Trends and risk factors for drug-resistant tuberculosis among children in Sichuan, China: A 10-year retrospective analysis, 2013-2022.

To investigate the status of the drug-resistant tuberculosis (DR-TB) among children in Sichuan, and to find out the risk factors and high-risk population related to drug resistance among children. The clinical data of tuberculosis patients ≤14 years old with culture-confirmed tuberculosis hospitalized in Chengdu Public Health Clinical Center from January 2013 through December 2022 were collected. Clinical data such as gender, age, ethnicity, history of anti-TB treatment, history of exposure to tuberculosis, nutritional status, and specific drug resistance of the children were collected and recorded. The drug resistance of children in different age groups (0-4 years old, 5-9 years old, 10-14 years old) and different periods (2013-2017 and 2018-2022) were grouped and compared. Logistic regression analysis was to analyze analysis of risk factors of drug resistance in children. A total of 438 children with culture-confirmed tuberculosis were screened. Among them, 26.19% (11/42) were 0 to 4 years old, 33.33% (22/66) were 5 to 9 years old, and 36.67% (121/330) were 10 to 14 years old among the resistant children. There was no statistically significant difference in the resistance rate among the 3 groups (P = .385). The proportions of DR-TB, monoresistant tuberculosis, polydrug-resistant tuberculosis were decreased during 2019 to 2022 compared with 2013 to 2017 (P < .0001). The resistance rates of drug resistant, monoresistant, polydrug-resistant, isoniazid-resistant, and rifampicin resistant during 2018 to 2022 were decreased compared with those from 2013 to 2017 (P < .05), but the multi-drug resistance rate was not decreased (P = .131, without statistical difference). The results of logistic regression analysis showed that male gender OR = 1.566 (95% CI 1.035-2.369), a history of antituberculosis therapy OR = 4.049 (95% CI 1.442-11.367), and pulmonary and extrapulmonary tuberculosis OR = 7.335 (95% CI 1.401-38.392) were risk factors for the development of drug resistance; but fever OR = 0.581 (95% CI 0.355-0.950) was Protective factor. The total drug resistance rate of children in Sichuan showed a downward trend, but the rate of multi-drug-resistant tuberculosis was still at a high level, and the form of drug resistance was still severe. Absence of fever, male, retreatment, and pulmonary concurrent with extrapulmonary tuberculosis are risk factors for DR-TB in children.

A comprehensive evaluation of risk factors for mortality, infection and colonization associated with CRGNB in adult solid organ transplant recipients: a systematic review and meta-analysis.

BACKGROUND: The burden of carbapenem-resistant gram-negative bacteria (CRGNB) among solid organ transplant (SOT) recipients has not been systematically explored. Here, we discern the risk factors associated with CRGNB infection and colonization in SOT recipients. METHODS: This study included observational studies conducted among CRGNB-infected SOT patients, which reported risk factors associated with mortality, infection or colonization. Relevant records will be searched in PubMed, Embase and Web of Science for the period from the time of database construction to 1 March 2023. RESULTS: A total of 23 studies with 13,511 participants were included, enabling the assessment of 27 potential risk factors. The pooled prevalence of 1-year mortality among SOT recipients with CRGNB was 44.5%. Prolonged mechanical ventilation, combined transplantation, reoperation and pre-transplantation CRGNB colonization are salient contributors to the occurrence of CRGNB infections in SOT recipients. Renal replacement therapy, post-LT CRGNB colonization, pre-LT liver disease and model for end-stage liver disease score increased the risk of infection. Re-transplantation, carbapenem use before transplantation and ureteral stent utilization increaesd risk of CRGNB colonization. CONCLUSION: Our study demonstrated that SOT recipients with CRGNB infections had a higher mortality risk. Invasive procedure may be the main factor contribute to CRGNB infection.

Evaluation of Sulfasalazine as an Adjunctive Therapy in Treating Pulmonary Pre-XDR-TB: Efficacy, Safety, and Treatment Implication.

Background: The rising prevalence and limited efficacy of treatments for pre-extensively drug-resistant tuberculosis (pre-XDR-TB) underscore an immediate need for innovative therapeutic options. A combination of host-directed therapy (HDT) and anti-TB treatment presents a viable alternative for pre-XDR-TB management. Sulfasalazine (SASP), by targeting the amino acid transport system xc (xCT), potentially reduces the intracellular Mycobacterium tuberculosis load and mitigates lung pathology, positioning it as a promising TB HDT agent. This study aims to assess the efficacy of SASP as a supplementary therapy for pre-XDR-TB. Methods: A pilot study examined the safety and effectiveness of two 9-month short-course, all-oral regimens for pre-XDR-TB treatment: Bdq-regimen (consisting of Bdq, linezolid, cycloserine, clofazimine, and pyrazinamide) and SASP-regimen (comprising SASP, linezolid, cycloserine, clofazimine, and pyrazinamide). The primary endpoint was the incidence of unfavorable outcomes 12 months post-treatment. Results: Of the 44 participants enrolled, 43 were assessable 12 months post-treatment. Culture conversion rates stood at 73.2% by Month 2 and escalated to 95.1% by Month 6. Overall, 88.4% (38/43) of the participants exhibited favorable outcomes, 85.2% (19/23) for the Bdq-regimen and 93.8% (14/15) for the SASP-regimen. The SASP-regimen group recorded no deaths or treatment failures. Conclusion: Both 9-month short-course, all-oral regimens manifested commendable primary efficacy in treating pre-XDR-TB patients. The SASP-regimen emerged as effective, safe, well-tolerated, and cost-effective.

Attenuated Cytokine-Induced Memory-Like Natural Killer Cell Responses to Mycobacterium tuberculosis in Tuberculosis Patients.

Purpose: This study aimed to investigate the phenotype, proliferation and functional alterations of cytokine-induced memory-like natural killer (CIML NK) cells from healthy subjects and TB patients, and assessed the efficacy of CIML NK cells in response to H37Rv-infected U937 cells in vitro. Methods: Fresh peripheral blood mononuclear cells (PBMCs) were isolated from healthy people and tuberculosis patients and activated for 16h using low-dose IL-15, or IL-12, IL-15, IL-18 combination or IL-12, IL-15, IL-18 and MTB H37Rv lysates, respectively, followed by low-dose IL-15 maintenance for another 7 days. Then, the PBMCs were co-cultured with K562 and H37Rv-infected U937, and the purified NK cells were co-cultured with H37Rv infected U937. The phenotype, proliferation and response function of CIML NK cells were assessed using flow cytometry. Finally, colony forming units were enumerated to confirm the survival of intracellular MTB. Results: CIML NK phenotypes from TB patients were similar to healthy controls. CIML NK cells undergo higher rates of proliferation after IL-12/15/18 pre-activation. Moreover, the poor expansion potential of CIML NK cells co-stimulated with MTB lysates. CIML NK cells from healthy individuals showed enhanced IFN-γ functional to H37Rv infected U937 cells, along with significantly enhanced killing of H37Rv. However, the CIML NK cells from TB patients show attenuated IFN-γ production and now enhanced the ability of killing intracellular MTB compared to those from healthy donors after co-cultured with H37Rv infected U937. Conclusion: CIML NK cells from healthy individuals exist the increased ability of IFN-γ secretion and boosted anti-MTB activity in vitro, which from TB patients show impaired IFN-γ production and no enhanced anti-MTB activity compared to those from healthy donors. Additionally, we observe the poor expansion potential of CIML NK cells co-stimulated with antigens from MTB. These results open up new possibilities for NK cell-based anti-tuberculosis immunotherapeutic strategies.

The Association of Peripheral T Lymphocyte Subsets Disseminated Infection by Mycobacterium Tuberculosis in HIV-Negative Patients: A Retrospective Observational Study.

Background and Objective: This study was performed to investigate the association of peripheral T lymphocyte subsets with disseminated infection (DI) by Mycobacterium tuberculosis (MTB) in HIV-negative patients. Methods and Materials: The study included 587 HIV-negative tuberculosis (TB) patients. Results: In TB patients with DI, the proportion of CD4+ T cells decreased, the proportion of CD8+ T cells increased, and the ratio of CD4+/CD8+ T cells decreased. According to univariate analysis, smoking, alcohol consumption, rifampicin-resistance, retreatment, and high sputum bacterial load were linked to lower likelihood of developing MTB dissemination. Multivariate analysis indicated that after adjustment for alcohol use, smoking, retreatment, smear, culture, rifampicin-resistance, and CD4+/CD8+, the proportion of CD8+ T cells (but not CD4+ T cells) was independently and positively associated with the prevalence of DI in HIV-negative pulmonary TB (PTB) patients. Conclusions: Examining T lymphocyte subsets is of great value for evaluating the immune function of HIV-negative TB patients, and an increase in the CD8+ T cell proportion may be a critical clue regarding the cause of DI in such patients.

Amplitude of low-frequency fluctuations in multiple-frequency bands in patients with intracranial tuberculosis: a prospective cross-sectional study.

Background: Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study brain functional alteration, but there have been no reports of research regarding the application of rs-fMRI in intracranial tuberculosis. The purpose of this prospective, cross-sectional study was to investigate spontaneous neural activity at different frequency bands in patients with intracranial tuberculosis using rs-fMRI with amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) methods. Methods: The rs-fMRI data of 31 patients with intracranial tuberculosis and 30 gender-, age-, and education-matched healthy controls (HCs) were included. The ALFF and fALFF values in the conventional frequency band (0.01-0.08 Hz) and 2 sub-frequency bands (slow-4: 0.027-0.073 Hz; slow-5: 0.01-0.027 Hz) were calculated and compared between the groups. The resultant T-maps were corrected using the Gaussian random field (GRF) theory (voxel P<0.01, cluster P<0.05). Correlations between the ALFF and fALFF values and neurocognitive scores were assessed. Results: Compared with the HCs, patients with intracranial tuberculosis showed decreased ALFF in the right paracentral lobule (T=-4.69) in the conventional frequency band, in the right supplementary motor area (T=-4.85) in the slow-4 band, and in the left supplementary motor area (T=-3.76) in the slow-5 band. Compared to the slow-5 band, the voxels with decreased ALFF were spatially more extensive in the slow-4 band. Compared with HCs, patients with intracranial tuberculosis showed decreased fALFF in the opercular parts of the right inferior frontal gyrus (T=-4.50) and the left inferior parietal lobe (T=-4.86) and increased fALFF in the left inferior cerebellum (T=5.84) in the conventional frequency band. In the slow-4 band, fALFF decreased in the opercular parts of the right inferior frontal gyrus (T=-5.29) and right precuneus (T=-4.34). In the slow-5 band, fALFF decreased in the left middle occipital gyrus (T=-4.65) and right middle frontal gyrus (T=-5.05). Conclusions: Patients with intracranial tuberculosis showed abnormal intrinsic brain activity at different frequency bands, and ALFF abnormalities in different brain regions could be better detected in the slow-4 band. This preliminary study might provide new insights into understanding the pathophysiological mechanism in intracranial tuberculosis.

[Association between isoniazid induced hepatotoxicity and host N-acetyltransferase 2 polymorphisms].

Isoniazid(INH, H) has been a key drug for treating drug-susceptible tuberculosis (TB) for nearly seventy years. The differences in the pharmacokinetic(PK) might affect INH absorption. Low plasma concentration is related to less treatment outcomes and vice versa, but higher plasma concentrations can induce hepatotoxicity or death. Factors that can cause fluctuations in blood concentration include INH absorption (i.e. drug-drug or drug-food interactions and other diseases such as gastrointestinal problems, diabetes or TB) and abnormal metabolization by the liver. N-acetyltransferase 2 (NAT2) genetic polymorphism significantly affects the plasma concentrations of INH. However, there is a lack of guidelines for the management of adverse drug reactions caused by isoniazid therapy, and the only measures taken to address adverse reactions to isoniazid are abrupt discontinuation of the drug or reduction in the dose of isoniazid based on clinical experience, but such measures could lead to the development of drug resistance in Mycobacterium tuberculosis. Therefore, further clarification of the correlation between the host NAT2 genotype and its phenotypic polymorphisms, plasma isoniazid concentration and adverse effects can help to improve the efficacy and minimize the adverse effects.

Clinical isolates of Mycobacterium tuberculosis with different genotypes exhibit distinct host macrophage responses in vitro.

Introduction. Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, can survive as an intracellular parasite after entering macrophages via phagocytosis. M.tb strains are genotypically distinct and engage in diverse pathogen-host interactions, with different host immune responses triggered by different M.tb strains. Importantly, differences in intracellular accumulation and triggering of host macrophage responses during early infection stages are key determinants that shape the final outcomes of host innate immune responses to different M.tb strains.Hypothesis/Gap Statement. Clinical M.tb strains with different genotypes elicit different host innate immune responses in vitro.Aim. This work aimed to compare host innate immune responses elicited by genotypically diverse, clinically derived M.tb strains in vitro.Methodology. RAW264.7 cells were infected with three lineage 2 and lineage 4 clinically derived M.tb strains and strain H37Rv. Strains were evaluated for differences in intracellular growth, induction of macrophage apoptosis, and induction of expression of proinflammatory cytokines and associated pattern recognition receptors.Results. Highly variable cytokine profiles were observed subsequent to RAW264.7 cell infection with the different strains. The Beijing genotype strain, a modern Beijing strain belonging to lineage 2, induced milder host proinflammatory responses and less apoptosis and exhibited greater intracellular growth as compared to the other strains. Moreover, mRNA expression levels of iNOS in Beijing and MANU2 genotype strains exceeded corresponding levels obtained for the T1 genotype strain. Meanwhile, mRNA expression levels of toll-like receptor (TLR)-encoding genes TLR2 and TLR7 in macrophages infected with the Beijing genotype strain were higher than corresponding levels observed in MANU2 genotype strain-infected macrophages.Conclusion. The higher intracellular survival rate and lower level of host cell apoptosis associated with macrophage infection with the Beijing genotype strain indicated greater virulence of this strain relative to that of the other strains. Furthermore, in vitro immune responses induced by the Beijing genotype strain were unique in that this strain induced a weaker inflammatory response than was induced by T1 or MANU2 genotype strains. Nevertheless, additional evidence is needed to confirm that Beijing genotype strains possess greater virulence than strains with other genotypes.

Identification of Hub Genes Associated with Diabetes Mellitus and Tuberculosis Using Bioinformatic Analysis.

PURPOSE: To investigate the potential pathophysiological association between tuberculosis (TB) and diabetes mellitus (DM) using bioinformatic analyses. PATIENTS AND METHODS: Gene expression datasets for healthy controls (HCs), TB patients, DM patients, TB+DM patients (GSE114192), and metformin-treated cells (GSE102677) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified from pairwise dataset comparisons TB vs HCs and DM vs HCs. DEGs were verified by comparing them to DEGs for TB+DM vs HCs. Enrichment analysis of DEGs common to all three dataset comparisons was conducted using DAVID. The protein-protein interaction (PPI) network was established via STRING and visualised in Cytoscape. Hub genes were identified using the Cytoscape plug-in cytoHubba and then were verified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Targeted miRNA prediction analysis identified metformin treatment-induced gene expression changes in peripheral blood mononuclear cells. RESULTS: A total of 422 DEGs were common to all three dataset comparisons. Functional enrichment analysis revealed these DEGs were enriched for functional terms of type I interferon signaling pathway, innate immune response, inflammatory response, and infectious diseases. Ten hub genes identified using PPI network analysis were screened for interactions with metformin target gene INS using cytoHubba based on maximal clique centrality (MCC) score. Subsequently, five hub genes were predicted to functionally interact with INS, including STAT1, IFIT3, RSAD2, IFI44L, and XAF1, as verified by RT-qPCR. Meanwhile, seven miRNAs (miR-3680-3p, miR-3059-5p, miR-629-3p, miR-29b-2-5p, miR-514b-5p, miR-4755-5p, miR-4691-3p) were associated with regulation of hub genes. Notably, six hub genes (STAT1, IFIT3, RSAD2, ISG15, IFI44, IFI6) were down-regulated in cells exposed to both metformin and Mycobacterium tuberculosis antigens. CONCLUSION: Network hub genes hold promise as disease status biomarkers and as metformin treatment targets for alleviating TB and DM. This study describes a strategy for exploring pathogenic mechanisms of diseases such as TB and DM.

Expression profiling of TRIM gene family reveals potential diagnostic biomarkers for rifampicin-resistant tuberculosis.

The epidemic of pulmonary tuberculosis (TB), especially rifampin-resistant tuberculosis (RR-TB) presents a major challenge for TB control today. However, there is a lack of reliable and specific biomarkers for the early diagnosis of RR-TB. We utilized reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to profile the transcript levels of 72 tripartite motif (TRIM) genes from a discovery cohort of 10 drug-sensitive tuberculosis (DS-TB) patients, 10 RR-TB patients, and 10 healthy controls (HCs). A total of 35 differentially expressed genes (DEGs) were screened out, all of which were down-regulated. The bio functions and pathways of these DEGs were enriched in protein ubiquitination, regulation of the viral process, Interferon signaling, and innate immune response, etc. A protein-protein interaction network (PPI) was constructed and analyzed using STRING and Cytoscape. Twelve TRIM genes were identified as hub genes, and seven (TRIM1, 9, 21, 32, 33, 56, 66) of them were verified by RT-qPCR in a validation cohort of 95 subjects. Moreover, we established the RR-TB decision tree models based on the 7 biomarkers. The receiver operating characteristic (ROC) analyses showed that the models exhibited the areas under the curve (AUC) values of 0.878 and 0.868 in discriminating RR-TB from HCs and DS-TB, respectively. Our study proposes potential biomarkers for RR-TB diagnosis, and also provides a new experimental basis to understand the pathogenesis of RR-TB.

Factors associated with differential T cell responses to antigens ESAT-6 and CFP-10 in pulmonary tuberculosis patients.

ABSTRACT: The T-SPOT.TB assay detects cellular immune responses to 2 core Mycobacterium tuberculosis antigens, early secreted antigenic target of 6-kDa protein (ESAT-6) and culture filtrate protein-10 (CFP-10). T-SPOT.TB has been recently used for auxiliary diagnosis of active pulmonary tuberculosis (PTB). However, testing can produce inconsistent results due to differential PTB patient immune responses to these antigens, prompting us to identify factors underlying inconsistent results.Data were retrospectively analyzed from 1225 confirmed PTB patients who underwent T-SPOT.TB testing at 5 specialized tuberculosis hospitals in China between December 2012 and November 2015. Numbers of spot-forming cells (SFCs) reflecting T cell responses to ESAT-6 and CFP-10 antigens were recorded then analyzed via multivariable logistic regression to reveal factors underlying discordant T cell responses to these antigens.The agreement rate of 84.98% (82.85%-86.94%) between PTB patient ESAT-6 and CFP-10 responses demonstrated high concordance. Additionally, positivity rates were higher for ESAT-6 than for CFP-10 (84.8% vs 80.7%, P < .001), with ESAT-6 and CFP-10 microwell SFC numbers for each single positive group not differing significantly (P > .99), while spot numbers of the single positive group were lower than numbers for the double positive group (P < .001). Elderly patients (aged ≥66 years) and patients receiving retreatment were most likely to have discordance results.ESAT-6 promoted significantly more positive T-SPOT.TB results than did CFP-10 in PTB patients. Advanced age and retreatment status were correlated with discordant ESAT-6 and CFP-10 results. Assessment of factors underlying discordance may lead to improved PTB diagnosis using T-SPOT.TB.

Biochemical characterization of mt-PemIK, a novel toxin-antitoxin system in Mycobacterium tuberculosis.

Toxin-antitoxin (TA) systems are regarded as genetic modules that facilitate bacterial survival under stress conditions. In this study, a novel TA system in Mycobacterium tuberculosis H37Rv chromosome was identified, termed as mt-PemIK, which consists of antitoxin mt-PemI and toxin mt-PemK (Rv3098A). Induction of mt-PemK leads to growth arrest in Mycobacterium smegmatis, while the toxic effect of mt-PemK is eliminated by co-expression of mt-PemI. mt-PemK is characterized as an endoribonuclease whose activity is pH-dependent. mt-PemK, as well as some other M. tuberculosis toxin/antitoxin proteins, can be modified by pupylation, suggesting that the Pup-proteasome system is involved in the regulation of TA systems. These results are helpful to understand the mechanisms of M. tuberculosis growth regulation under stress conditions.

Factors associated with negative T-SPOT.TB results among smear-negative tuberculosis patients in China.

We compared the positive rates of T-SPOT.TB and bacterial culture in the smear-negative PTB, and analyzed the factors affecting the results of negative T-SPOT.TB and bacterial culture. Retrospective evaluation of data from smear-negative PTB patients who underwent T-SPOT.TB and bacterial culture were done. The agreement and concordance were analyzed between T-SPOT.TB and bacterial culture. Multivariable logistic regression analysis was used to explore the factors associated with positive results of T-SPOT.TB and bacterial culture in smear-negative PTB. 858 eligible smear-negative PTB patients were included in the study. The agreement rate was 25.6% (22.7~28.5%) between T-SPOT.TB and bacterial culture in smear- negative PTB patients. The positive rate of T-SPOT.TB was higher than that of bacterial culture in smear-negative PTB patients (p < 0.001). There were nearly no concordance between T-SPOT.TB and bacterial culture (p > 0.05). Using multivariable logistic regression analysis we found that older age ≥ 60 years (OR = 0.469, 95% CI: 0.287-0.768) and decreased albumin (OR = 0.614, 95% CI: 0.380-0.992) were associated with negative diagnostic results of T-SPOT.TB in smear-negative PTB patients. Female (OR = 0.654, 95% CI: 0.431-0.992) were associated with negative diagnostic results of bacteria culture in smear-negative PTB patients. Our results indicated that the older age and decreased albumin were independently associated with negative T-SPOT.TB responses.

Interferon-Gamma Release Assay is Not Appropriate for the Diagnosis of Active Tuberculosis in High-Burden Tuberculosis Settings: A Retrospective Multicenter Investigation.

BACKGROUND: Interferon-gamma release assay (IGRA) has been used in latent tuberculosis (TB) infection and TB diagnosis, but the results from different high TB-endemic countries are different. The aim of this study was to investigate the value of IGRA in the diagnosis of active pulmonary TB (PTB) in China. METHODS: We conducted a large-scale retrospective multicenter investigation to further evaluate the role of IGRA in the diagnosis of active PTB in high TB-epidemic populations and the factors affecting the performance of the assay. All patients who underwent valid T-SPOT.TB assays from December 2012 to November 2015 in six large-scale specialized TB hospitals in China and met the study criteria were retrospectively evaluated. Patients were divided into three groups: Group 1, sputum culture-positive PTB patients, confirmed by positive Mycobacterium tuberculosis sputum culture; Group 2, sputum culture-negative PTB patients; and Group 3, non-TB respiratory diseases. The medical records of all patients were collected. Chi-square tests and Fisher's exact test were used to compare categorical data. Multivariable logistic analyses were performed to evaluate the relationship between the results of T-SPOT in TB patients and other factors. RESULTS: A total of 3082 patients for whom complete information was available were included in the investigation, including 905 sputum culture-positive PTB cases, 914 sputum culture-negative PTB cases, and 1263 non-TB respiratory disease cases. The positive rate of T-SPOT.TB was 93.3% in the culture-positive PTB group and 86.1% in the culture-negative PTB group. In the non-PTB group, the positive rate of T-SPOT.TB was 43.6%. The positive rate of T-SPOT.TB in the culture-positive PTB group was significantly higher than that in the culture-negative PTB group (χ2 = 25.118, P < 0.01), which in turn was significantly higher than that in the non-TB group (χ2 = 566.116, P < 0.01). The overall results were as follows: sensitivity, 89.7%; specificity, 56.37%; positive predictive value, 74.75%; negative predictive value, 79.11%; and accuracy, 76.02%. CONCLUSIONS: High false-positive rates of T-SPOT.TB assays in the non-TB group limit the usefulness as a single test to diagnose active TB in China. We highly recommend that IGRAs not be used for the diagnosis of active TB in high-burden TB settings.

Efficacy of ultra-short course chemotherapy for new smear positive drug susceptible pulmonary tuberculosis: study protocol of a multicenter randomized controlled clinical trial.

BACKGROUND: Shortening the standard 6-month treatment for drug-susceptible pulmonary tuberculosis (DS-PTB) would be a major improvement for TB case management and disease control. METHODS: We are conducting a randomized, open-label, controlled, non-inferiority trial involving patients with smear-positive, newly diagnosed DS-PTB cases nationwide to assess the efficacy and safety of two 4.5- month regimens in comparison to the standard 6-month WHO recommended regimen. The regimen used in one experiment group is a 4.5-month fluoroquinolone-containing regimen, which consists of full course of levofloxacin, isoniazid (H), rifampin (R), parazinamid (Z) and ethambutol (E). Regimen used in the second experiment group includes 4.5-month full course of H, R, Z, E with levofloxacin removed. Patients in the control group, receive H, R, Z and E for 2 months, followed by 4 months of H and R. The primary endpoint is treatment failure or relapse within 24 month after treatment completion. DISCUSSION: Results from this trial along with other studies will contribute to the science of constructing a shorter, effective and safe regiment for TB patients. TRIAL REGISTRATION: The protocol has been registered on ClinicalTrials.gov on 2 September,2016 with identifier NCT02901288 .

A Large Cohort Study on the Clinical Value of Simultaneous Amplification and Testing for the Diagnosis of Pulmonary Tuberculosis.

The AmpSure simultaneous amplification and testing method for the detection of Mycobacterium tuberculosis (SAT-TB assay) was designed to diagnose rapidly pulmonary tuberculosis (PTB). Unfortunately, the diagnostic advantage is unclear from previous small sample studies. In the current inquiry, a large sample size was used to reevaluate the clinical accuracy of the SAT-TB assay using sputum specimens. A total of 3608 patients with suspected PTB were enrolled prospectively for diagnosis from sputum specimens using the SAT-TB assay. Of these, 2457 had a definite diagnosis of PTB confirmed by positive microbiology, or pathologic findings of TB in the lung, or clinical diagnosis of active PTB following anti-TB treatment with a favorable response. The sensitivity, specificity and accuracy of the SAT-TB assay were 75.8%, 100%, and 80.2%, respectively. The sensitivity of SAT-TB was significantly higher than that of the sputum smear (23.8%) (X(2) = 1327.437; P = 0.000), wheresa significantly lower than that of sputum culture (89.0%) (X(2) = 148.197; P = 0.000). The specificity of SAT-TB was significantly higher than that of sputum smears (96.3%) (X(2) = 20.375, P = 0.000), whereas no significant difference was found compared with sputum cultures (99.6%) (X(2) = 2.004, P = 0.500). Positive results in the SAT-TB assay using sputum specimens indicates that active PTB is present and anti-TB treatment is strongly recommended regardless of smear and culture test results. Simultaneous amplification and testing method for detection of Mycobacterium tuberculosis is an accurate, cheap, and rapid method for PTB diagnosis.

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis.

Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline.Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24 weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120 weeks after starting bedaquiline.Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120 weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively.Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.

Clinical features and treatment of drug fever caused by anti-tuberculosis drugs.

BACKGROUND AND AIMS: Tuberculosis is a major global health problem. However, anti-tuberculosis drug treatment has many adverse effects, such as drug-caused fever. The aim of this study was to investigate the clinical features and treatments of anti-tuberculosis drugs-induced fever. METHODS: A total of 78 inpatients and outpatients with pulmonary tuberculosis accompanied by drug fever during the anti-tuberculosis treatment were analysed retrospectively from April 2006 to March 2013. RESULTS: Among the anti-tuberculosis drugs that caused the drug fever, rifampicin was the most common one, followed by para-aminosalicylic and pyrazinamide. The symptoms occurred within 2 months after treatment, mainly in the 1-3 weeks, and the main symptom was high fever with body temperature above 39°C. The accompanying symptoms include rash, chills, headache, stuffy nose, runny nose, nausea, vomiting and joint pain. Routine blood examination found that eosinophilia increased in 15 cases and decreased in another 15. Among 63 patients who underwent liver function tests, there were 10 cases of abnormal function and 4 cases of liver damage. When the drug fever was suspected, the measure of withdrawal was taken first. All the suspected drugs were withdrawn in 59 cases, while gradual withdrawal was conducted in 19 cases. Patients with complications were first treated in accordance with the principles of complications treatment and then were gradually given some drugs after recovery. The patients without complications were gradually given some drugs after the body temperature was back to normal. CONCLUSION: Drug fever is an allergic reaction, the resolution of which depends on whether it was accompanied by liver damage and/or rash or not.

An open-label, randomized and multi-center clinical trial to evaluate the efficacy of Silibinin in preventing drug-induced liver injury.

UNLABELLED: To assess the clinical efficacy and safety of Silibinin in preventing drug-induced liver injury (DILI) in the general population (high-risk patients with non-drug induced liver injury). METHOD: A prospective, multi-center, randomized, open-label and controlled trial was conducted with 568 patients undergoing primary treatment of pulmonary tuberculosis. The study included 277 patients in experimental group and 291 patients in control group. The patients in the two group were treated with conventional 2HREZ (S)/4HR for tuberculosis (TB), and additional Silibinin capsules (oral administration of 70 mg/time, 3 times/day for 8 weeks in experimental group. Outcomes of liver function, interruption of anti-TB treatment and therapeutic results, as well as adverse reactions were observed and analyzed. RESULTS: At 2, 4 and 8 weeks of treatment, the incidences of liver injury in experimental group were 3.97%, 1.44% and 2.17%, respectively; the incidences in control group were 4.12%, 4.12% and 2.41%, respectively. Statistical analysis showed that there was no difference in the incidence between the two groups at each treatment period (P>0.05). At 8 weeks, the numbers of patients diagnosed of DILI were 18 (7.22%) and 27 (9.28%) in experimental and control groups, respectively (P>0.05). 34.30% and 27.49% of the patients in experimental and control groups had transient abnormal liver function or symptoms, respectively; similar percentages (3.25% and 6.19%) of the patients in two groups have liver function injury and symptoms, and were suspended for anti-TB treatment (P>0.05). The incidence of anorexia and nausea symptoms was lower in experimental group than in control group, and the differences were significant at 4 and 8 weeks (P<0.05). 8 weeks after the treatment, 98.30% of the sputum smear culture were negative in experimental group, which was significantly higher (P<0.01) than that in control group (92.98%). CONCLUSION: Preventive hepatoprotective therapy in the general population may reduce drug discontinuation rate, improve patient's compliance and outcomes of anti-TB treatment.

Clofazimine for the treatment of multidrug-resistant tuberculosis: prospective, multicenter, randomized controlled study in China.

BACKGROUND: Clofazimine (Cfz) has shown activity against Mycobacterium tuberculosis, including multidrug-resistant (MDR) strains in vitro and in animal studies. Here we evaluate the clinical efficacy and tolerability of using Cfz to treat MDR tuberculosis in China. METHODS: We enrolled 105 patients who had sputum culture-positive MDR tuberculosis in 6 major tuberculosis specialty hospitals in China. Patients were randomly assigned to either the Cfz therapy group (n = 53) or control group (n = 52). Patients in the 2 groups were given 21 months of individual-based chemotherapy regimens based on medication history and drug susceptibility test results. The Cfz therapy group regimens incorporated 100 mg of Cfz once daily for 21 months. RESULTS: Three patients in each group discontinued therapy because of side effects or other reasons. Sputum culture conversion to negative was earlier in patients who received Cfz compared with controls (P = .042 by log-rank test). Chest computed tomography showed cavitary changes in 46 patients in the Cfz therapy group and 45 in the control group. Cavity closure was earlier in patient who received Cfz compared with controls (P = .047 by log-rank test). The treatment success rate in the Cfz group was 73.6%, higher than that in control group (53.8%; P = .035). Side effects in skin only occurred in the Cfz group. The rates of skin discoloration and ichthyosis were 94.3% and 47.2%, respectively. CONCLUSIONS: Using Cfz to treat MDR tuberculosis promotes cavity closure, accelerates sputum culture conversion, and improves treatment success rates.