Serial electrocardiogram recordings revealed a high prevalence of QT interval prolongation in patients with tuberculosis receiving fluoroquinolones.

BACKGROUND: Fluoroquinolones, crucial components of treatment regimens for drug-resistant tuberculosis (TB), are associated with QT interval prolongation and risks of fatal cardiac arrhythmias. However, few studies have explored dynamic changes in the QT interval in patients receiving QT-prolonging agents. METHODS: This prospective cohort study recruited hospitalized patients with TB who received fluoroquinolones. The study investigated the variability of the QT interval by using serial electrocardiograms (ECGs) recorded four times daily. This study analyzed the accuracy of intermittent and single-lead ECG monitoring in detecting QT interval prolongation. RESULTS: This study included 32 patients. The mean age was 68.6 ± 13.2 years. The results revealed mild-to-moderate and severe QT interval prolongation in 13 (41%) and 5 (16%) patients, respectively. The incremental yields in sensitivity of one to four daily ECG recordings were 61.0%, 26.1%, 5.6%, and 7.3% in detecting mild-to-moderate QT interval prolongation, and 66.7%, 20.0%, 6.7%, and 6.7% in detecting severe QT interval prolongation. The sensitivity levels of lead II and V5 ECGs in detecting mild-to-moderate and severe QT interval prolongation exceeded 80%, and their specificity levels exceeded 95%. CONCLUSION: This study revealed a high prevalence of QT interval prolongation in older patients with TB who receive fluoroquinolones, particularly those with multiple cardiovascular risk factors. Sparsely intermittent ECG monitoring, the prevailing strategy in active drug safety monitoring programs, is inadequate owing to multifactorial and circadian QT interval variability. Additional studies performing serial ECG monitoring are warranted to enhance the understanding of dynamic QT interval changes in patients receiving QT-prolonging anti-TB agents.

Integrative utility of long read sequencing-based whole genome analysis and phenotypic assay on differentiating isoniazid-resistant signature of Mycobacterium tuberculosis.

BACKGROUND: With the advancement of next generation sequencing technologies (NGS), whole-genome sequencing (WGS) has been deployed to a wide range of clinical scenarios. Rapid and accurate classification of drug-resistant Mycobacterium tuberculosis (MTB) would be advantageous in reducing the amplification of additional drug resistance and disease transmission. METHODS: In this study, a long-read sequencing approach was subjected to the whole-genome sequencing of clinical MTB clones with susceptibility test profiles, including isoniazid (INH) susceptible clones (n = 10) and INH resistant clones (n = 42) isolated from clinical specimens. Non-synonymous variants within the katG or inhA gene associated with INH resistance was identified using Nanopore sequencing coupled with a corresponding analytical workflow. RESULTS: In total, 54 nucleotide variants within the katG gene and 39 variants within the inhA gene associated with INH resistance were identified. Consistency among the results of genotypic profiles, susceptibility test, and minimal inhibitory concentration, the high-INH resistance signature was estimated using the area under the receiver operating characteristic curve with the existence of Ser315Thr (AUC = 0.822) or Thr579Asn (AUC = 0.875). CONCLUSIONS: Taken together, we curated lists of coding variants associated with differential INH resistance using Nanopore sequencing, which may constitute an emerging platform for rapid and accurate identification of drug-resistant MTB clones.

Psychological distress assessment among patients with suspected and confirmed COVID-19: A cohort study.

BACKGROUND: Global pandemic resulted from the coronavirus disease-19 (COVID-19) demands mental health concerns on the affected population. We examine the time-course shift of psychological burden among suspected and confirmed COVID-19 patients. METHODS: Participants with suspected or confirmed COVID-19 were included in the cohort. Consecutive surveys were conducted upon hospital admission, discharge, and during outpatient follow-up by adapting the 5-item brief symptom rating scale (BSRS-5) assessing psychological symptoms including anxiety, depression, hostility, interpersonal sensitivity, and insomnia. The sixth measure to observe suicidal ideation was also included. RESULTS: A total of 109 eligible patients participated in the study, in which 83.49% reported no distress upon hospital admission, while 2.75%, 3.66%, and 10.1% patients were assessed as being with severe, moderate and mild psychological distress, respectively. Overall, age, sex, and history of contact did not significantly differ between patients with and without psychological distress. Multivariate logistic regression revealed that patients admitted during April-May (OR: 7.66, 95% CI: 1.46-40.28) and presented with symptoms including sore throat (OR: 4.24, 95% CI: 1.17-15.29) and malaise (OR: 5.24, 95% CI: 1.21-22.77) showed significantly higher risk of psychological distress. Cough symptom interestingly showed lower risk of emotional distress (OR: 0.25, 95% CI: 0.08-0.81). Subsequent surveys upon hospital discharge and during outpatient follow-up revealed steadily declining distress among all cohort. CONCLUSION: At least 16.5% of our cohort reported psychological distress upon hospital admission, with distinct time-dependent decline. Access to mental health support, alongside with promoting positive activities for good mental health are pivotal for those directly affected.

Mycobacterium tuberculosis induces connective tissue growth factor expression through the TLR2-JNK-AP-1 pathway in human lung fibroblasts.

Mycobacterium tuberculosis (M.tb) infection in lung causes pulmonary fibrosis, which leads to the irreversible reduction of pulmonary function. Fibrotic protein connective tissue growth factor (CTGF) expression has been confirmed to play a crucial role in lung fibrosis. However, the underlying signal pathway and effect of M.tb on CTGF expression in human lung fibroblasts are unclear. Our results revaled that M.tb caused time- and concentration-dependent increases in CTGF expression in human lung fibroblasts. A mechanistic investigation revealed that M.tb induced CTGF expression through TLR2 but not TLR4. The promoter activity assay indicated that M.tb-induced CTGF activity was mainly controlled by the promoter region at -747 to -184 bp, which contained signal transducer and activator of transcription 3 and activator protein 1 (AP-1) binding sites. Moreover, curcumin (AP-1 inhibitor) restrained M.tb-induced CTGF expression. M.tb also induced increases in AP-1 luciferase activity and DNA binding activity of c-Jun and c-Fos on the CTGF promoter. Furthermore, the knockdown of c-Jun by small interfering RNA attenuated M.tb-induced CTGF expression and AP-1 luciferase activity. A JNK inhibitor (SP600125) and a JNK dominant-negative mutant suppressed M.tb-induced CTGF expression. We also discovered that M.tb could induce the phosphorylation of JNK and c-Jun. Furthermore, SP600125 inhibited M.tb-induced c-Jun phosphorylation and AP-1- luciferase activity. M.tb-induced fibronectin expression was inhibited by anti-CTGF antibody. These results demonstrate that M.tb is activated through TLR2 to induce JNK activation, further increasing the DNA binding activity of c-Jun and c-Fos and finally inducing CTGF expression and extracellular matrix production.-Lee, H.-S., Hua, H.-S., Wang, C.-H., Yu, M.-C., Chen, B.-C., Lin, C.-H. Mycobacterium tuberculosis induces connective tissue growth factor expression through the TLR2-JNK-AP-1 pathway in human lung fibroblasts.

Effect of ventilation improvement during a tuberculosis outbreak in underventilated university buildings.

The role of ventilation in preventing tuberculosis (TB) transmission has been widely proposed in infection control guidance. However, conclusive evidence is lacking. Modeling suggested the threshold of ventilation rate to reduce effective reproductive ratio (ratio between new secondary infectious cases and source cases) of TB to below 1 is corresponding to a carbon dioxide (CO2 ) level of 1000 parts per million (ppm). Here, we measured the effect of improving ventilation rate on a TB outbreak involving 27 TB cases and 1665 contacts in underventilated university buildings. Ventilation engineering decreased the maximum CO2 levels from 3204 ± 50 ppm to 591-603 ppm. Thereafter, the secondary attack rate of new contacts in university dropped to zero (mean follow-up duration: 5.9 years). Exposure to source TB cases under CO2 >1000 ppm indoor environment was a significant risk factor for contacts to become new infectious TB cases (P < .001). After adjusting for effects of contact investigation and latent TB infection treatment, improving ventilation rate to levels with CO2 <1000 ppm was independently associated with a 97% decrease (95% CI: 50%-99.9%) in the incidence of TB among contacts. These results show that maintaining adequate indoor ventilation could be a highly effective strategy for controlling TB outbreaks.

Identification and drug susceptibility testing for nontuberculous mycobacteria.

Great progress has recently been made in methodologies for identifying nontuberculous mycobacteria (NTM). Recommendations for drug susceptibility testing (DST) of NTM have been expanded and updated by the Clinical and Laboratory Standards Institute and are crucial in the management of NTM infections. This article summarizes the clinically relevant molecular methods used to discriminate NTM species and updates the information on DST. Furthermore, recent progress on new antimicrobials against NTM infections is reviewed.

Treatment Outcomes of Multidrug-Resistant Tuberculosis in Taiwan: Tackling Loss to Follow-up.

Background: The proportion of treatment success among patients with multidrug-resistant tuberculosis (MDR-TB) enrolled between 1992 and 1996 was 51.2%, and that among patients enrolled between 2000 and April 2007 was 61%. To address the challenge of MDR-TB, the Taiwan MDR-TB Consortium (TMTC) was established in May 2007. To assess the performance of the TMTC, we analyzed the data of patients enrolled in its first 5 years. Methods: Comprehensive care was provided at no cost to patients, who were usually hospitalized for 1 month initially. Treatment regimens consisted of 4-5 drugs and the duration of treatment was 18-24 months. A case manager and a directly observed therapy provider were assigned to each patient. Psychosocial support was provided to address emotional stress and stigma. Financial support was offered to avoid the financial hardship faced by patients and their families. We assessed treatment outcomes at 30 months using internationally recommended outcome definitions. Results: Of the 692 MDR-TB patients, 570 (82.4%) were successfully treated, 84 (12.1%) died, 18 (2.6%) had treatment failure, and 20 (2.9%) were lost to follow-up. Age ≥65 years (adjusted odds ratio [aOR], 6.78 [95% confidence interval {CI}, 3.14-14.63]), cancer (aOR, 11.82 [95% CI, 5.55-25.18]), and chronic kidney disease (aOR, 3.62 [95% CI, 1.70-7.71]) were significantly associated with death. Resistance to fluoroquinolone (aOR, 10.89 [95% CI, 3.97-29.88]) was significantly associated with treatment failure. Conclusions: The TMTC, which operates under a strong collaboration between the public health authority and clinical teams, has been a highly effective model of care in the management of MDR-TB.

Prognostic value of localization of epidermal growth factor receptor in lung adenocarcinoma.

BACKGROUND: The nuclear translocation of epidermal growth factor receptor (EGFR) has been considered to play a role in carcinogenesis. However, the relevance of differentially located EGFR proteins in lung cancer remains unclear. METHODS: We examined 161 patients with primary lung adenocarcinoma to detect EGFR expression in lung cancer cells using immunohistochemistry and determined the correlations of EGFR expression with clinical characteristics, EGFR mutations, and survival time. Moreover, we graded complete membranous staining with strong intensity as high membranous EGFR (mEGFR) expression, and nuclear EGFR staining with strong intensity as high nuclear (nEGFR) expression. RESULTS: The prevalence of high mEGFR and nEGFR expression in lung adenocarcinoma was 42.86 and 39.13%, respectively. After multivariate analyses, high mEGFR expression was associated with a significantly reduced mortality risk in older patients, those with a history of smoking, and those without brain metastasis (hazard ratio[95% confidential interval], HR[95% CI] = 0.55[0.32~ 0.92]; 0.51[0.26~ 0.98] and 0.56[0.33~ 0.94], in overall survival, respectively). An association between high nEGFR expression and early recurrence was observed in patients with metastasis (HR[95% CI] =1.68[1.05~ 2.68], in progression-free survival). Notably, patients with low mEGFR and low nEGFR expression had the lowest survival rate in cases without brain metastasis (p = 0.018) and with a history of smoking (p = 0.062) and total EGFR (any high mEGFR or nEGFR) expression indicated a more favorable response to platinum-based chemotherapy regardless of EGFR mutations (HR[95% CI] =0.33[0.12-0.92]; adjusted HR[95% CI] = 0.36[0.13~ 1.02] with the use of tyrosine kinase inhibitor). CONCLUSIONS: EGFR proteins at different cellular locations in lung adenocarcinoma might influence the biology of cancer cells and are an independent indicator of more favorable prognosis and treatment response.

Effect of pulmonary tuberculosis on clinical outcomes of long-term dialysis patients: Pre- and post-DOTS implementation in Taiwan.

BACKGROUND AND OBJECTIVE: The link between tuberculosis (TB) and dialysis is known; however, the impact of TB on the clinical outcomes remains to be elucidated. This study aims to determine the clinical consequences of pulmonary TB among patients under long-term dialysis. METHODS: A retrospective propensity-scores matched (1:4) cohort study was conducted by retrieving patient data for pulmonary TB after long-term dialysis commencement from the Taiwan National Health Insurance Research Database between 1999 and 2013. Patients with TB (n = 1993) or without TB (n = 7972) were compared for 3-year morbidity and mortality. The effect of Directly Observed Treatment, Short-Course (DOTS) implementation was also evaluated. Cox proportional hazards models were used to determine adjusted hazard ratios (HRs). RESULTS: TB patients had a significantly higher risk of mortality than non-TB patients even after multivariate adjustment (HR: 1.48; 95% CI: 1.36-1.60; P < 0.001). DOTS implementation reduced the risk of some morbidities such as pneumonia, hospitalization and intensive care unit stay >7 days, but not inotropic agent usage, ventilator therapy >21 days and mortality in TB patients. In pulmonary TB patients with treatment duration ≥180 days, DOTS implementation also lowered the risk of TB relapse (HR: 0.33; 95% CI: 0.19-0.55; P < 0.001), irrespective of treatment duration (180-224 or ≥225 days). CONCLUSION: Pulmonary TB increases the risk of morbidity and mortality in dialysis patients; DOTS implementation reduces some morbidities and TB relapse. Continuing DOTS implementation should be encouraged to improve clinical outcomes in dialysis patients.

Plasma Monocyte Chemoattractant Protein-1 Level as a Predictor of the Severity of Community-Acquired Pneumonia.

Monocyte chemoattractant protein (MCP)-1 increases in the serum of immunocompetent patients with community-acquired pneumonia (CAP). However, the correlation between the circulating level of MCP-1 and severity of CAP remains unclear. This study investigated differential changes in the plasma MCP-1 levels of patients with CAP before and after an antibiotic treatment and further analyzes the association between the CAP severity and MCP-1 levels. We measured the plasma MCP-1 levels of 137 patients with CAP and 74 healthy controls by using a commercial enzyme-linked immunosorbent assay. Upon initial hospitalization, Acute Physiology and Chronic Health Evaluation II (APACHE II); confusion, urea level, respiratory rate, blood pressure, and age of >64 years (CURB-65); and pneumonia severity index (PSI) scores were determined for assessing the CAP severity in these patients. The antibiotic treatment reduced the number of white blood cells (WBCs) and neutrophils as well as the level of C-reactive protein (CRP) and MCP-1. The plasma MCP-1 level, but not the CRP level or WBC count, correlated with the CAP severity according to the PSI (r = 0.509, p < 0.001), CURB-65 (r = 0.468, p < 0.001), and APACHE II (r = 0.360, p < 0.001) scores. We concluded that MCP-1 levels act in the development of CAP and are involved in the severity of CAP.

Outcome correlation of smear-positivity but culture-negativity during standard anti-tuberculosis treatment in Taiwan.

BACKGROUND: The appearance of smear-positivity but culture-negativity (SPCN) for acid-fast bacilli among sputum specimen is frequently found in pulmonary tuberculosis (TB) patients during treatment. This study aimed to investigate clinical risk factors, impacts on treatment course, and relapse pattern associated with sputum SPCN. METHODS: We retrospectively enrolled 800 patients with culture-proven pulmonary TB who were receiving standard treatment and follow-up at six TB-referral hospitals in Taiwan between January 2006 and December 2007. Relevant patient characteristics and chemotherapy data were analyzed for associations with incidence of SPCN. Data from patients who relapsed within 3 years after completing treatment were analyzed for associations with SPCN during treatment. RESULTS: Of the 800 subjects, 111 (13.8%) had sputum SPCN during treatment. Three factors were found to predict the development of SPCN; namely, high initial acid-fast staining grading (OR, 3.407; 95% CI, 2.090-5.553), cavitation on chest-X ray films (OR, 2.217; 95% CI, 1.359-3.615), and smoking (OR, 1.609; 95% CI, 1.006-2.841). Patients with SPCN had longer treatment duration (rifampicin: 284 ± 91 vs. 235 ± 69 days, P <0.001; isoniazid: 289 ± 90 vs. 234 ± 69 days, P < 0.001) than those without SPCN. Finally, the rate of relapse within 3 years of completing treatment was similar for groups with/without SPCN (2.7%, 3/111 vs. 1.0%, 7/689, respectively; P = 0.15). CONCLUSIONS: In conclusion, severity of infection was a major risk factor for SPCN during treatment; however, the relapse rate within 3 years of completing treatment was not affected by the appearance of SPCN.

Mycobacterium tuberculosis nucleic acid amplification tests reduce nosocomial tuberculosis exposure in intensive care units: A nationwide cohort study.

BACKGROUND AND OBJECTIVE: This retrospective national surveillance study investigated the burden of and risk factors for nosocomial exposure of pulmonary tuberculosis (TB) in intensive care units. METHODS: Patients admitted to intensive care units were identified from the National Health Insurance Research Database. During 2004-2009, there were 1 387 707 intensive care unit admissions of 900 562 adult patients. Pulmonary tuberculosis association was considered if the patient was diagnosed with pulmonary tuberculosis during admission or within 3 months after discharge. Nosocomial transmissible period was calculated based on the length of anti-tuberculosis treatment and negative-pressure isolation during admission. RESULTS: Pulmonary tuberculosis was associated with 1.20% of all intensive care unit admissions and 6731 (38.9%) started anti-TB treatment during admission. For the other 10 583 admissions, the diagnosis was made after discharge and anti-TB treatment was not prescribed during admission. The probability paralleled the regional tuberculosis incidence. On average, 2794 pulmonary tuberculosis associated intensive care unit admissions contributed to 42 999-44 062 days of nosocomial exposure per year. The length of nosocomial transmissible period decreased with the gradual implementation of Mycobacterium tuberculosis nucleic acid amplification tests in intensive care practice. Multivariate linear regression analysis revealed that the length of nosocomial transmissible period was inversely associated with male gender, airway symptoms prior to admission and performing M. tuberculosis nucleic acid amplification tests and mycobacterial culture. CONCLUSIONS: Nosocomial tuberculosis exposure is not uncommon in intensive care units. Performing rapid molecular diagnostic tests in those suspected of tuberculosis is recommended to reduce the risk of nosocomial exposure.

Connective tissue growth factor induces collagen I expression in human lung fibroblasts through the Rac1/MLK3/JNK/AP-1 pathway.

Connective tissue growth factor (CTGF) plays an important role in lung fibrosis. In this study, we investigated the role of Rac1, mixed-lineage kinase 3 (MLK3), c-Jun N-terminal kinase (JNK), and activator protein-1 (AP-1) in CTGF-induced collagen I expression in human lung fibroblasts. CTGF caused concentration- and time-dependent increases in collagen I expression. CTGF-induced collagen I expression was inhibited by the dominant negative mutant (DN) of Rac1 (RacN17), MLK3DN, MLK3 inhibitor (K252a), JNK1DN, JNK2DN, a JNK inhibitor (SP600125), and an AP-1 inhibitor (curcumin). Treatment of cells with CTGF caused activation of Rac1, MLK3, JNK, and AP-1. The CTGF-induced increase in MLK3 phosphorylation was inhibited by RacN17. Treatment with RacN17 and the MLK3DN inhibited CTGF-induced JNK phosphorylation. CTGF caused increases in c-Jun phosphorylation and the recruitment of c-Jun and c-Fos to the collagen I promoter. Furthermore, stimulation of cells with the CTGF resulted in increases in AP-1-luciferase activity; this effect was inhibited by Rac1N17, MLK3DN, JNK1DN, and JNK2DN. Moreover, CTGF-induced α-smooth muscle actin (α-SMA) expression was inhibited by the procollagen I small interfering RNA (siRNA). These results suggest for the first time that CTGF acting through Rac1 activates the MLK3/JNK signaling pathway, which in turn initiates AP-1 activation and recruitment of c-Jun and c-Fos to the collagen I promoter and ultimately induces collagen I expression in human lung fibroblasts.

Human papillomavirus infections as a marker to predict overall survival in lung adenocarcinoma.

Human papillomavirus (HPV) has been implicated in multiple cancers, but its significance in lung cancer has remained controversial. As the prevalence of HPV 16/18 infection was higher in lung adenocarcinoma among Taiwanese females, the aim of our study was to evaluate the clinical impact of HPV infections in lung adenocarcinoma. Two hundred and ten patients were enrolled to investigate the associations of HPV status in tumors with clinical characteristics as well as its impact on overall survival. The methods to assess HPV status were by immunohistochemistry for HPV L1 capsid protein and E6 protein and by nested polymerase chain reaction for HPV 16 and HPV 18. HPV infections were identified in 35.2% of patients, and associated with localized and smaller sized tumors (p = 0.022 and p = 0.002, respectively). Patients with HPV infections had a significantly better survival (p = 0.023, by log-rank test) and a significantly reduced mortality risk after adjustments of age, tumor extent, epidermal growth factor receptor (EGFR) mutations status and treatments [adjusted hazard ratio = 0.68, 95% confidence interval (CI) = 0.49-0.96, p = 0.026, by multivariate Cox proportional hazards models]. Specifically, patients with both HPV infections and EGFR mutations had the best survival outcome [1-year survival rate, 68.5% (95% CI = 52.2-4.8%)]. Our findings indicate that HPV infections represent an independent prognostic factor for overall survival in patients with lung adenocarcinoma.

Plasma endothelial cell-specific molecule-1 (ESM-1) in management of community-acquired pneumonia.

BACKGROUND: Endothelial cell-specific molecule (ESM)-1 is a soluble proteoglycan expressed by the vascular endothelium and which also circulates in the bloodstream. Inflammatory cytokines and proangiogenic growth factors increase its expression, and increased serum levels are found in immunocompetent patients with sepsis. The aim of this study was to investigate differential changes in plasma levels of ESM-1 before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). METHODS: Plasma ESM-1 levels were measured in 82 adult patients with CAP and 82 healthy controls using a commercial enzyme-linked immunosorbent assay (ELISA). Upon initial hospitalization, Acute Physiology and Chronic Health Evaluation II (APACHE II), CURB-65, and Pneumonia Severity Index (PSI) scores were determined to assess CAP severity in these patients. RESULTS: Results showed a decline in the number of white blood cells (WBCs) and neutrophils, and decreases in the concentrations of C-reactive protein (CRP) and ESM-1 after antibiotic treatment. The plasma concentration of ESM-1, but not CRP or the WBC count, was correlated with the severity of CAP based on the PSI (r=0.554, p<0.001), CURB-65 (r=0.510, p<0.001), and APACHE II scores (r=0.447, p<0.001). CONCLUSIONS: Plasma levels of ESM-1 may be able to play a role in the diagnosis and clinical assessment of the severity of CAP, which could potentially guide the development of treatment strategies.

Impact of food intake on the pharmacokinetics of first-line antituberculosis drugs in Taiwanese tuberculosis patients.

BACKGROUND/PURPOSE: Under the directly observed treatment, short course (DOTS) program, antituberculosis (anti-TB) medications were possibly taken at random time, regardless of whether it was prior to or after meals. This study was to evaluate the impact of food intake on pharmacokinetic profiles of first-line TB drugs in Taiwanese TB patients, as well as the relationship between drug levels and pharmacogenetics. METHODS: This open-label, randomized, cross-over study included newly diagnosed Taiwanese TB patients treated between January 2010 and February 2011 at Taipei Medical University-Wan Fang Hospital. Rifater [a fixed-dose combination formulation of isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA)] and ethambutol (EMB) were given according to national TB guidelines. Blood samples were collected prior to and 1 hour, 2 hours, 4 hours, 6 hours, and 10 hours after dosing under fasting or postprandial conditions. Pharmacokinetic parameters of the maximum serum concentration (Cmax), time to Cmax, and area under the serum concentration-time curve from the beginning to the 10(th) hour (AUC0-10) were calculated. RESULTS: Sixteen TB patients were included and received anti-TB treatment under the DOTS program after discharge. The overall effects showed that food intake reduced the mean Cmax (INH: 40.6%, RIF: 40.2%, EMB 34.4%, PZA: 24.4%) and AUC0-10 (INH: 21.3%, RIF: 26.4%, EMB: 12.2%, PZA: 12.0%). Meanwhile, food increased the time to Cmax (INH: 78.1%, RIF: 151.3%, EMB: 41.4%, PZA: 148.9%). CONCLUSION: Significantly lower serum drug concentrations were observed under postprandial conditions than fasting conditions for INH, RIF, and PZA. The impact of taking random anti-TB drugs under the DOTS program instead of taking drugs regularly prior to meals requires further study.

Emerging insight of whole genome sequencing coupled with protein structure prediction into the pyrazinamide-resistance signature of Mycobacterium tuberculosis.

Pyrazinamide (PZA) is considered to be a pivotal drug to shorten the treatment of both drug-susceptible and drug-resistant tuberculosis, but its use is challenged by the reliability of drug-susceptibility testing (DST). PZA resistance in Mycobacterium tuberculosis (MTB) is relevant to the amino acid substitution of pyrazinamidase that is responsible for the conversion of PZA to active pyrazinoic acid (POA). The single nucleotide variants (SNVs) within ribosomal protein S1 (rpsA) or aspartate decarboxylase (panD), the binding targets of POA, has been reported to drive the PZA-resistance signature of MTB. In this study, whole genome sequencing (WGS) was used to identify SNVs within the pncA, rpsA and panD genes in 100 clinical MTB isolates associated with DST results for PZA. The potential influence of high-confidence, interim-confidence or emerging variants on the interplay between target genes and PZA or POA was simulated computationally, and predicted with a protein structure modelling approach. The DST results showed weak agreement with the identification of high-confidence variants within the pncA gene (Cohen's kappa coefficient=0.58), the analytic results of WGS coupled with protein structure modelling on pncA mutants (Cohen's kappa coefficient=0.524) or related genes (Cohen's kappa coefficient=0.504). Taken together, these results suggest the practicable application of a genotypic-coupled bioinformatic approach to manage PZA-containing regimens for patients with MTB.

Mitigating treatment failure of pulmonary pre-extensively drug-resistant tuberculosis: The role of new and repurposed drugs.

BACKGROUND: Pre-extensively drug-resistant tuberculosis (pre-XDR-TB), defined as multidrug-resistant TB (MDR-TB) with additional resistance to any fluoroquinolone (FQ) is difficult to treat. We assessed whether the use of new or repurposed drugs (bedaquiline, delamanid, linezolid, carbapenem, clofazimine, pretomanid) mitigated treatment failure of pre-XDR-TB. METHODS: MDR-TB patients managed in the Taiwan MDR-TB consortium between July 2009-December 2019 were eligible. Treatment outcomes at 30 months were assessed. Logistic regression models were constructed to investigate factors associated with treatment outcomes. RESULTS: 109 patients with FQ-resistant MDR-TB and 218 patients with FQ-susceptible MDR-TB were included. 60 (55.1%) patients with FQ-resistant MDR-TB and 63 (28.9%) patients with FQ-susceptible MDR-TB have been treated with new or repurposed drugs (p < 0.01). Of the 218 patients with FQ-susceptible MDR-TB, 187 (85.8%) had treatment success, 30 (13.8%) died, no treatment failure, and 1 (0.5%) was loss-to-follow-up; of the 109 patients with FQ-resistant MDR-TB, 78 (71.6%) had treatment success, 21 (19.3%) died, 9 (8.3%) had treatment failure, and 1 (0.9%) was loss-to-follow-up (p < 0.01). The use of new or repurposed drugs was not associated with treatment outcomes among patients with FQ-susceptible MDR-TB. No patients with FQ-resistant MDR-TB treated with ≥2 new or repurposed drugs within 6 months of treatment initiation had treatment failure (p = 0.03). Patients with FQ-resistant MDR-TB treated with 1 new or repurposed drugs was more likely to have treatment failure as compared with patients not treated with new or repurposed drugs (adjOR 7.06, 95% CI 1.72-29.06). CONCLUSIONS: Proper use of new or repurposed anti-TB drugs can mitigate treatment failure in FQ-resistant MDR-TB.

Clofazimine and QT prolongation in the treatment of rifampicin-resistant tuberculosis: Findings of aDSM in Taiwan.

BACKGROUND: Bedaquiline, delamanid and fluoroquinolones are associated with increased QTcF. Whether clofazimine is associated with QTcF prolongation is less clear. METHODS: All patients with rifampicin-resistant TB enrolled between May 2017 and Dec 2019 were included. ECGs were performed at baseline, month 1, month 3 and month 6 for patients treated with conventional regimens, and at additional timepoint for patients treated with bedaquiline, delamanid and short regimen. We estimated the maximum increase of QTcF and constructed cox proportional hazards models to assess factors associated with QTcF≥501ms. RESULTS: Among 321 patients, 59 (18.4%) patients had QTcF≥501ms during a mean follow-up of 242 days (median 189, range 4-1091). The median maximum increase of QTcF was 43.4 ms (IQR 31.3-65.9) in patients treated with clofazimine. Treatment with clofazimine was significantly associated with QTcF≥501ms as compared to without clofazimine (adjusted hazards ratio (adjHR) 4.35, 95% confidence interval (CI) 2.01-9.44). Among patients not treated with bedaquiline and delamanid, those treated with clofazimine and a fluoroquinolone (adjHR 3.43, 95% CI 1.61-7.34) and those treated with clofazimine and high dose moxifloxacin (adjHR 6.54, 95% CI 2.43-17.60) had a significantly higher risk of QTcF≥501ms as compared to those treated with a fluoroquinolone without other QTcF prolonging agents. Four (1.6%) patients had documented ventricular tachycardia, in which one was Torsade de pointes. One patient was found to have sudden death during hospitalization. CONCLUSIONS: Clofazimine was significantly associated with an increased risk of QTcF prolongation. QTcF≥501ms was potentially associated with fatal event and needed to be managed cautiously.

Plasma long pentraxin 3 (PTX3) concentration is a novel marker of disease activity in patients with community-acquired pneumonia.

BACKGROUND: Long pentraxin 3 (PTX3) is an acute-phase protein secreted by various cells, including leukocytes and endothelial cells. Like C-reactive protein (CRP), it belongs to the pentraxin superfamily. The aim of this study was to investigate the differential changes in plasma levels of PTX3 between before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). METHODS: Plasma PTX3 levels were measured in 61 adult patients with CAP and 60 healthy controls using a commercial enzyme-linked immunosorbent assay (ELISA). Upon initial hospitalization, APACHE II, CURB-65, and pneumonia severity index (PSI) scores were determined to assess CAP severity in patients. RESULTS: The results showed a decline in the number of white blood cells (WBCs) and neutrophils, and decreases in the concentrations of CRP and PTX3 observed after antibiotic treatment. The plasma concentration of PTX3, but not CRP, was correlated with the severity of CAP based on the PSI (r=0.290, p=0.023), CURB-65 (r=0.312, p=0.015), and APACHE II scores (r=0.427, p=0.001). The PTX3 level also exhibited a significant correlation with the length of hospital stay (r=0.500, p<0.0001). CONCLUSIONS: PTX3 may be able to play a role in the diagnosis and clinical assessment of the severity of CAP, which could potentially guide the development of treatment strategies.