@article{WaltherGonzalesGroegeretal.2022, author = {Walther, Kay-Arne and Gonzales, Jos{\´e} Roberto and Gr{\"o}ger, Sabine and Ehmke, Benjamin and Kaner, Dogan and Lorenz, Katrin and Eickholz, Peter and Kocher, Thomas and Kim, Ti-Sun and Schlagenhauf, Ulrich and Koch, Raphael and Meyle, J{\"o}rg}, title = {The role of polymorphisms at the Interleukin-1, Interleukin-4, GATA-3 and Cyclooxygenase-2 genes in non-surgical periodontal therapy}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {13}, issn = {1422-0067}, doi = {10.3390/ijms23137266}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284386}, year = {2022}, abstract = {Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression.}, language = {en} } @article{KoehlerHendricksKastneretal.2021, author = {K{\"o}hler, Franziska and Hendricks, Anne and Kastner, Carolin and M{\"u}ller, Sophie and Boerner, Kevin and Wagner, Johanna C. and Lock, Johan F. and Wiegering, Armin}, title = {Laparoscopic appendectomy versus antibiotic treatment for acute appendicitis-a systematic review}, series = {International Journal of Colorectal Disease}, volume = {36}, journal = {International Journal of Colorectal Disease}, number = {10}, issn = {1432-1262}, doi = {10.1007/s00384-021-03927-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266616}, pages = {2283-2286}, year = {2021}, abstract = {Background Over the last years, laparoscopic appendectomy has progressively replaced open appendectomy and become the current gold standard treatment for suspected, uncomplicated appendicitis. At the same time, though, it is an ongoing discussion that antibiotic therapy can be an equivalent treatment for patients with uncomplicated appendicitis. The aim of this systematic review was to determine the safety and efficacy of antibiotic therapy and compare it to the laparoscopic appendectomy for acute, uncomplicated appendicitis. Methods The PubMed database, Embase database, and Cochrane library were scanned for studies comparing laparoscopic appendectomy with antibiotic treatment. Two independent reviewers performed the study selection and data extraction. The primary endpoint was defined as successful treatment of appendicitis. Secondary endpoints were pain intensity, duration of hospitalization, absence from work, and incidence of complications. Results No studies were found that exclusively compared laparoscopic appendectomy with antibiotic treatment for acute, uncomplicated appendicitis. Conclusions To date, there are no studies comparing antibiotic treatment to laparoscopic appendectomy for patients with acute uncomplicated appendicitis, thus emphasizing the lack of evidence and need for further investigation.}, language = {en} } @article{MuehlbergUmstaetterDomhanetal.2020, author = {M{\"u}hlberg, Eric and Umst{\"a}tter, Florian and Domhan, Cornelius and Hertlein, Tobias and Ohlsen, Knut and Krause, Andreas and Kleist, Christian and Beijer, Barbro and Zimmermann, Stefan and Haberkorn, Uwe and Mier, Walter and Uhl, Philipp}, title = {Vancomycin-lipopeptide conjugates with high antimicrobial activity on vancomycin-resistant enterococci}, series = {Pharmaceuticals}, volume = {13}, journal = {Pharmaceuticals}, number = {6}, issn = {1424-8247}, doi = {10.3390/ph13060110}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205879}, year = {2020}, abstract = {Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure-activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria.}, language = {en} } @article{BarthelsMarincolaMarciniaketal.2020, author = {Barthels, Fabian and Marincola, Gabriella and Marciniak, Tessa and Konh{\"a}user, Matthias and Hammerschmidt, Stefan and Bierlmeier, Jan and Distler, Ute and Wich, Peter R. and Tenzer, Stefan and Schwarzer, Dirk and Ziebuhr, Wilma and Schirmeister, Tanja}, title = {Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A}, series = {ChemMedChem}, volume = {15}, journal = {ChemMedChem}, number = {10}, doi = {10.1002/cmdc.201900687}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214581}, pages = {839 -- 850}, year = {2020}, abstract = {Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with drug-resistant strains being responsible for tens of thousands of deaths per year. S. aureus sortase A inhibitors are designed to interfere with virulence determinants. We have identified disulfanylbenzamides as a new class of potent inhibitors against sortase A that act by covalent modification of the active-site cysteine. A broad series of derivatives were synthesized to derive structure-activity relationships (SAR). In vitro and in silico methods allowed the experimentally observed binding affinities and selectivities to be rationalized. The most active compounds were found to have single-digit micromolar Ki values and caused up to a 66 \% reduction of S. aureus fibrinogen attachment at an effective inhibitor concentration of 10 μM. This new molecule class exhibited minimal cytotoxicity, low bacterial growth inhibition and impaired sortase-mediated adherence of S. aureus cells.}, language = {en} } @article{UmstaetterDomhanHertleinetal.2020, author = {Umst{\"a}tter, Florian and Domhan, Cornelius and Hertlein, Tobias and Ohlsen, Knut and M{\"u}hlberg, Eric and Kleist, Christian and Zimmermann, Stefan and Beijer, Barbro and Klika, Karel D. and Haberkorn, Uwe and Mier, Walter and Uhl, Philipp}, title = {Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides}, series = {Angewandte Chemie International Edition}, volume = {59}, journal = {Angewandte Chemie International Edition}, number = {23}, doi = {10.1002/anie.202002727}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215550}, pages = {8823 -- 8827}, year = {2020}, abstract = {Multidrug-resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site-specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000-fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d-Ala-d-Ala revealed a mode of action beyond inhibition of cell-wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics.}, language = {en} } @phdthesis{Munz2019, author = {Munz, Martin Reinhold}, title = {Individualization of drug therapy considering pharmacokinetic and clinical factors}, doi = {10.25972/OPUS-17339}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173396}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {In the „Position Paper of the Division of Clinical Pharmacy of the German Pharmaceutical Society (DPhG)" clinical pharmacy is defined as the science and practice of the rational use of drugs1, which includes the individualization of drug therapy. Clinical pharmacists therefore need a profound knowledge of the pharmacokinetic properties of relevant drugs, and clinical factors that are influencing these properties. Against the background of individualizing drug therapy, pharmacokinetic and clinical factors are studied in this thesis. In order to obtain an overview of the existing data on the pharmacokinetics of imipenem / cilastatin and meropenem in critically ill patients, a literature review for each of these carbapenem antibiotics was performed. These reviews included studies in critically ill patients as well as studies in healthy volunteers. While the reported results of studies in healthy volunteers had a small variability, studies in critically ill patients show significant differences in the resulting pharmacokinetics. These differences were not only between, but also within these studies, resulting in a high variability of the pharmacokinetic parameters of the carbapenems in critically ill patients. Furthermore, the results of studies in critically ill patients indicate that clinical factors and in particular renal function have different effects on the pharmacokinetics of imipenem and cilastatin. A therapeutic drug monitoring (TDM) program for antibiotics was initiated in an intensive care unit. The calculation of the pharmacokinetics of imipenem / cilastatin and meropenem was carried out with a population pharmacokinetic approach (POP-PK) and in addition with a non-compartmental approach (NCA). The POP-PK analysis showed that the pharmacokinetics of imipenem and cilastatin could be described adequately with a 1-compartment model. The resulting mean total body clearance (CL) of imipenem and cilastatin was 11.6 L/h (4.24 to 27.5) and 6.14 L/h (0.520 to 26.6 L/h). The nonrenal clearance was estimated to be 5.30 L / h (24.9\% CV) for imipenem and 0.138 L / h (33.3\% CV) for cilastatin. The results of the NCA were in good agreement with the results of the POP-PK approach, as the NCA resulted in an imipenem clearance of 15.5 ± 7.3 L / hr and cilastatin clearance of 10.1 ± 9.9 L / h. The individual clearances resulting from the different pharmacokinetic approaches were in good correlation showing correlation coefficients (r) of 0.882 (p <0.001) and 0.908 (p <0.001) for imipenem and cilastatin. In summary, this study identified and quantified significant differences between the individual clearance mechanisms of imipenem and cilastatin. This is particularly true for patients with impaired renal function and sepsis. As imipenem / cilastatin is only available in a fixed dose combination, those patients might be treated inadequately with this combination. The great variability in the pharmacokinetics of imipenem and cilastatin in septic patients underscores the importance of a TDM program of both substances. For meropenem, a PK/PD model was developed that predicts the concentration gradients of meropenem, serum creatinine, C-reactive protein and procalcitonin simultaneously. A non-linear relationship between the clearance of creatinine and meropenem was identified and the resulting equation for the calculation of the total body clearance of meropenem (for a 70 kg patient) was: 0.480 L/h + 9.86 L/h. (CLCR/6L/h)0.593, with 0.480 L/h representing the nonrenal clearance of meropenem. The resulting mean meropenem clearance of the NCA was 11.9 ± 8.7 L/h. The individual clearances resulting from the different pharmacokinetic approaches were poorly correlated showing a correlation coefficient (r) of 0.502 (p <0.001). In summary, this study showed a non-linear relationship of meropenem clearance and creatinine clearance. The model shows that the renal function may change rapidly and to a significant extent in patients with sepsis and septic shock, which in turn, underscores that creatinine concentrations are not in steady state in these patients. Conversely, dose adjustment based on creatinine values might lead to inappropriate therapy. This underlines the importance of a TDM program for meropenem in critically ill patients. The two most important considerations when choosing an antibiotic for the prophylaxis of postoperative bone infections are its activity against the whole spectrum of bacteria, which might be involved in bone infections, and its ability to penetrate bone tissue and thus to achieve concentrations above the minimum inhibitory concentration (MIC) of the corresponding pathogens. In order to gain information on this data, a study was conducted which investigated the pharmacokinetics of ampicillin / sulbactam in plasma, cortical and cancellous bone. Pharmacokinetic parameters in plasma were determined using NCA. The bone penetration represents the ratio of the concentration in the bone tissue to plasma concentration at the time of bone removal. The resulting half-life of ampicillin and sulbactam in plasma was 1.60  0.37 h and 1.70  0.42 h. The elimination of both substances was in a good correlation with creatinine clearance and resulted in correlation coefficients (r) of 0.729 (p = 0.003) for ampicillin and 0.699 (p = 0.005) for sulbactam. The mean clearance and the mean volume of distribution of ampicillin and sulbactam were 10.7  3.9 and 10.3  3.3 L/h, and 23.9  7.9 and 24.3  6.8 L. The mean concentrations of ampicillin in the cortical and cancellous bone were 6.60  4.22 and 10.15  7.40 µg/g, resulting in bone penetration ratios of 9.1  5.7 and 16.2  16.9 \%. For sulbactam the corresponding concentrations were 3.91  2.52 and 5.73  4.20 µg/g, resulting in bone penetration ratios of 10.6  6.3 and 17.5  16.1 \%. In summary, this study shows that the bone penetration of both substances is on average rather unsatisfactory and has a high variability, which can lead to inadequate bone concentrations for the prophylaxis of bone infections. One factor that could be identified for the penetration of both substances into cancellous bone was the period between the application of the drug and the removal of the bone. Therefore, a time interval between the administration of the antibiotic and the incision should be considered. Immunosuppression is a risk factor for the development of various malignancies, including hematologic diseases. While the relationship between the use of immunosuppressive therapy with methotrexate and the development of an Epstein-Barr virus (EBV) associated lymphoproliferative disease (LPD) has been well established, this connection is less evident for immunosuppressive therapy with azathioprine. The patient presented by us was immunosuppressed with azathioprine for autoimmune hepatitis. The development of an EBV-associated Hodgkin-like lymphoma under this immunosuppressive therapy and especially the regression of the lymphoma after cessation of azathioprine confirms the relationship between this immunosuppressant, EBV-infection and the development of Hodgkin-like lymphoma. Therefore, albeit in rare cases, azathioprine-related lymphomas may respond to mere cessation of immunosuppressive therapy without need for chemotherapy. Apart from viral infections, drugs are a major cause of acute liver failure. Due to the lack of specific symptoms or tests, it is difficult to diagnose a drug-induced liver injury. We report a case of a young patient in whom different antibiotics, the analgesic and antipyretic acetaminophen or a combination of these drugs may have led to DILI resulting in life-threatening ALF. Based on this case report, we describe a procedure to exclude non-drug related causes and discuss the hepatotoxic potential of the involved drugs in this case.}, subject = {Pharmakokinetik}, language = {en} } @phdthesis{Rasheed2019, author = {Rasheed, Huma}, title = {Development of simple and cost-effective High Performance Liquid Chromatography methods for quality control of essential beta-lactam antibiotics in low- and middle-income countries}, doi = {10.25972/OPUS-17721}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177214}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Assay and impurity profiling of the pharmaceuticals are the key routine quality control methods employed worldwide for which High Performance Liquid Chromatography (HPLC) is the most widely used technique. The ability to carry out these routine laboratory procedures in low- and middle- income countries (LMICs) need the methods to be based upon simple instruments manageable with moderate levels of personnel skill and costs involved. Simple, convenient, and cost effective reverse phase HPLC methods were developed using phosphate buffer and methanol as mobile phase with C18 column as stationary phase for the impurity profiling and assay of beta lactam antibiotics. Isocratic elution and UV detection was employed in these methods. Impurity profiling method was developed for coamoxiclav tablets and ceftriaxone bulk drug. The method for ceftriaxone included a supplementary method to quantify one of its known impurity (Impurity D of ceftriaxone). This method involved use of acetonitrile where as the two main methods were achieved on the targeted method design, described above. With the exception of impurity A of ceftriaxone, the methods developed can successfully quantify impurities to the concentration as low as ≤0.05\%, which is in accordance with the current guidelines for the impurity profiling of antibiotics issued by European Medicines Agency. As ensuring cost reduction was one of the key objectives of carrying out the method development exercise, in situ methods for the preparation of impurities were also identified and some new methods were introduced. The stability of beta lactam antibiotics and the choice of solvent were given due attention during the process of method development revealing information on the presence of new impurities. Deacetyl cefotaxime and 2-mercaptobenzathiazole were identified in this process as new impurities of ceftriaxone currently not listed under known impurities by United States Pharmacopoeia and European Pharmacopoeia. However, deacetyl cefotaxime is a known impurity of cefotaxime whereas the latter molecule is a degradation product of one of the synthesis impurities of ceftriaxone. This substance is reported to be carcinogenic and is resolved using the supplementary method developed for ceftriaxone, hence making its detection and quantification possible. A known inactive impurity of ceftriaxone (Impurity A, E-isomer of ceftriaxone) was` also shown to be produced by exposure to day light, thus warranting the light protection of the ceftriaxone solution, an information that is of critical importance in the clinical settings. A series of experimentation was carried out on the finished products of beta lactam antibiotics sampled from Pakistan and few other countries, to identify key quality issues in the samples. Though the limited sample size and convenient sampling did not provide results that could yield a decisive figure for the country status for prevalence of substandard and falsified medical products, but the experiments have clearly indicated that the problems in drug quality do exist and beta lactam antibiotics form a class of high-risk medicine with respect to surveillance for poor-quality medicines. Isolation of unknown impurities was also carried out along with the introduction of new and modified methods for preparation of impurities of beta-lactam antibiotics. In addition, detailed literature survey was carried out for understanding the complex problem of the poor-quality medicine, impact of poor quality antimicrobials on health care system and the magnitude of the problem at the global level. The country status of Pakistan regarding quality of medicines was recorded based upon the available documentary evidence. The current technologies and strategic options available for low- and middle-income countries in aiding fight for combating poor quality medicines was also laid down to design recommendations for Pakistan. A comprehensive review of the information technology tools used for identification and control of substandard and falsified medicines was also conducted.}, subject = {HPLC}, language = {en} } @phdthesis{Reimer2017, author = {Reimer, Anastasija}, title = {Search for novel antimicrobials against \(Neisseria\) \(gonorrhoeae\) and \(Chlamydia\) \(trachomatis\)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143168}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {The obligate human pathogen Neisseria gonorrhoeae is responsible for the widespread sexually transmitted disease gonorrhoea, which in rare cases also leads to the development of disseminated gonococcal infection (DGI). DGI is mediated by PorBIA-expressing bacteria that invade host cells under low phosphate condition by interaction with the scavenger receptor-1 (SREC-I) expressed on the surface of endothelial cells. The interaction of PorBIA and SREC-I was analysed using different in vitro approaches, including surface plasmon resonance experiments that revealed a direct phosphate-independent high affinity interaction of SREC-I to PorBIA. However, the same binding affinity was also found for the other allele PorBIB, which indicates unspecific binding and suggests that the applied methods were unsuitable for this interaction analysis. Since N. gonorrhoeae was recently classified as a "super-bug" due to a rising number of antibiotic-resistant strains, this study aimed to discover inhibitors against the PorBIA-mediated invasion of N. gonorrhoeae. Additionally, inhibitors were searched against the human pathogen Chlamydia trachomatis, which causes sexually transmitted infections as well as infections of the upper inner eyelid. 68 compounds, including plant-derived small molecules, extracts or pure compounds of marine sponges or sponge-associated bacteria and pipecolic acid derivatives, were screened using an automated microscopy based approach. No active substances against N. gonorrhoeae could be identified, while seven highly antichlamydial compounds were detected. The pipecolic acid derivatives were synthesized as potential inhibitors of the virulence-associated "macrophage infectivity potentiator" (MIP), which exhibits a peptidyl prolyl cis-trans isomerase (PPIase) enzyme activity. This study investigated the role of C. trachomatis and N. gonorrhoeae MIP during infection. The two inhibitors PipN3 and PipN4 decreased the PPIase activity of recombinant chlamydial and neisserial MIP in a dose-dependent manner. Both compounds affected the chlamydial growth and development in epithelial cells. Furthermore, this work demonstrated the contribution of MIP to a prolonged survival of N. gonorrhoeae in the presence of neutrophils, which was significantly reduced in the presence of PipN3 and PipN4. SF2446A2 was one of the compounds that had a severe effect on the growth and development of C. trachomatis. The analysis of the mode of action of SF2446A2 revealed an inhibitory effect of the compound on the mitochondrial respiration and mitochondrial ATP production of the host cell. However, the chlamydial development was independent of proper functional mitochondria, which excluded the connection of the antichlamydial properties of SF2446A2 with its inhibition of the respiratory chain. Only the depletion of cellular ATP by blocking glycolysis and mitochondrial respiratory chain inhibited the chlamydial growth. A direct effect of SF2446A2 on C. trachomatis was assumed, since the growth of the bacteria N. gonorrhoeae and Staphylococcus aureus was also affected by the compound. In summary, this study identified the severe antichlamydial activity of plant-derived naphthoquinones and the compounds derived from marine sponges or sponge-associated bacteria SF2446A2, ageloline A and gelliusterol E. Furthermore, the work points out the importance of the MIP proteins during infection and presents pipecolic acid derivatives as novel antimicrobials against N. gonorrhoeae and C. trachomatis.}, subject = {Neisseria gonorrhoeae}, language = {en} } @article{RadakovicReboredoHelmetal.2017, author = {Radakovic, D. and Reboredo, J. and Helm, M. and Weigel, T. and Sch{\"u}rlein, S. and Kupczyk, E. and Leyh, R. G. and Walles, H. and Hansmann, J.}, title = {A multilayered electrospun graft as vascular access for hemodialysis}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {10}, doi = {10.1371/journal.pone.0185916}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159102}, pages = {e0185916}, year = {2017}, abstract = {Despite medical achievements, the number of patients with end-stage kidney disease keeps steadily raising, thereby entailing a high number of surgical and interventional procedures to establish and maintain arteriovenous vascular access for hemodialysis. Due to vascular disease, aneurysms or infection, the preferred access—an autogenous arteriovenous fistula—is not always available and appropriate. Moreover, when replacing small diameter blood vessels, synthetic vascular grafts possess well-known disadvantages. A continuous multilayered gradient electrospinning was used to produce vascular grafts made of collagen type I nanofibers on luminal and adventitial graft side, and poly-ɛ-caprolactone as medial layer. Therefore, a custom-made electrospinner with robust environmental control was developed. The morphology of electrospun grafts was characterized by scanning electron microscopy and measurement of mechanical properties. Human microvascular endothelial cells were cultured in the graft under static culture conditions and compared to cultures obtained from dynamic continuous flow bioreactors. Immunofluorescent analysis showed that endothelial cells form a continuous luminal layer and functional characteristics were confirmed by uptake of acetylated low-density-lipoprotein. Incorporation of vancomycin and gentamicin to the medial graft layer allowed antimicrobial inhibition without exhibiting an adverse impact on cell viability. Most striking a physiological hemocompatibility was achieved for the multilayered grafts.}, language = {en} } @article{HertleinSturmJakobetal.2013, author = {Hertlein, Tobias and Sturm, Volker and Jakob, Peter and Ohlsen, Knut}, title = {\(^{19}\)F Magnetic Resonance Imaging of Perfluorocarbons for the Evaluation of Response to Antibiotic Therapy in a Staphylococcus aureus Infection Model}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0064440}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130113}, pages = {e64440}, year = {2013}, abstract = {Background The emergence of antibiotic resistant bacteria in recent decades has highlighted the importance of developing new drugs to treat infections. However, in addition to the design of new drugs, the development of accurate preclinical testing methods is essential. In vivo imaging technologies such as bioluminescence imaging (BLI) or magnetic resonance imaging (MRI) are promising approaches. In a previous study, we showed the effectiveness of \(^{19}\)F MRI using perfluorocarbon (PFC) emulsions for detecting the site of Staphylococcus aureus infection. In the present follow-up study, we investigated the use of this method for in vivo visualization of the effects of antibiotic therapy. Methods/Principal findings Mice were infected with S. aureus Xen29 and treated with 0.9\% NaCl solution, vancomycin or linezolid. Mock treatment led to the highest bioluminescence values during infection followed by vancomycin treatment. Counting the number of colony-forming units (cfu) at 7 days post-infection (p.i.) showed the highest bacterial burden for the mock group and the lowest for the linezolid group. Administration of PFCs at day 2 p.i. led to the accumulation of \(^{19}\)F at the rim of the abscess in all mice (in the shape of a hollow sphere), and antibiotic treatment decreased the \(^{19}\)F signal intensity and volume. Linezolid showed the strongest effect. The BLI, cfu, and MRI results were comparable. Conclusions \(^{19}\)F-MRI with PFCs is an effective non-invasive method for assessing the effects of antibiotic therapy in vivo. This method does not depend on pathogen specific markers and can therefore be used to estimate the efficacy of antibacterial therapy against a broad range of clinically relevant pathogens, and to localize sites of infection.}, language = {en} }