Lokales Erregerspektrum der sekundären Peritonitis und Besonderheiten der Pharmakokinetik von Ceftriaxon und Linezolid bei kritisch kranken Patienten

The common goal of these studies was optimizing antibiotic therapy for critically ill patients with secondary peritonitis. We focused on the pharmacokinetics of two common antibiotics, ceftriaxone and linezolid. The first study investigated the unbound concentrations of ceftriaxone in 20 ICU patients, treated with 2g daily, by a new ultrafiltration method and high-performance liquid chromatography (HPLC). All but one patient showed concentrations in published therapeutic ranges. Compared to healthy volunteers, the unbound fraction was higher in ICU patients. The highest fractions were found in patients with renal impairment and/or severe hyperbilirubinemia. The clearance was linearly correlated with the estimated glomerular filtration rate. After all, protein binding of ceftriaxone does not seem to have high influence on the question whether standard dosing of ceftriaxone for ICU patients is appropriate or not. In the second study, plasma concentrations of linezolid were determined in 20 ICU patients treated with 600 mg twice daily. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (Cmin) were calculated and compared to published therapeutic ranges (AUC 200-400mg*h/L, Cmin 2-10mg/dl). Coadministration of inhibitors and inducers of cytochrome P450 and/or P-glycoprotein, which are suspected to influence pharmacokinetics of linezolid, was noted. Drug exposure was highly variable. Only a minority of patients had values within the target ranges. Coadministration of inhibitors was associated with a trend to higher drug-exposure. Patients treated with levothyroxine, an inductor of P-glycoprotein, showed exceedingly low drug exposure (AUC ~60 mg*h/L, Cmin < 0.4mg/L). In the third study antibiotic regimens for treatment of secondary peritonitis were investigated for their presumed activity. We defined the “spectrum adequacy rate” (SAR) as the probability that all relevant pathogens in one patient are covered by the used antibiotic regimen. Data from 242 patients (88 community acquired, 154 postoperative cases) were obtained retrospectively. Enterococci were isolated in 47.1% of all patients, followed by Eschericia coli (42.6%), other enterobacteriaceae (33.1%) and anaerobes (29.8%). The susceptibility rates and SAR were lower in postoperative cases. The following regimens yielded a SAR>95 % when Enterobacteriaceae only were considered: piperacillin/tazobactam+gentamicin, cefotaxim (equivalent to ceftriaxone, only for community acquired cases), cefotaxim+gentamicin, meropenem+gentamicin or tigecyclin+ciprofloxacin. When also enterococci were considered, all betalactam based regimens required combination with vancomycin or linezolid for a SAR>95%. These three studies showed, that there are population-specific particularities for both, pharmacokinetics and susceptibility of pathogens. This knowledge might be helpful in choosing an optimized antibiotic therapy.Das gemeinsame Ziel der vorliegenden Arbeiten war eine Optimierung antibiotischer Therapien kritisch kranker Patienten mit sekundärer Peritonitis. Der Fokus lag auf der Pharmakokinetik zweier gängiger Antibiotika, Ceftriaxon und Linezolid. Zum einen wurde bei 20 Intensivpatienten, unter Ceftriaxontherapie (2g täglich intravenös), die ungebundene Fraktion des Antibiotikums mittels Ultrafiltration und high-performance liquid chromatography (HPLC) bestimmt. Bei 19 Patienten zeigten sich Konzentrationen im publizierten sicher therapeutischen Bereich. Verglichen mit Proben gesunder Freiwilliger wurden generell höhere ungebundene Fraktionen gefunden. Die höchsten zeigten Patienten mit schwerer Niereninsuffizienz und/oder Hyperbilirubinämie. Die Clearance korrelierte gut mit der glomerulären Filtrationsrate. Die Proteinbindung von Ceftriaxon scheint somit eine untergeordnete Rolle für die Frage zu spielen, ob Standarddosen bei Intensivpatienten angemessen sind oder nicht. Zum anderen wurde bei 20 Intensivpatienten unter Linezolidtherapie (2x600 mg täglich intravenös) die totalen und ungebundenen Medikamentenspiegel bestimmt. Als Maß für die Linezolidexposition wurden die area under the concentration-time curve (AUC) und die Tal-Konzentrationen (Cmin) berechnet und mit publizierten therapeutischen Bereichen (AUC 200-400mg*h/L, Cmin 2-10mg/dl) verglichen. Komedikationen mit Inhibitoren bzw. Induktoren des CYP450 und/oder P-Glycoprotein (P-gp) wurden berücksichtigt, da diese in Verdacht stehen die Pharmakokinetik (PK) von Linezolid zu beeinflussen. Es zeigte sich eine deutliche Streuung bei den Medikamentenspiegeln, nur 6 Patienten zeigten Werte im therapeutischen Zielbereich. Eine Komedikation mit Inhibitoren des CYP450 und/oder P-gp ging tendenziell mit höheren freien Medikamentenspiegeln einher, wohingegen Patienten unter Levothyroxin, einem Induktor des P-gp, auffällig niedrige Werte boten (AUC ~60 mg*h/L, Cmin < 0.4mg/L). In der dritten Arbeit wurde die prinzipielle Wirksamkeit antibiotischer Regime bei der Therapie von sekundären Peritonitiden untersucht. Als „spectrum adequacy rate“ (SAR) wurde die Wahrscheinlichkeit, alle bei einem Patienten nachgewiesenen relevanten Erreger durch ein angewandtes Antibiotikaregime abzudecken, definiert. Retrospektiv wurden die Daten von 242 Patienten (88 mit ambulant erworbener und 154 mit postoperativer Peritonitis) ausgewertet. In 47.1% der Fälle wurden Enterokokken isoliert, gefolgt von Escherichia coli (42.6%), anderen Enterobacteriaceae (33.1%), Anaerobiern (29.8%). Bei postoperativen Peritonitiden war sowohl die Sensibilität allgemein als auch die SAR geringer. Wurden nur Enterobacteriaceae berücksichtigt, lieferten folgende Therapieregime eine SAR >95%: Piperacillin/Tazobactam+Gentamicin, Cefotaxim (äquivalent zu Ceftriaxon; nur bei ambulant erworbenen Fällen), Cefotaxim+Gentamicin, Meropenem+Gentamicin oder Tigecyclin+Ciprofloxacin. Wurden zudem noch Enterokokken berücksichtigt, war für Therapieregime die auf Betalaktamantibiotika basierten eine Kombination mit Vancomycin oder Linezolid nötig um eine SAR >95% zu erzielen. Es konnte gezeigt werden, dass sowohl bei der Pharmakokinetik als auch bei Häufigkeit und Sensibilität relevanter Pathogene populationsspezifische Unterschiede bestehen, deren Kenntnis für eine optimierte Antibiotikatherapie hilfreich sein kann

Enabling Quality-oriented Process Development for sulfidic All-Solid-State Battery Cathodes

After major advances in material research throughout recent years, the industrialization of all-solid-state batteries now depends on the development of cost-effective production technology for novel materials and components. To enable a fast production scale-up and complex process interdependency handling, production engineering needs a quantitative evaluation and comparison approach for manufacturing strategies and process parameter settings. To address this challenge, we derive microstructural quality criteria from specifications at the product-level such as driving range and charging speed of battery electric vehicles. These range from porosity and agglomerate density on a macroscopic level to microscopic properties such as pore size distribution and particle contacts. By listing comprehensive characterization methods, the work enables engineers to efficiently evaluate these criteria. Experimentally applying the proposed approach, the influence of different mixing process parameters is analyzed. Thereby, sulfidic composite cathodes manufactured in a scalable procedure are used as samples

Adaptive Equalization and Capacity Analysis for Amplify-and-Forward Relays

Recent research has shown that multiple-input multiple-output (MIMO) systems provide high spectral efficiencies and error performance gains. However, the use of multiple antennas in mobile terminals may not be very practical. Certainly there is limited space and other implementation issues which make this a challenging problem. Therefore, to harness the diversity gains afforded by MIMO transmitter diversity techniques, while maintaining a minimal number of antennas on each handset, cooperative diversity techniques have been proposed. In addition, attention has also been given to combining wireless relaying systems with MIMO techniques to improve capacity, coverage, and obtain better diversity at the expense of increased node complexity. This thesis considers the design and analysis of cooperative diversity systems and MIMO amplify-and-forward relaying systems. In particular, we investigate adaptive time- and frequency-domain equalization techniques for cooperative diversity systems using space-time block codes (STBC). For MIMO relaying systems, we analyze the ergodic capacity of various systems and compare different amplify-and-forward methods in terms of system capacity performance. We propose a new block time-domain adaptive equalization structure for time reversal-space time block coding (TR-STBC) systems, which eliminates the separate decoder and also the need for explicit channel state information (CSI) estimation at the receiver. Our simulation results show that the time-domain adaptive block equalizer performs better than the frequency-domain counterpart but at the cost of increased complexity. Then, we extend this time-domain adaptive equalization scheme to distributed TR-STBC systems. We also develop a frequency-domain counterpart for the distributed systems. Our simulation results show that the adaptive algorithms work well for Protocols I and III proposed by Nabar et al. The time-domain adaptive algorithms perform better than the frequency-domain algorithms, and overall the Protocol I receivers outperform the Protocol III receivers. We also show that, if only the Protocol III receiver is used, it can be susceptible to noise amplification due to a weaker source-to-relay link compared to the relay-to-destination link. This problem can be mitigated by using the Protocol I receivers with some extra complexity but much superior diversity performance. We also present an ergodic capacity analysis of an amplify-and-forward (AF) MIMO two-hop system including the direct link and validate the analysis with simulations. We show that having the direct link improves the capacity due to diversity and quantify this improvement. We also present an ergodic capacity analysis of an AF MIMO two-hop, two relay system. Our results verify the capacity gain of relaying systems with two relays due to the extra diversity compared to a single relaying system. However, the results also show that when one of the source-to-relay links has a markedly higher SNR compared to the other, a single relay system has better capacity than a two relay system. Finally, we compare three types of relay amplification methods: a) average amplification, b) instantaneous channel amplification, and c) instantaneous power amplification. The instantaneous power amplification method has a higher mean capacity but with a higher variance. Also, it requires additional information at the destination and would create enormous overheads compared to the other methods. We also find that the instantaneous channel amplification method has almost no advantage in terms of the mean capacity but its capacity is less variable than the average amplification method. On the other hand, the average amplification method is simpler to implement as it does not require channel estimation at the relaying terminal

Framework for the Application of Industry 4.0 in Lithium-Ion Battery Cell Production

The application of Industry 4.0 in lithium-ion battery cell production enables companies to achieve increased product quality and global competitiveness, since the majority of value creation takes place in this process. Studies have shown, that improving production performance is the most effective way for battery cell manufacturers to become competitive in the increasingly globalized market. To achieve operational excellence, battery manufacturers must adopt the concepts of networked and digitized production. However, holistically introducing digitalization, data systems and Industry 4.0 methods in all sectors of lithium-ion battery cell production currently poses a major challenge as comprehensive approaches are not available. Therefore, a tailored methodology for the evaluation of suitability and introduction of digitalization and Industry 4.0 is presented. The approach addresses all production-related sectors from logistics to plant engineering to quality management via so called application areas. Multiple development stages divide these into the maturity levels in terms of Industry 4.0. To design each application area and stage, Industry 4.0 use cases from battery cell producers, plant manufacturers, and battery-related research projects are clustered and abstracted for general accessibility. It is shown, that abstracted application areas may be assigned either to all production sectors such as communication or to specific fields such as quality methods. Based on the application areas, corresponding toolboxes are established forming the core of a digitalization guide. To increase the level of maturity with regard to Industry 4.0, the presented paper aims at enabling companies to apply appropriate tools from the toolbox to their production. The systematic and efficient development and implementation of digitalization as well as the holistic assessment of a company's maturity are enabled and provide an essential tool towards increased competitiveness

Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial

AIMS: Various beta-blockers with distinct pharmacological profiles are approved in heart failure, yet they remain underused and underdosed. Although potentially of major public health importance, whether one agent is superior in terms of tolerability and optimal dosing has not been investigated. The aim of this study was therefore to compare the tolerability and clinical effects of two proven beta-blockers in elderly patients with heart failure. METHODS AND RESULTS: We performed a double-blind superiority trial of bisoprolol vs. carvedilol in 883 elderly heart failure patients with reduced or preserved left ventricular ejection fraction in 41 European centres. The primary endpoint was tolerability, defined as reaching and maintaining guideline-recommended target doses after 12 weeks treatment. Adverse events and clinical parameters of patient status were secondary endpoints. None of the beta-blockers was superior with regards to tolerability: 24% [95% confidence interval (CI) 20-28] of patients in the bisoprolol arm and 25% (95% CI 21-29) of patients in the carvedilol arm achieved the primary endpoint (P= 0.64). The use of bisoprolol resulted in greater reduction of heart rate (adjusted mean difference 2.1 b.p.m., 95% CI 0.5-3.6, P= 0.008) and more, dose-limiting, bradycardic adverse events (16 vs. 11%; P= 0.02). The use of carvedilol led to a reduction of forced expiratory volume (adjusted mean difference 50 mL, 95% CI 4-95, P= 0.03) and more, non-dose-limiting, pulmonary adverse events (10 vs. 4%; P < 0.001). CONCLUSION: Overall tolerability to target doses was comparable. The pattern of intolerance, however, was different: bradycardia occurred more often in the bisoprolol group, whereas pulmonary adverse events occurred more often in the carvedilol group. This study is registered with controlled-trials.com, number ISRCTN34827306