A Dose-Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h ) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

Endobronchial ultrasound sonographic characteristics of mediastinal lymph node in evaluation of lung cancer.

Endobronchial ultrasound (EBUS) and contrast enhanced computed tomography (CECT) are essential components of lung cancer evaluation. Features of mediastinal lymph nodes on EBUS and CECT can help in predicting metastatic disease. Clinical, radiological and EBUS data of patients with clinico-radiological suspicion of lung cancer and have undergone EBUS with no trans-bronchial needle aspiration (TBNA) or nonyielding EBUS-TBNA were retrospectively collected from medical records. EBUS features of lymph nodes for metastatic disease [Size >1cm, round shape, heterogeneous echo-texture, indistinct margin, coagulation necrosis(CN), absence of central hilar structures (CHS) and grade II-III vascularity] were noted. CECT findings were noted from CECT films and reports to analyse and compare with EBUS findings. Scoring criteria of EBUS sonographic characteristics from previous studies for discriminating benign and malignant lymph-nodes were also assessed for possible prediction. Thirty-one (31) patients [male=18 (58.1%), female=13 (41.9); age (mean±SD) =52.9±15.7 years] with CECT findings suggesting lung cancer were studied. EBUS showed mediastinal lymphadenopathy at 82 lymph node station in 29 patients. Size>1cm, round shape, heterogeneous echo-texture, distinct margin, CN, absence of CHS and grade II-III vascularity at 33 (40%), 28 (34%), 31 (38%), 55 (67%), 3 (4%), 77 (94%) and 6 (7.3%) lymph nodes, respectively. Malignant or benign status assigned to lymph nodes using different scoring criteria were highly discordant. Compared to EBUS, CECT revealed abnormal mediastinal lymph nodes (LN) in significantly less number of patients [21( 67.7%) vs 29 (93.5%), p=0.01] involving less number of lymph node stations (LNS) [(37 vs 82, p<0.001]. Lymphadenopathy frequency at different LNS on EBUS and CECT showed a weak positive but significant correlation (r=0.356; p=0.0426). EBUS characteristics and related scores have limited accuracy in differentiating benign and malignant nodes. CECT underestimates lymph-adenopathy in comparison to EBUS. Larger prospective study of EBUS features with cyto/histo-pathology correlation may elicit its clinical significance and help to create a better and composite scoring criteria.

A dose-finding study to guide use of verapamil as an adjunctive therapy in tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/ml (AUC 0-12h), similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Norverapamil:verapamil, R:S verapamil and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin, suggesting that rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers. Finally, rifampin exposures were significantly greater after verapamil administration. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

Quantification of Epistemic Capacity and Physical Frailty in Chronic Kidney Disease: Koch's Disease Co-infection.

Background Chronic kidney disease (CKD) and tuberculosis (TB) co-infection devastates the affected individual physically and psychologically. Moreover, poor immune status and mental turmoil worsen cognition and quality of life. Hence, studying the cognitive function and quality of life among such patients is necessary. This study aimed to determine the changes in mini-mental state examination (MMSE) score and general health questionnaire (GHQ-12) score at six months from baseline. Methodology This prospective, observational study was conducted at Sriram Chandra Bhanja Medical College and Hospital, India, from February 2020 to December 2021. A total of 40 patients with stage 3-4 CKD and pulmonary TB were assessed with MMSE and GHQ-12 scales at baseline, two, and six months. The study population was grouped as ≤50 and >50 years of age. We used R software (version 4.1.1) for data analysis. Results In total, 40 (69%) of the 58 enrolled participants completed this study. The mean age of the study population was 50.93 ± 9.83 years. The baseline MMSE scores (≤50 years: 20.8 ± 2.1, >50 years: 20.1 ± 1.7, p = 0.17) were increased (≤50 years: 25.4 ± 1.8, >50 years: 22.4 ± 1.6, p = 0.08) at six months. The baseline GHQ-12 scores (≤50 years: 22.8 ± 2.6, >50 years: 23.1 ± 2.8, p = 0.56) were reduced (≤50 years: 17.9 ± 1.9, >50 years: 20.3 ± 2.3, p = 0.14) at six months. Conclusions The study participants' cognitive function and quality of life improved after six months of modified antitubercular drugs. Nevertheless, the intergroup differences were not statistically significant.

Effects of the Modified Antitubercular Treatment Regimen on Renal Function in Patients With Chronic Kidney Disease and Pulmonary Tuberculosis: An Observational Study.

INTRODUCTION: Chronic kidney disease (CKD) increases an individual's vulnerability to infections like tuberculosis. Doses of pyrazinamide and ethambutol are modified to treat such individuals. Additionally, the renal function tends to decline with advancing age. Therefore, it is crucial to study the effect of antitubercular drugs on renal function in young and elderly patients. The primary objective of this study was to determine the change in serum creatinine levels at six months from baseline in two study groups that included patients aged ≤50 and >50 years. The secondary objective was to determine changes in estimated glomerular filtration rate (eGFR) and BMI six months from baseline. METHODS: We recruited 40 patients with CKD and pulmonary tuberculosis from Srirama Chandra Bhanja (SCB) Medical College and Hospital, India. Each participant received the modified doses of antitubercular drugs. Their serum creatinine, eGFR, and BMI were assessed at baseline, two and six months. Participants had a mean age of 50.93±9.83 years. RESULTS: The median changes in serum creatinine and eGFR values from baseline were -0.19 and -0.23 mg/dl and 4.16 and 3.93 ml/min/m2 for the two study groups, respectively. Furthermore, the differences in BMI from baseline were 1.91 and 2.14 kg/m2, respectively, for the two groups. The renal function was found to be improved after six months of treatment with modified antitubercular drugs. The intergroup comparisons were not statistically significant. CONCLUSION: We conclude that the modified regimen helps effectively cure pulmonary tuberculosis and significantly improves renal function in CKD patients. Further studies are required to generalize these findings.

Atrial Fibrillation (AFIB) in the ICU: Incidence, Risk Factors, and Outcomes: The International AFIB-ICU Cohort Study.

OBJECTIVES: To assess the incidence, risk factors, and outcomes of atrial fibrillation (AF) in the ICU and to describe current practice in the management of AF. DESIGN: Multicenter, prospective, inception cohort study. SETTING: Forty-four ICUs in 12 countries in four geographical regions. SUBJECTS: Adult, acutely admitted ICU patients without a history of persistent/permanent AF or recent cardiac surgery were enrolled; inception periods were from October 2020 to June 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 1,423 ICU patients and analyzed 1,415 (99.4%), among whom 221 patients had 539 episodes of AF. Most (59%) episodes were diagnosed with continuous electrocardiogram monitoring. The incidence of AF was 15.6% (95% CI, 13.8-17.6), of which newly developed AF was 13.3% (11.5-15.1). A history of arterial hypertension, paroxysmal AF, sepsis, or high disease severity at ICU admission was associated with AF. Used interventions to manage AF were fluid bolus 19% (95% CI 16-23), magnesium 16% (13-20), potassium 15% (12-19), amiodarone 51% (47-55), beta-1 selective blockers 34% (30-38), calcium channel blockers 4% (2-6), digoxin 16% (12-19), and direct current cardioversion in 4% (2-6). Patients with AF had more ischemic, thromboembolic (13.6% vs 7.9%), and severe bleeding events (5.9% vs 2.1%), and higher mortality (41.2% vs 25.2%) than those without AF. The adjusted cause-specific hazard ratio for 90-day mortality by AF was 1.38 (95% CI, 0.95-1.99). CONCLUSIONS: In ICU patients, AF occurred in one of six and was associated with different conditions. AF was associated with worse outcomes while not statistically significantly associated with 90-day mortality in the adjusted analyses. We observed variations in the diagnostic and management strategies for AF.

Adverse Drug Reaction Monitoring in Multidrug-Resistant Tuberculosis Patients Receiving Bedaquiline and Delamanid-Based Regimen.

Background and objectives  Tuberculosis (TB) is an airborne contagious illness caused by Mycobacterium tuberculosis. Ineffective anti-TB medication prolongs and exasperates illness, promotes disease spread, increases the probability of developing resistance to treatment, and increases death rate. Bedaquiline (BDQ) and Delamanid (DLM) were conditionally made available in the treatment of multidrug-resistant TB (MDR TB). In drug-resistant TB patients, adverse drug reactions (ADR) management is essential to improve medication compliance. In addition, we performed this study since there are very few studies published on the analysis of ADR monitoring of BDQ and DLM-based regimen. This study was performed to study the spectrum of ADR in drug-resistant TB patients receiving BDQ and DLM-based regimen. Methodology The study was conducted over a period of 26 months, in a hospital's departments of pharmacology and pulmonary medicine. Pre-extensively drug-resistant (Pre-XDR) and XDR TB were established on the basis of cartridge-based nucleic acid amplification (CB-NAAT), line probe assay (LPA), drug susceptibility testing (DST), and bacteriological culture. Patients were prescribed with appropriate medicines at the initial visit and any adverse reactions to medication were assessed in the subsequent visit. The statistical analysis was done using frequency distribution procedure, chi-square test of independence. The significance level was set at p<0.05. Results It was revealed that there were as many as 24 types of ADRs manifested in different patients. The most frequent ADR was QTcF (corrected heart rate) prolongation. Conclusion The maximum number of patients had some form of ADR and the percentage was slightly higher in the BDQ group than in the DLM group.

Diagnosis and treatment of pulmonary tuberculosis in one day: Way forward for END TB Strategy 2015.

BACKGROUND: According to Revised National Tuberculosis Control Program (RNTCP), diagnosis of pulmonary tuberculosis (TB) in India requires examination of two sputum samples collected over 2 days, that is, "spot" and next day "morning" samples. OBJECTIVE: To assess the feasibility of diagnosing pulmonary TB by examining two spot sputum samples in 1 day and to compare this approach with the current RNTCP protocol. MATERIALS AND METHOD: A total of 375 subjects having cough >2 weeks were enrolled into the study. Three sputum samples were collected from each of the study participant; first spot (S1), second extra-spot (S2) sample 1 h after collection of the first sample, and third morning (M) sample collected next day morning. These specimens were subjected to standard sputum smear microscopy for acid-fast bacilli as per RNTCP guidelines. For 1-day protocol, results of "S1 and S2" samples and for 2-day protocol results of "S1 and M" samples were considered. RESULTS: The number of sputum-positive pulmonary TB cases diagnosed with standard 2-day protocol was 119, whereas the experimental 1-day protocol diagnosed 120 cases (P = 0.7). Comparing with standard 2-day protocol, this new 1-day protocol had sensitivity 98.32%, specificity 100%, positive predictive value 100%, and negative predictive value 99.17%. CONCLUSION: Single-day method can be adopted as the standard diagnostic approach for pulmonary TB after large-scale multicenter randomized controlled trials.