BACKGROUND: In critical care patients, reaching optimal β-lactam concentrations poses challenges, as infections are caused more often by microorganisms associated with higher MICs, and critically ill patients typically have an unpredictable pharmacokinetic/pharmacodynamic profile. Conventional intermittent dosing frequently yields inadequate drug concentrations, while continuous dosing might result in better target attainment. Few studies address cefotaxime concentrations in this population.OBJECTIVES: To assess total and unbound serum levels of cefotaxime and an active metabolite, desacetylcefotaxime, in critically ill patients treated with either continuously or intermittently dosed cefotaxime.METHODS: Adult critical care patients with indication for treatment with cefotaxime were randomized to treatment with either intermittent dosing (1 g every 6 h) or continuous dosing (4 g/24 h, after a loading dose of 1 g). We defined a preset target of reaching and maintaining a total cefotaxime concentration of 4 mg/L from 1 h after start of treatment. CCMO trial registration number NL50809.042.14, Clinicaltrials.gov NCT02560207.RESULTS: Twenty-nine and 30 patients, respectively, were included in the continuous dosing group and the intermittent dosing group. A total of 642 samples were available for analysis. In the continuous dosing arm, 89.3% met our preset target, compared with 50% in the intermittent dosing arm. Patients not reaching this target had a significantly higher creatinine clearance on the day of admission.CONCLUSIONS: These results support the application of a continuous dosing strategy of β-lactams in critical care patients and the practice of therapeutic drug monitoring in a subset of patients with higher renal clearance and need for prolonged treatment for further optimization, where using total cefotaxime concentrations should suffice.
Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.
MULTIFILE
With a market demand for low cost, easy to produce, flexible and portable applications in healthcare, energy, biomedical or electronics markets, large research programs are initiated to develop new technologies to provide this demand with new innovative ideas. One of these fast developing technologies is organic printed electronics. As the term printed electronics implies, functional materials are printed via, e.g. inkjet, flexo or gravure printing techniques, on to a substrate material. Applications are, among others, organic light emitting diodes (OLED), sensors and Lab-on-a-chip devices. For all these applications, in some way, the interaction of fluids with the substrate is of great importance. The most used substrate materials for these low-cost devices are (coated) paper or plastic. Plastic substrates have a relatively low surface energy which frequently leads to poor wetting and/or poor adhesion of the fluids on the substrates during printing and/ or post-processing. Plasma technology has had a long history in treating materials in order to improve wetting or promote adhesion. The µPlasma patterning tool described in this thesis combines a digital inkjet printing platform with an atmospheric dielectric barrier discharge plasma tool. Thus enabling selective and local plasma treatment, at atmospheric pressure, of substrates without the use of any masking materials. In this thesis, we show that dependent on the gas composition the substrate surface can either be functionalized, thus increasing its surface energy, or material can be deposited on the surface, lowering its surface energy. Through XPS and ATR-FTIR analysis of the treated (polymer) substrate surfaces, chemical modification of the surface structure was confirmed. The chemical modification and wetting properties of the treated substrates remained present for at least one month after storage. Localized changes in wettability through µPlasma patterning were obtained with a resolution of 300µm. Next to the control of wettability of an ink on a substrate in printed electronics is the interaction of ink droplets with themselves of importance. In printing applications, coalescence of droplets is standard practice as consecutive droplets are printed onto, or close to each other. Understanding the behaviour of these droplets upon coalescence is therefore important, especially when the ink droplets are of different composition and/or volume. For droplets of equal volume, it was found that dye transport across the coalescence bridge could be fully described by diffusion only. This is as expected, as due to the droplet symmetry on either side of the bridge, the convective flows towards the bridge are of equal size but opposite in direction. For droplets of unequal volume, the symmetry across the bridge is no longer present. Experimental analysis of these merging droplets show that in the early stages of coalescence a convective flow from the small to large droplet is present. Also, a smaller convective flow of shorter duration from the large into the small droplet was identified. The origin of this flow might be due to the presence of vortices along the interface of the bridge, due to the strong transverse flow to open the bridge. To conclude, three potential applications were showcased. In the first application we used µPlasma patterning to create hydrophilic patterns on hydrophobic dodecyl-trichlorosilane (DTS) covered glass. Capillaries for a Lab-on-a-chip device were successfully created by placing two µPlasma patterned glass slides on top of each other separated by scotch tape. In the second application we showcased the production of a RFID tag via inkjet printing. Functional RFID-tags on paper were created via inkjet printing of silver nanoparticle ink connected to an integrated circuit. The optimal operating frequency of the produced tags is in the range of 860-865 MHz, making them usable for the European market, although the small working range of 1 m needs further improvement. Lastly, we showed the production of a chemresistor based gas sensor. In house synthesised polyemeraldine salt (PANi) was coated by hand on top of inkjet printed silver electrodes. The sensor proved to be equally sensitive to ethanol and water vapour, reducing its selectivity in detecting changes in gas composition.
