Research Area A - Risk Assessment and Sepsis Control
After decades of sobering research in sepsis we have to admit that there is no “magic bullet” for treatment of sepsis and hence mortality in patients with septic shock is still unacceptably high. Therefore we have to rethink our strategy and place stronger focus on prevention.
For example, in the largest and only representative nationwide epidemiological study so far, from the German SepNet, underlying healthcare-associated infections accounted for 57% of the 75,000 severe sepsis cases treated annually in German intensive care units and hospital mortality was between 55-60% in these patients. Healthcare-associated infections are infections that patients acquire while receiving treatment for medical or surgical conditions. In Germany approximately 5-10% of hospitalized patients develop a healthcare-associated infection during their hospital stay, equating 400,000 - 600,000 cases annually. Hitherto, there has been a lack of pragmatic, but rigorous and well-designed studies investigating the effectiveness of hospital-wide infection control programs to prevent severe healthcare-associated infections frequently associated with sepsis. The overarching objective of the trial Alerts is to demonstrate the feasibility of an institutional program to reduce these infections and associated sepsis. Beyond reducing the incidence of sepsis in improving infection prevention, a better understanding of patient-centered, easily identifiable risk factors for early recognition of patients at high risk of sepsis might lead to an innovative approach for sepsis prevention. In this spirit, in project CNV the impact of the copy number variants of two human genes on sepsis is under investigation. Project Peiras attends to determine predictive physiological parameters indicating sepsis outcome. To find correlations and predictive parameters of infectious complications due to obstructive sleep apnea (OSA) and stroke-induced immunosuppression are the aims of observational studies Osarst and Pred-Sep, respectively. In project Anti-biofilm natural metabolites are searched that are able to eradicate existing biofilms that commonly occur on devices and catheters and may induce severe sepsis.
Studies and Projects in Research Area A
Alerts
Effectiveness of a Hospital-wide Educational Programme for Infection Control to Reduce the Rate of Health-Care Associated Infections and related Sepsis (clinical trial)
S. Hagel, F. Brunkhorst
Anti-biofilm
Screening for bio-active and anti-biofilm substances of Bacillus and Paenibacillus species
Acronym: Anti-biofilm
Principal Investigator: Mareike Klinger
Scientific Advisors: Prof. Dr. Mathias Pletz, Dr. Oliwia Makarewicz
Research Area: A Risk Assessment and Sepsis Control
Project Number: A5.1
Duration: 16.09.2011 - 15.09.2014
Module: PhD Fellowship
The Problem
It is suggested that biofilms, sessile and matrix-enclosed communities of bacteria on catheters, devices or tissues, are presented in more than 65 % of all bacterial infections. Biofilms show increased antibiotic tolerance and protection against immune defense thus they are hardly eradicable. The aim of our project is to screen for substances produced by environmental, soil living bacteria exhibiting anti-biofilm activity and to analyze the chemical properties of these compounds.
Results so far
In total, we harvested supernatants of 10 Gram-positive strains (B. amyloliquefaciens (n=5), B. pumilus (n=1), B. licheniformis (n=1) and P. polymyxa (n=3)) cultured under different conditions after 24 hours and 48 hours and performed disc diffusion tests on agar plates treated with multi-drug resistant isolates (E. coli (n=3), K. pneumoniae (n=2), P. auruginosa (n=4), S. aureus (n=3), E. faecalis (n=2) and P. mirabilis (n=1)). We found some supernatants with high activities against human pathogen bacteria. These supernatants were separated by thin-layer chromatography and analyzed using bioautography against the pathogenic indicator strains. Here we found some distinct bands that were highly active against specific bacteria (data not shown). The Gram-positive strains produce bio-active compounds only under distinct conditions and during defined growth phase, thus we are now able to scale up the production of the compounds of interest under optimal conditions. Three of the obtained total supernatants effectively eradicated existing biofilms. Thereby best results were obtained using all three supernatants on biofilms of S. epidermidis. Supernatant of B. licheniformis was also effective against biofilms of E. feacalis and S. aureus MSSA. Supernatant of B. amyloliquefaciens FZB42 suffciently eradicated biofilms of P. aeruginosa PA01 and K. pneumoniae. The active compounds of the supernatants have been extracted by organic solvents and will be now analyzed by LC-MS.
Publications
Sobke A, Klinger M, Hermann B, Sachse S, Nietzsche S, Makarewicz O, Keller PM, Pfister W, Straube E. The urinary antibiotic 5-nitro-8-hydroxyquinoline (nitroxoline) reduces the formation and induces the dispersal of Pseudomonas aeruginosa biofilms by chelation of iron and zinc. Antimicrob Agents Chemother. 2012 Nov;56(11):6021-5. doi: 10.1128/AAC.01484-12
Mariappan A, Makarewicz O, Chen XH, Borriss R: Two-Component Response Regulator DegU Controls the Expression of Bacilysin in Plant-Growth-Promoting Bacterium Bacillus amyloliquefaciens FZB42. J Mol Microbiol Biotechnol. 2012 Jun 7, 22(2):114-125.
Contact
Tel.: +49 (0)3641 - 9 32 42 27
Institut für Infektionsmedizin und Krankenhaushygiene
Am Klinikum 1
07747 Jena
CNV-Sepsis (completed)
Impact of copy number variations within the defensin locus on 8p23 and the cystathionine beta synthase gene in human sepsis and sepsis complications
Acronym: CNV
Principal Investigator: Dr. med. Christoph Sponholz
Research Area: A Risk Assessment and Sepsis Control
Project Number: A3.1
Duration: 01.04.2011 - 31.03.2013
Module: Rotational Position
The Problem
The project represents a genetic association study, focussing on two different gene loci that may affect susceptibility and outcome of severe sepsis. In addition to single nucleotide polymorphisms (SNP), Copy number variations (CNV) may reflect a hitherto underestimated molecular mechanism affecting gene expression. While in the defensin locus on chromosome 8p23 a cluster of whole genes are involved by CNV´s, the CBS gene is only partially affected by CNV represented by a variable number of tandem repeats (VNTR) at the exon15-intron15 boundary. We therefore focus our investigation on these two gene loci, that have also been shown to have impact on infectious diseases.
Results so far
CNV in human beta-defensin cluster:
N=220 patients suffering from severe sepsis/septic shock were genotyped for CNV and SNPs within the beta-defensin gene cluster. Genotypes were compared to non-septic age and gender matched patients, resulting in a similar pattern of copy numbers and SNP distribution in both groups. Within further project ᴀow we aim to enlarge the number of affected patients to increase validity of our results.
CNV in human cystathionine-beta-synthase gene:
N=405 patients with severe sepsis/septic shock and n=405 age and gender matched controls were genotyped for the VNTR and hitherto non reported haplotypes of CBS. We found significant deviation of the VNTR length distribution towards longer CBS alleles in affected patients compared to non-septic controls. In both groups a similar pattern of haplotype distribution could be found, but septic patients showed a haplotype dependent difference in 28-survival.
Contact
Tel.: +49 (0)3641 - 9 32 22 25
Center for Sepsis Control and Care
Universitätsklinikum Jena
Am Klinikum 1
07747 Jena
Impact
Immune Response Against Mould Species in Patients With Acute Myeloid Leukaemia
M. von Lilienfeld-Toal
NuRe-demirCa (completed)
Nuclear Receptor-dependent modulation of the immune response induced by Candida albicans: Impact of Pattern Recognition Receptor transrepression
A. Hanisch, H. Slevogt
Osarst (completed)
Obstructive Sleep Apnea postoperative Risk Stratification Trial (clinical trial)
S. Rupprecht
Peiras (completed)
Response to Homeostatic Disturbance for Individualized Risk Assessment in Sepsis
Acronym: Peiras
Principal Investigator: Dr. phil. Maik Soßdorf
Research Area: A Risk Assessment and Sepsis Control
Project Number: A1.2
Duration: 01.05.2011 - 30.04.2013
Module: Start-up Scientist
The Problem
The loss of homeostasis is a crucial event during sepsis and associated with a poor prognosis. Strenuous physical exercise is considered as an effective physiological tool to test the body’s homeostatic control systems. The project aims to identify predictive parameters for outcome in sepsis after a single bout of strenuous exercise.
Results so far
We established a rat exercise model and defined a cut-off lactate concentration value as inevitable study inclusion criteria. We showed that a single bout of strenuous physical exercise provokes a pattern of distinct systemic changes (e.g. hyperthermia, leukopenia, and cytokine release) which are comparable to the sepsis-associated host response. Metabolic profiling of plasma samples revealed distinct clusters of exercise-induced and sepsis-related metabolic changes. As a consequence of the sepsis-associated inflammatory response accompanied by cell activation, apoptosis and necrosis the concentration of plasma phospholipids significantly discriminates between sepsis and exercise. Post exercise we identified several parameters with the potential to distinguish between survival and non-survival in sepsis. These parameters include concentration of cytokines, metabolites from different compound classes and blood gas parameters.
Publications
Otto GP, Wissuwa B, Mehnert A, Marx S, Raessler M, Lösche W, Claus RA, Sossdorf M: A method for detection and quantification of hydroxyethyl starch in plasma, Critical Care 2012, 16:426
Otto GP, Neugebauer S, Claus RA, Sossdorf M. Arginine metabolism is markedly impaired in polymicrobial infected mice. Crit Care. 2012, 16(2):412.
Sossdorf M, Fischer J, Meyer S, Dahlke K, Wissuwa B, Lupp A, Kiehntopf M, Otto GP. Physical excercise influences the host response and mortality rate in polymicrobial infected mice. 5th International Congress “Sepsis and Multiorgan Dysfunction”, Weimar Sepsis Update 2011 - Bridging the Gap Weimar, 07. - 10. September 2011
Sossdorf M, Otto GP, Fischer J, Meyer S, Claus RA, Bauer M, Loesche W. Endurance training improves survival rate in an experimental model of polymicrobial sepsis. XIV Congress of the European Shock Society, Taormina, Giardini Naxos, August 31, September 2, 2011
Contact
Tel. +49 (0)3641 - 9 32 58 67
Center for Sepsis Control and Care
Universitätsklinikum Jena
Forschungszentrum Lobeda
Am Klinikum 1
07747 Jena
Pred-Sep
Predictors of Sepsis - Assessment of brain induced immunodepression by markers of autonomic control (clinical trial)
Acronym: Pred-Sep
Principal Investigator: Dr. med. Dirk Brämer
Team: Samuel Nowack
Project Number: A4.2
Duration: 01.07.2011 - 30.06.2014
Module: Rotational position
The Problem
Our main hypothesis is that stroke-induced post-acute infections can be predicted from HRV parameters of the acute stroke phase (primary end point). Furthermore, we investigate if SIRS, severe sepsis and the functional outcome can be predicted from HRV parameters (secondary endpoints).
Publications
- Salzmann, D. Hoyer, S. Nowack, A. Günther, M. Schwab, R. Surber, H. Hoyer, O.W. Witte: Heart rate variability changes predict sub-acute post-stroke infections, Weimar Sepsis Update 2011, September 2011.
- Hoyer, S. Nowack, I. Salzmann, A. Günther, M. Schwab, R. Surber, H. Hoyer, O.W. Witte: Reduced fractal short term scaling exponent of heart rate pattern - an early marker of sub-acute post-stroke infections, 10. Conference on Complexity in Acute Illness (ICCAI), Bonn, September 2011.
Contact
Tel. +49 (0)3641 - 9 32 34 91
Universitätsklinikum Jena
Hans-Berger-Klinik für Neurologie
Am Klinikum 1
07747 Jena
Tel. +49 (0)3641 - 9 32 57 95
Universitätsklinikum Jena
Hans-Berger-Klinik für Neurologie
Biomagnetisches Zentrum
Am Klinikum 1
07747 Jena
SepsEXOME
High-throughput DNA sequencing to identify rare host variants in bacterial sepsis
S. Taudien
SepsiMet
Sepsis and metabolic alterations
A. Scherag
TRAFFIC
The role of TRAF6 in modulating monocytic immune responses and mediating infections in cirrhosis
T. Bruns