Smolensk State Medical Academy

Smolensk, Russia

Smolensk State Medical Academy

Smolensk, Russia
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Novikov V.E.,Smolensk State Medical Academy | Levchenkova O.S.,Smolensk State Medical Academy
Eksperimental'naya i Klinicheskaya Farmakologiya | Year: 2013

The modem notions about mechanisms of the organism adaptation to hypoxia are reviewed. Promising new directions in the search for effective medicinal agents with antihypoxant action are proposed. Probable targets for antihypoxant action, including mitochondrial ATP-dependent potassium channel (mito-K ATP), mitochondrial megapore (mPTP), and hypoxia-inducible factor-1 alfa (HIF-1α) are discussed.

Jacobson I.M.,New York Medical College | Dore G.J.,University of New South Wales | Foster G.R.,Queen Mary, University of London | Fried M.W.,University of North Carolina at Chapel Hill | And 12 more authors.
The Lancet | Year: 2014

Background Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection. Methods In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with, number NCT01289782. Findings Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1-38·6; p<0·0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration. Interpretation Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin. Funding Janssen Infectious Diseases-Diagnostics. © 2014 Elsevier Ltd.

Rossolini G.M.,University of Siena | Dryden M.S.,Royal Hampshire County Hospital | Kozlov R.S.,Smolensk State Medical Academy | Quintana A.,Johnson and Johnson Pharmaceutical Research and Development L.L.C. | And 4 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2011

Objectives: To assess the in vitro activity of ceftobiprole and comparators against a recent collection of Gram-positive and Gram-negative pathogens, in order to detect potential changes in susceptibility patterns, and to evaluate the Etest assay for ceftobiprole susceptibility testing. Methods: Contemporary Gram-positive and Gram-negative isolates (excluding extended-spectrum β-lactamase-producing isolates) from across Europe and the Middle East were collected, and their susceptibility to ceftobiprole, vancomycin, teicoplanin, linezolid, ceftazidime and cefepime was assessed using the Etest method. Quality testing [using Etest and broth microdilution (BMD)] was conducted at a central reference laboratory. Results: Some 5041 Gram-positive and 4026 Gram-negative isolates were included. Against Gram-positive isolates overall, ceftobiprole had the lowest MIC 50 (0.5 mg/L), compared with 1 mg/L for its comparators (vancomycin, teicoplanin and linezolid). Against methicillin-resistant Staphylococcus aureus, all four agents had a similar MIC 90 (2 mg/L), but ceftobiprole had a 4-fold better MIC 90 (0.5 mg/L) against methicillin-susceptible strains. Only 38 Gram-positive isolates were confirmed as ceftobiprole resistant. Among Gram-negative strains, 86.9%, 91.7% and 95.2% were susceptible to ceftobiprole, ceftazidime and cefepime, respectively. Pseudomonas aeruginosa was less susceptible to all three antimicrobials than any other Gram-negative pathogen. There was generally good agreement between local Etest results and those obtained at the reference laboratory (for ceftobiprole: 86.8% with Gram-negatives; and 94.7% with Gram-positives), as well as between results obtained by BMD and Etest methods (for ceftobiprole: 98.2% with Gram-negatives; and 98.4% with Gram-positives). Conclusions: Ceftobiprole exhibits in vitro activity against a wide range of Gram-positive and Gram-negative pathogens, including multidrug-resistant strains. No changes in its known susceptibility profile were identified. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Edelstein M.V.,Smolensk State Medical Academy | Skleenova E.N.,Smolensk State Medical Academy | Shevchenko O.V.,Smolensk State Medical Academy | D'souza J.W.,Smolensk State Medical Academy | And 7 more authors.
The Lancet Infectious Diseases | Year: 2013

Background: Multidrug-resistant and extensively-drug-resistant Pseudomonas aeruginosa are increasing therapeutic challenges worldwide. We did a longitudinal epidemiological and clinical study of extensively-drug-resistant P aeruginosa in Belarus, Kazakhstan, and Russia. Methods: The study was done in three prospectively defined phases: Jan 1, 2002-Dec 31, 2004; Jan 1, 2006-Dec 31, 2007; and Jan 1, 2008-Dec 31, 2010. The first two phases were in Russia only. All consecutive, non-duplicate, nosocomial isolates and case report forms were sent to the coordinating centre (Institute of Antimicrobial Chemotherapy, Smolensk, Russia), where species reidentification, susceptibility testing, and molecular typing of isolates were done. We did susceptibility testing by agar dilution. The presence of metallo-β-lactamase (MBL) genes was established by PCR and sequencing, and class 1 integrons containing MBL gene cassettes were analysed by the PCR restriction fragment length polymorphism approach. Strain relatedness was analysed by multiple loci variable-number tandem-repeat (VNTR) analysis (at six VNTR loci) and multilocus sequence typing. Results: In 2002-04, 628 of 1053 P aeruginosa isolates were insusceptible to carbapenems and 47 (4·5%) possessed MBLs. In 2006-07, 584 of 787 isolates were insusceptible to carbapenems and 160 (20·3%) possessed MBLs. In 2008-10, 1238 of 1643 Russian P aeruginosa isolates were insusceptible to carbapenems and 471 (28·7%) possessed MBLs. Additionally, the 32 P aeruginosa isolates from Belarus and Kazakhstan were all carbapenem insusceptible and all possessed MBLs. More than 96% of MBL-positive P aeruginosa isolates were resistant to all antibiotics except colistin (ie, extensively drug resistant), and, in 2010, 5·9% were resistant to colistin. 685 (96·5%) of 710 MBL-positive P aeruginosa belonged to ST235. blaVIM-2 genes were detected in 707 (99·6%) of 710 MBL-positive isolates. Interpretation: Extensively-drug-resistant ST235 P aeruginosa has rapidly spread throughout Russia and into Belarus and Kazakhstan via clonal dissemination. Increases in the use of colistin will probably result in further spread of ST235 P aeruginosa resistant to all drugs. Funding: HEFC, Ministry of Health of the Russian Federation, Government of the Republic of Belarus, Government of the Republic of Kazakhstan, European Union, Medical Research Council UK-Canada partnership. © 2013 Elsevier Ltd.

Kozyreva V.K.,West Virginia University | Ilina E.N.,Karpov Institute of Physical Chemistry | Malakhova M.V.,Karpov Institute of Physical Chemistry | Carattoli A.,Instituto Superiore Of Sanita | And 4 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

In this paper, we present evidence of long-term circulation of cefotaxime-resistant clonally related Salmonella enterica serovar Typhimurium strains over a broad geographic area. The genetic relatedness of 88 isolates collected from multiple outbreaks and sporadic cases of nosocomial salmonellosis in various parts of Russia, Belarus, and Kazakhstan from 1996 to 2009 was established by multilocus tandem-repeat analysis (MLVA) and multilocus sequence typing (MLST). The isolates belong to sequence type 328 (ST328) and produce CTX-M-5 β-lactamase, whose gene is carried by highly related non-self-conjugative but mobilizable plasmids. Resistance to nalidixic acid and low-level resistance to ciprofloxacin is present in 37 (42%) of the isolates and in all cases is determined by various single point mutations in the gyrA gene quinolone resistance-determining region (QRDR). Isolates of the described clonal group exhibit a hypermutable phenotype that probably facilitates independent acquisition of quinolone resistance mutations. Copyright © 2014 American Society for Microbiology. All Rights Reserved.

Shevchenko O.V.,Smolensk State Medical Academy | Mudrak D.Y.,Moscow Medical Academy | Skleenova E.Y.,Smolensk State Medical Academy | Kozyreva V.K.,Smolensk State Medical Academy | And 5 more authors.
Clinical Microbiology and Infection | Year: 2012

An Escherichia coli isolate co-producing VIM-4 metallo-β-lactamase and CTX-M-15 extended spectrum β-lactamase was recovered from the urine of a patient with head trauma in Moscow, Russia. The bla VIM-4 and bla CTX-M-15 genes were carried, respectively, by transmissible plasmids of IncW and IncI1 groups. The nucleotide sequence of the VIM-4-encoding integron was nearly identical to that of In416, which represent a large group of structurally related integrons previously found in Enterobacteriaceae all around the Mediterranean basin. This is the first report of a metallo-β-lactamase-producing E. coli in Russia. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.

Alimova I.L.,Smolensk State Medical Academy | Kostyakov S.E.,Smolensk State Medical Academy
Diabetes Mellitus | Year: 2013

Aims: To estimate an impact of glycemic variability on the development of gastroesophageal reflux disease (GERD) in adolescents with type 1 diabetes mellitus (T1DM). Materials and methods: We enrolled 33 patients with T1DM aged from 12 to 17 years. 24-h pH-monitoring was performed with "Gastroskan 24" system (Istok-Sistema, Fryazino); 24-h continuous glucose monitoring utilized CGMS MMT-7310 (Medtronic Minimed, USA) with subsequent night-time analysis. Results: As compared to stable night-time glycemia controls (SD <2.0 mmol/L), patients with higher night-time glycemic variability (SD>2.0 mmol/L) showed longer period of esophageal acidification (17% [2-58]; p<0.001), higher incidence of acid reflux events with duration above 5 min (2 ev. [1-10]; p<0.001), longer period of most protracted acid reflux event (63 min [5-132]; p<0.001), as well as higher prevalence of pathologic acid GER events (76.4%; 2=17.11; p<0.001) during night-time. Increase in glycemic instability positively correlated with incidence and severity of acid GER events. 6-8 months follow-up supported these findings. Conclusion: Glycemic variability in adolescents with T1DM is a significant risk factor for development of GERD with hypomotor dysfunction according to pH-monitoring.

Firsov A.A.,Russian Academy of Medical Sciences | Strukova E.N.,Russian Academy of Medical Sciences | Shlykova D.S.,Russian Academy of Medical Sciences | Portnoy Y.A.,Russian Academy of Medical Sciences | And 5 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

In light of the concept of the mutant selection window, i.e., the range between the MIC and the mutant prevention concentration (MPC), MPC-related pharmacokinetic indices should be more predictive of bacterial resistance than the respective MIC-related indices. However, experimental evidence of this hypothesis remains limited and contradictory. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and the MIC, the selection of ciprofloxacin- resistant mutants of four Escherichia coli strains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. Resistant E. coli was intensively enriched at AUC24/MPCs from 1 to 10 h (AUC24/MIC from 60 to 360 h) but not at the lower or higher AUC24/MPC and AUC24/MIC ratios. AUC24/MPC and AUC24/MIC relationships of the areas under the time courses of ciprofloxacin-resistant E. coli (AUBCM) were bell-shaped. A Gaussian-like function fits the AUBCM-AUC24/MPC and AUBCM-AUC24/MIC data combined for all organisms (r2 0.69 and 0.86, respectively). The predicted anti-mutant AUC24/MPC ratio was 58 ± 35 h, and the respective AUC24/MIC ratio was 1,080 ± 416 h. Although AUC24/MPC was less predictive of strain-independent E. coli resistance than AUC24/MIC, the established anti-mutant AUC24/MPC ratio was closer to values reported for Staphylococcus aureus (60 to 69 h) than the respective AUC24/MIC ratio (1,080 versus 200 to 240 h). This implies that AUC24/MPC might be a better interspecies predictor of bacterial resistance than AUC24/MIC. Copyright © 2013, American Society for Microbiology. All Rights Reserved.

Rubtsova M.Y.,Moscow State University | Ulyashova M.M.,Moscow State University | Edelstein M.V.,Smolensk State Medical Academy | Egorov A.M.,Moscow State University
Biosensors and Bioelectronics | Year: 2010

Production of extended-spectrum β-lactamases (ESBLs) is the one of most widespread and clinically significant mechanism of Enterobacteriaceae resistance towards modern β-lactam antibiotics. There are known 400 ESBLs, with the majority represented by the enzymes of TEM, SHV and CTX-M families. Oligonucleotide microarrays with colorimetric detection have been developed for the purposes of determination of ESBLs and inhibitor-resistant β-lactamases using horseradish peroxidase (HRP). Specific oligonucleotide probes have been designed for the identification of β-lactamase family and important SNPs responsible for the broadening of substrate specificity and tolerance to inhibitors. Multiplex PCR has been developed for simultaneous amplification and labeling of full-size genes of TEM-, SHV- and CTX-M-type β-lactamases with biotin. The labeled target DNA is then hybridized with specific oligonucleotide probes immobilized on a porous membrane support. After hybridization, biotin-labeled DNA duplexes are stained with the streptavidin-HRP conjugate detected colorimetrically. Design of oligonucleotide probes and optimization of hybridization conditions ensure the specificity of all control ESBLs identification. The newly developed method has been successfully used to identify blaTEM, blaSHV and blaCTX-M genes in 90 clinical isolates of Enterobacteriaceae: 70% were found to carry blaTEM, 50% blaSHV, 50% blaCTX-M; with the following distribution of CTX-M subclusters: 68% blaCTX-M-1, 4% blaCTX-M-2, and 14% blaCTX-M-9. No ESBL of TEM-type and IRT phenotype assigned to TEM- or SHV-type β-lactamases had been detected; 24.6% of clinical samples show two types of ESBLs simultaneously. A mixture of CTX-M-1-like and SHV-5-like genes was the most abundant combination detected. Membrane microarray technique with colorimetric detection provides both high specificity and effectiveness of screening for ESBL- and IRT-producing samples. © 2010 Elsevier B.V.

Firsov A.A.,Russian Academy of Medical Sciences | Golikova M.V.,Russian Academy of Medical Sciences | Strukova E.N.,Russian Academy of Medical Sciences | Portnoy Y.A.,Russian Academy of Medical Sciences | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Bacterial resistance studies using in vitro dynamic models are highly dependent on the starting inoculum that might or might not contain spontaneously resistant mutants (RMs). To delineate concentration-resistance relationships with linezolid-exposed Staphylococcus aureus, a mixed inoculum containing both susceptible cells and RMs was used. An RM selected after the 9th passage of the parent strain (MIC, 2 μg/ml) on antibiotic-containing media (RM9; MIC, 8 μg/ml) was chosen for the pharmacodynamic studies, because the mutant prevention concentration (MPC) of linezolid against the parent strain in the presence of RM9 at 102 (but not at 104) CFU/ml did not differ from the MPC value determined in the absence of the RMs. Five-day treatments with twice-daily linezolid doses were simulated at concentrations either between the MIC and MPC or above the MPC. S. aureus RMs (resistant to 2X and 4X MIC but not 8 X and 16X MIC) were enriched at ratios of the 24-h area under the concentrationtime curve (AUC24) to the MIC that provide linezolid concentrations between the MIC and MPC for 100% (AUC24/MIC, 60 h) and 86% (AUC24/MIC, 120 h) of the dosing interval. No such enrichment occurred when linezolid concentrations were above the MIC and below the MPC for a shorter time (37% of the dosing interval; AUC24/MIC, 240 h) or when concentrations were consistently above the MPC (AUC24/MIC, 480 h). These findings obtained using linezolid-susceptible staphylococci supplemented with RMs support the mutant selection window hypothesis. This method provides an option to delineate antibiotic concentrationresistance relationships with bacteria that exhibit low mutation frequencies. Copyright © 2015 American Society for Microbiology. All Rights Reserved. This study was supported by grants from Pfizer Inc., in part, from the Presidium of the Russian Academy of Sciences.

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