-9 (FL-Gal9), and total-Gal9 (T-Gal9) levels in 32 patients with HIV/TB coinfection treated with anti-tuberculosis and antiretroviral therapies over 6-18 months to determine the amelioration of inflammatory conditions in response to the therapies. We observed a significant time-dependent decrease in FL-Gal9 in both pulmonary TB (PTB, n = 20) and extrapulmonary TB (EPTB, n = 12) patients. The levels of T-Gal9, OPN, and CRP decreased significantly after treatment in only PTB patients. We calculated the inflammatory score (INS) indicating immunologic recovery based on the decline in OPN, FL-Gal9, T-Gal9, and CRP levels. Baseline levels of T-Gal9 and OPN positively correlated with INS in all TB and only PTB patients, respectively, indicating that their levels predict better recovery. In contrast, FL-Gal9 levels at the second visit negatively correlated with INS in EPTB patients. The decrease rate in OPN levels at the second visit also correlated positively with INS in PTB patients. Women showed a higher INS and lower levels of FL-Gal9 than men. The patients with moderate grade severity on chest X-ray had higher CD4 cell numbers than those with limited grade severity. Monitoring these markers will help to predict and assess the response to therapy as well as to devise strategies to reduce the complications caused by chronic immune activation in patients with HIV/TB coinfection.
Topics: Humans; HIV Infections; Female; Male; Coinfection; Adult; Osteopontin; Galectins; Tuberculosis; Middle Aged; Prospective Studies; Biomarkers; Antitubercular Agents; Tuberculosis, Pulmonary; C-Reactive Protein
PubMed: 38793546
DOI: 10.3390/v16050664