Bedaquiline Drug Resistance Emergence Assessment in Multidrug-Resistant Tuberculosis (MDR-TB): a 5-Year Prospective In Vitro Surveillance Study of Bedaquiline and Other Second-Line Drug Susceptibility Testing in MDR-TB Isolates.

Bedaquiline Drug Resistance Emergence Assessment in Multidrug-resistant tuberculosis (MDR-TB) (DREAM) was a 5-year (2015 to 2019) phenotypic drug resistance surveillance study across 11 countries. DREAM assessed the susceptibility of 5,036 MDR-TB isolates of bedaquiline treatment-naive patients to bedaquiline and other antituberculosis drugs by the 7H9 broth microdilution (BMD) and 7H10/7H11 agar dilution (AD) MIC methods. Bedaquiline AD MIC quality control (QC) range for the H37Rv reference strain was unchanged, but the BMD MIC QC range (0.015 to 0.12 µg/ml) was adjusted compared with ranges from a multilaboratory, multicountry reproducibility study conforming to Clinical and Laboratory Standards Institute Tier-2 criteria. Epidemiological cutoff values of 0.12 µg/ml by BMD and 0.25 µg/ml by AD were consistent with previous bedaquiline breakpoints. An area of technical uncertainty or intermediate category was set at 0.25 µg/ml and 0.5 µg/ml for BMD and AD, respectively. When applied to the 5,036 MDR-TB isolates, bedaquiline-susceptible, -intermediate, and -resistant rates were 97.9%, 1.5%, and 0.6%, respectively, for BMD and 98.8%, 0.8%, and 0.4% for AD. Resistance rates were the following: 35.1% ofloxacin, 34.2% levofloxacin, 33.3% moxifloxacin, 1.5% linezolid, and 2% clofazimine. Phenotypic cross-resistance between bedaquiline and clofazimine was 0.4% in MDR-TB and 1% in pre-extensively drug-resistant (pre-XDR-TB)/XDR-TB populations. Coresistance to bedaquiline and linezolid and clofazimine and linezolid were 0.1% and 0.3%, respectively, in MDR-TB and 0.2% and 0.4%, respectively, in pre-XDR-TB/XDR-TB populations. Resistance rates to bedaquiline appear to be low in the bedaquiline-treatment-naive population. No treatment-limiting patterns for cross-resistance and coresistance have been identified with key TB drugs to date.

DiHS/DRESS syndrome induced by second-line treatment for tuberculosis and Epstein-Barr virus.

Drug-induced hypersensitivity syndrome (DiHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe adverse drug-induced reaction characterized by various symptoms: skin rash, fever, lymph node enlargement and internal organ involvement, which starts within 2 weeks to 3 months after drug initiation. It is challenging to diagnose this syndrome due to the variety of cutaneous and visceral symptoms. Different mechanisms have been implicated in its development, including genetic susceptibility associated with human leucocyte antigen (HLA) loci, detoxification defects leading to reactive metabolite formation and subsequent immunological reactions, slow acetylation, and reactivation of human herpes, including Epstein-Barr virus and human herpes virus (HHV)-6 and HHV-7. The most frequently reported causes of DiHS/DRESS are antiepileptic agents, allopurinol and sulfonamides. We report a case of DiHS/DRESS induced by second-line treatment for tuberculosis, prothionamide and para-aminosalicylic acid, and Epstein-Barr virus re-infection. Patch testing, which was performed in this case, is not fully standardized, but it can be helpful and a safe way to evaluate and diagnose DiHS/DRESS.

Diagnostic Yield of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Cytological Smears and Cell Blocks: A Single-Institution Experience.

Background and Objective: Endobronchial ultrasound (EBUS) is a minimally invasive endobronchial technique, which uses ultrasound along with a bronchoscope to visualize the airway wall and structures that are adjacent to it. Indications for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are samplings of mediastinal, hilar lymph nodes, and tumors adjacent to airway walls. EBUS-TBNA has been used in our clinic since 2009. The aim of the study is to evaluate the sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy of cytological and histological specimens, and the safety of EBUS-TBNA in an unselected patient population that has been referred to our hospital. Materials and Methods: We have retrospectively analyzed the medical documentation of 215 patients who had EBUS-TBNA performed in our clinic from April 2009 to February 2014. Results: There were 215 patients who underwent EBUS-TBNA. A total of 296 lymph nodes were sampled. EBUS-TBNA was diagnostic in 176 (81.9%) cases of cytological, 147 (68.4%) cases of histological, and 191 (88.9%) cases of the combined evaluation. In the lung cancer patients, EBUS-TBNA cytology had a sensitivity of 72.9% and histology of 72.9%, and in the sarcoidosis group, it had a cytology of 55.8% and histology of 64.5%. As all positive cytology and histology specimens were assumed to be true positive, specificity and positive predictive value (PPV) were 100%. The sensitivity and diagnostic accuracy was significantly higher when cytology and histology specimens were combined, compared with cytology or histology results evaluated separately (p < 0.05) (for lung cancer 84.1% and for sarcoidosis 78.8%). The sensitivity and diagnostic accuracy of EBUS-TBNA procedures increased significantly over time, with increased experience. There were no complications with EBUS-TBNA in our clinical practice. Conclusions: EBUS-TBNA had a high diagnostic yield and was safe in the diagnosis of lung cancer and sarcoidosis. It was most informative when cytology and histology were combined. The informative value of EBUS-TBNA histology increased with our experience.

Factors associated with sputum culture conversion in patients with pulmonary tuberculosis.

OBJECTIVE: The aim of this study was to determine what factors are associated with sputum culture conversion after 1 month of tuberculosis (TB) treatment. MATERIALS AND METHODS: A total of 52 patients with new drug susceptible pulmonary TB were included in the study. Patients completed St. George respiratory questionnaire (SGRQ), they were asked about smoking, alcohol use, living conditions and education. Body mass index (BMI) measurements, laboratory tests (C reactive protein [CRP], vitamin D, albumin) were performed, and chest X-ray was done. After 1 month of treatment sputum culture was repeated. RESULTS: Culture conversion after 1 month of treatment was found in 38.5% cases. None of investigated social factors appeared to have an effect on conversion, but worse overall health status (as reported in SGRQ) and longer duration of tobacco smoking were detected in the "no conversion" group. Concentrations of albumin, CRP, X-ray score and the time it took Mycobacterium tuberculosis culture to grow also differed. Patients who scored 30 or more on SGRQ were more than 7 times as likely to have no conversion. However, the most important factor predicting sputum culture conversion was sputum smear grade at the beginning of treatment: patients with grade of 2+ or more had more than 20-fold higher relative risk for no conversion. Using receiver operating characteristic curve analysis, we also developed a risk score for no conversion. CONCLUSIONS: The most important factors in predicting sputum culture conversion after 1 month of treatment were grades of acid-fast bacilli in sputum smears at time of diagnosis and scores of SGRQ.

Multidrug-resistant tuberculosis in Lithuania - Still a long way ahead.

Despite the recent advances in the diagnosis of tuberculosis, treatment of the disease, for the most part, remains the same as it was half a century ago. In recent years only two new anti-tuberculosis drugs have been approved by the European Medicines Agency and Food and Drug Administration. Though the prevalence of this disease is slowly decreasing all over Europe, new challenges appear. One of them is multidrug-resistant tuberculosis (MDR-TB). This problem is especially prominent in Lithuania, which is one of the 27 high MDR-TB burden countries in the world and falls behind neighboring countries in terms of the prevalence of the disease. The objective of this paper was to review the situation of tuberculosis and MDR-TB in Lithuania, and current available methods of treatment, control and diagnosis of this disease.

Is analysis of inflammatory biomarkers and lymphocyte subpopulations useful in prediction of tuberculosis treatment outcomes?

Analysis of inflammatory biomarkers and lymphocytes during the treatment of tuberculosis (TB) could yield findings that influence the routine clinical practice and use of new anti-TB drugs. This study aimed to evaluate whether the selected biomarkers-soluble intercellular adhesion molecule type 1, soluble urokinase-type plasminogen activator receptor (suPAR), and C-reactive protein (CRP)-and T-cell subpopulations are useful for predicting culture conversion, treatment outcomes, and the extent of radiological lesions (calculated using X-ray score) in patients with drug-sensitive pulmonary TB. This study included 62 patients with drug-sensitive pulmonary TB. CRP and suPAR levels significantly decreased after 1 month of treatment. Before treatment initiation, CRP and suPAR levels were significantly higher in patients without culture conversion; however, none of the selected host biomarkers appeared to significantly influence the conversion status or treatment outcomes. Some lymphocyte subpopulations were correlated with X-ray scores before TB treatment initiation, but lung destruction, as determined using X-ray scores, showed the highest correlation with the baseline CRP value. We conclude that selected host biomarkers have a very limited role in predicting TB treatment outcomes and culture conversion and do not appear to be superior to CRP in monitoring TB treatment.

A case report and literature review: previously excluded tuberculosis masked by amiodarone induced lung injury.

BACKGROUND: Amiodarone is an antiarrhythmic drug which is used to treat and prevent several dysrhythmias. This includes ventricular tachycardia and fibrillation, wide complex tachycardia, as well as atrial fibrillation (AF) and paroxysmal supraventricular tachycardia. Amiodarone may prove to be the agent of choice where the patient is hemodynamically unstable and unsuitable for direct current (DC) cardioversion. Although, it is not recommended for long-term use. The physician might encounter issues when differentiating amiodarone-induced lung toxicity with suspicion of interstitial lung disease, cancer or vasculitis. Adverse drug reactions are difficult to confirm and it leads to serious problems of pharmacotherapy. CASE PRESENTATION: A 78-year-old Caucasian male pensioner complaining of fever, dyspnea, malaise, non-productive cough, fatigue, weight loss, diagnosed with acute respiratory failure with a 16-year long history of amiodarone use and histologically confirmed temporal arteritis with long-term glucocorticosteroid (GCC) therapy. Patient was treated for temporal arteritis with GCC for ~ 1 year, then fever and dyspnea occurred, and the patient was hospitalized for treatment of bilateral pneumonia. Chest X-ray and chest high resolution computed tomography (HRCT) indicated several possible diagnoses: drug-induced interstitial lung disease, autoimmune interstitial lung disease, previously excluded pulmonary TB. Amiodarone was discontinued. Antibiotic therapy for bilateral pneumonia was started. Fiberoptic bronchoscopy with bronchial washings and brushings was performed. Acid fast bacilli (AFB) were found on Ziehl-Nielsen microscopy and tuberculosis (TB) was confirmed (later confirmed to be Mycobacterium tuberculosis in culture), initial treatment for TB was started. After a few months of treating for TB, patient was diagnosed with pneumonia and sepsis, empiric antibiotic therapy was prescribed. After reevaluation and M. Tuberculosis identification, the patient was referred to the Tuberculosis hospital for further treatment. After 6 months of TB treatment, pneumonia occurred which was complicated by sepsis. Despite the treatment, multiple organ dysfunction syndrome evolved and patient died. Probable cause of death: pneumonia and sepsis. CONCLUSIONS: The current clinical case emphasizes issues that a physician may encounter in the differential diagnostics of amiodarone-induced lung toxicity with other lung diseases.