Characterization of Genomic Variants Associated with Resistance to Bedaquiline and Delamanid in Naive Mycobacterium tuberculosis Clinical Strains.

The role of mutations in genes associated with phenotypic resistance to bedaquiline (BDQ) and delamanid (DLM) in Mycobacterium tuberculosis complex (MTBc) strains is poorly characterized. A clear understanding of the genetic variants' role is crucial to guide the development of molecular-based drug susceptibility testing (DST). In this work, we analyzed all mutations in candidate genomic regions associated with BDQ- and DLM-resistant phenotypes using a whole-genome sequencing (WGS) data set from a collection of 4,795 MTBc clinical isolates from six countries with a high burden of tuberculosis (TB). From WGS analysis, we identified 61 and 163 unique mutations in genomic regions potentially involved in BDQ- and DLM-resistant phenotypes, respectively. Importantly, all strains were isolated from patients who likely have never been exposed to these medicines. To characterize the role of mutations, we calculated the free energy variation upon mutations in the available protein structures of Ddn (DLM), Fgd1 (DLM), and Rv0678 (BDQ) and performed MIC assays on a subset of MTBc strains carrying mutations to assess their phenotypic effect. The combination of structural and phenotypic data allowed for cataloguing the mutations clearly associated with resistance to BDQ (n = 4) and DLM (n = 35), only two of which were previously described, as well as about a hundred genetic variants without any correlation with resistance. Significantly, these results show that both BDQ and DLM resistance-related mutations are diverse and distributed across the entire region of each gene target, which is of critical importance for the development of comprehensive molecular diagnostic tools.

Alarming levels of multidrug-resistant tuberculosis in Ukraine: results from the first national survey.

SETTING: The true prevalence of multidrug-resistant tuberculosis (MDR-TB) in Ukraine is not known. Available data are a decade old and limited to only one province. OBJECTIVE: To determine the prevalence of MDR-TB among new and previously treated TB cases in Ukraine and explore the risk factors associated with drug resistance. METHODS: A total of 1550 sputum smear-positive pulmonary TB patients were recruited from 40 clusters throughout Ukraine. Sputum specimens were examined using culture, drug susceptibility testing and pncA gene sequencing. RESULTS: The proportion of MDR-TB among new and previously treated TB cases was respectively 24.1% (95%CI 20.7-27.6) and 58.1% (95%CI 52.1-64.1). More than one third (38.0%) of MDR-TB or rifampicin (RMP) resistant cases showed resistance to either a fluoroquinolone (FQ) or a second-line injectable agent or both. Resistance to pyrazinamide and FQs was low in patients with RMP-susceptible TB. Among new TB cases, the odds of MDR-TB were higher among patients who were younger, female and living in south-eastern provinces, as well as among human immunodeficiency virus-positive patients who belonged to a low socio-economic group. CONCLUSIONS: Our study showed that the burden of MDR-TB in Ukraine was much greater than previously assumed. Urgent actions are needed to prevent further spread of drug-resistant TB in Ukraine.

Management of multi- and extensively drug-resistant tuberculosis in Ukraine: how well are we doing?

SETTING: A tertiary care facility in Ukraine, a high multi- and extensively drug-resistant tuberculosis (MDR/XDR-TB) burden country. OBJECTIVES: To assess the management and treatment outcomes of MDR, pre-XDR-TB and XDR-TB. DESIGN: Cohort study using programme data, 2006-2011. RESULTS: Of 484 individuals with drug-resistant TB, 217 (45%) had MDR-, 153 (32%) pre-XDR- and 114 (24%) XDR-TB. Of all resistant types completing the intensive phase of treatment, 322 (67%) were alive and had culture converted. This included 157 (72%) with MDR- and 61 (54%) with XDR-TB. At the end of the continuation phase of treatment, 106 (22%) had treatment success and 378 (78%) had unfavourable outcomes, including 110 (23%) failures, 21 (4%) deaths, 71 (15%) losses to follow-up and 176 (36%) with an unknown outcome. This was associated with more than one lung cavity being affected, a history of treatment with second-line anti-tuberculosis drugs, poor adherence and XDR-TB. A total of 226 (47%) patients reported at least one adverse drug reaction, the most common being gastrointestinal and vestibular toxicity. CONCLUSION: Outcomes of MDR- and XDR-TB were satisfactory in the intensive phase; however, this was not sustained during the ambulatory period. If we are to do better, urgent measures are needed to improve ambulatory management, including making safer, shorter and more effective drug regimens available.

[New hydrogels of methylsilicic acid with metals and the in-vitro evaluation of their sorption activity in relation to rotaviruses]. / Novye gidrogeli metilkremnievoi kisloty s metallami i otsenka in vitro ikh sorbtsionnoi aktivnosti v otnoshenii rotavirusov.

Processes of adsorption of rotaviruses of different strains by enterol sorbents on the basis of hydrogel of methylsilicic acid with bi- and trivalent ions of 3d-metals (iron, cobalt, copper) fastened in their matrix have been studied.

[The sorption of human and animal rotaviruses by Enterosgel]. / Sorbtsiia rotavirusov cheloveka i zhivotnykh Enterosgelem.

Adsorptive activity of enterosgel has been studied as applied to different strains of rotaviruses of man and animals. Optimal amounts of the sorbent and pH values of the reaction medium at which rotaviruses were most efficiently sorbed from the virus-containing liquid were determined experimentally.