Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis

Treatment of sepsis remains a significant challenge with persisting high mortality and morbidity. Early and appropriate antibacterial therapy remains an important intervention for such patients. To optimise antibacterial therapy, the clinician must possess knowledge of the pharmacokinetic and pharmacodynamic properties of commonly used antibacterials and how these parameters may be affected by the constellation of pathophysiological changes occurring during sepsis. Sepsis, and the treatment thereof, increases renal preload and, via capillary permeability, leads to 'third-spacing', both resulting in higher antibacterial clearances. Alternatively, sepsis can induce multiple organ dysfunction, including renal and/or hepatic dysfunction, causing a decrease in antibacterial clearance. Aminoglycosides are concentration-dependent antibacterials and they display an increased volume of distribution (V-d) in sepsis, resulting in decreased peak serum concentrations. Reduced clearance from renal dysfunction would increase the likelihood of toxicity. Individualised dosing using extended interval dosing, which maximises the peak serum drug concentration (C-max)/minimum inhibitory concentration ratio is recommended. beta-Lactams and carbapenems are time-dependent antibacterials. An increase in Vd and renal clearance will require increased dosing or administration by continuous infusion. If renal impairment occurs a corresponding dose reduction may be required. Vancomycin displays predominantly time-dependent pharmacodynamic properties and probably requires higher than conventionally recommended doses because of an increased V-d and clearance during sepsis without organ dysfunction. However, optimal dosing regimens remain unresolved. The poor penetration of vancomycin into solid organs may require alternative therapies when sepsis involves solid organs (e.g. lung). Ciprofloxacin displays largely concentration-dependent kill characteristics, but also exerts some time-dependent effects. The V-d of ciprofloxacin is not altered with fluid shifts or over time, and thus no alterations of standard doses are required unless renal dysfunction occurs. In order to optimise antibacterial regimens in patients with sepsis, the pathophysiological effects of systemic inflammatory response syndrome need consideration, in conjunction with knowledge of the different kill characteristics of the various antibacterial classes. In conclusion, certain antibacterials can have a very high V-d, therefore leading to a low C-max and if a high peak is needed, then this would lead to underdosing. The Vd of certain antibacterials, namely aminoglycosides and vancomycin, changes over time, which means dosing may need to be altered over time. Some patients with serum creatinine values within the normal range can have very high drug clearances, thereby producing low serum drug levels and again leading to underdosing. Copyright © 2010 Elsevier Inc. All rights reserved.

Continuous chromatographic biochemical reaction-separation

Combined bioreaction separation studies have been carried out for the first time on a moving port semi-continuous counter-current chromatographic reactor-separator (SCCR-S1) consisting of twelve 5.4cm id x 75cm long columns packed with calcium charged cross-linked polystyrene resin (KORELA V07C). The inversion of sucrose to glucose and fructose in the presence of the enzyme invertase and the biochemIcal synthesis of dextran and fructose from sucrose in the presence of the enzyme dextransucrase were investigated. A dilute stream of the appropriate enzyme in deionised water was used as the eluent stream. The effect of switch time, feed concentration, enzyme activity, eluent rate and enzyme to feed concentration ratio on the combined bioreaction-separation were investigated. For the invertase reaction, at 20.77% w/v sucrose feed concentrations complete conversions were achieved. The enzyme usage was 34% of the theoretical enzyme amount needed to convert an equivalent amount of sucrose over the same time period when using a conventional fermenter. The fructose rich (FRP) and glucose rich (GRP) product purities obtained were over 90%. By operating at 35% w/v sucrose feed concentration and employing the product splitting and recycling techniques, the total concentration and purity of the GRP increased from 32% w/v to 4.6% and from 92.3% to 95% respectively. The FRP concentration also increased from 1.82% w/v to 2.88% w/v. A mathematical model was developed for the combined reaction-separation and used to simulate the continuous inversion of sucrose and product separation using the SCCR-S1. In the biosynthesis of dextran studies, 52% conversion of a 2% w/v sucrose concentration feed was achieved. An average dextran molecular weight of 4 millIon was obtained in the dextran rich (DRP) product stream. The enzyme dextransucrase was purifed successfully using centrifugation and ultrafiltration techniques.

Electrografting of poly (carbazole-co-acrylamide) onto highly oriented pyroltic graphite. A cyclovoltammetric, atomic force microscopic and ellipsometric study

The electrocopolymerization of carbazole and acrylamide on highly oriented pyrolytic graphite (HOPG) from ACN solutions via cyclovoltammetry (CV) was studied in order to evaluate the possibility to deposit uniform and thin but pinhole-free and still reactive coatings onto graphite-like substrates. The morphology of the coatings was investigated using atomic force microscopy and the coating thicknesses and optical parameters were measured using ellipsometry. It was found that under the chosen conditions thin (coating thickness hf>180 nm) and relatively smooth (root mean square surface roughness RMS<150 nm) P(Cz-co-AAm)-coatings exhibiting a uniform globuoidal morphology can be deposited onto graphite. From a certain coating thickness (hf>50 nm) no pinholes could be detected. It was found that the thickness of the deposited coatings increases almost linearly with increasing number of CV-cycles while keeping all other experimental parameters (scan rate and comonomer concentration ratio) constant. No influence of the comonomer concentration ratio on the film thickness and coating appearance could be observed, however, at quite low initial concentrations. However, the CV-scanning rate has quite a significant influence on the thickness of the deposited coatings. Higher scan rates (100 mV/s) result in thin (hf≈22 nm) coatings whereas at lower scan rates (<50 mV/s) coatings with thicknesses of approximately 50 nm were obtained. The optical coating parameters (the refractive index n and extinction coefficient k) seem to be independent of the deposition parameters and therefore averaged values of n̄=1.54±0.03 and k̄=0.08±0.03 were obtained.

(Figure 2) Stratigraphic distribution of Schizosphaerella in DSDP Hole 79-547B

The Jurassic (hemi)pelagic continental margin deposits drilled at Hole 547B, off the Moroccan coast, reveal striking Tethyan affinity. Analogies concern not only types and gross vertical evolution of facies, but also composition and textures of the fine sediment and the pattern of diagenetic alteration. In this context, the occurrence of the nanno-organism Schizosphaerella Deflandre and Dangeard (sometimes as a conspicuous portion of the fine-grained carbonate fraction) is of particular interest. Schizosphaerella, an incertae sedis taxon, has been widely recorded as a sediment contributor from Tethyan Jurassic deeper-water carbonate facies exposed on land. Because of its extremely long range (Hettangian to early Kimmeridgian), the genus Schizosphaerella (two species currently described, S. punctulata Deflandre and Dangeard and S. astrea Moshkovitz) is obviously not of great biostratigraphic interest. However, it is of interest in sedimentology and petrology. Specifically, Schizosphaerella was often the only component of the initial fine-grained fraction of a sediment that was able to resist diagenetic obliteration. However, alteration of the original skeletal structure did occur to various degrees. Crystal habit and mineralogy of the fundamental skeletal elements, as well as their mode of mutual arrangement in the test wall with the implied high initial porosity of the skeleton (60-70%), appear to be responsible for this outstanding resistance. Moreover, the ability to concentrate within and, in the case of the species S. punctulata, around the skeleton, large amounts of diagenetic calcite also contributed to the resistance. In both species of Schizosphaerella, occlusion of the original skeletal void space during diagenesis appears to have proceeded in an analogous manner, with an initial slight uniform syntaxial enlargement of the basic lamellar skeletal crystallites followed, upon mutual impingement, by uneven accretion of overgrowth cement in the remaining skeletal voids. However, distinctive fabrics are evident according to the different primary test wall architecture. In S. punctulata, intraskeletal cementation is usually followed by the growth of a radially structured crust of bladed to fibrous calcite around the valves. These crusts are interpreted as a product of aggrading neomorphism, associated with mineralogic stabilization of the original, presumably polyphase, sediment. Data from Hole 547B, along with inferences, drawn from the fabric relationships, suggest that the crusts formed and (inferentially) mineralogic stabilization occurred at a relatively early time in the diagenetic history in the shallow burial realm. An enhanced rate of lithification at relatively shallow burial depths and thus the chance for neomorphism to significantly influence the textural evolution of the buried sediment may be related to a lower Mg/Ca concentration ratio in the oceanic system and, hence, in marine pore waters in pre-Late Jurassic times.

Seawater carbonate chemistry and hydrogen ions and carbonate chemistry in calcifying fluid of coral Astrangia poculata during experiments, 2011

A generalized physicochemical model of the response of marine organisms' calcifying fluids to CO2-induced ocean acidification is proposed. The model is based upon the hypothesis that some marine calcifiers induce calcification by elevating pH, and thus Omega aragonite, of their calcifying fluid by removing protons (H+). The model is explored through two end-member scenarios: one in which a fixed number of H+ is removed from their calcifying fluid, regardless of atmospheric pCO2, and another in which a fixed external-internal proton ratio ([H+]E/[H+]I) is maintained. The model is able to generate the full range of calcification response patterns observed in prior ocean acidification experiments and is consistent with the assertion that organisms' calcification response to ocean acidification is more negative for marine calcifiers that exert weaker control over their calcifying fluid pH. The model is empirically evaluated for the temperate scleractinian coral Astrangia poculata with in situ pH microelectrode measurements of the coral's calcifying fluid under control and acidified conditions. These measurements reveal that (1) the pH of the coral's calcifying fluid is substantially elevated relative to its external seawater under both control and acidified conditions, (2) the coral's [H+]E/[H+]I remains constant under control and acidified conditions, and (3) the coral removes fewer H+ from its calcifying fluid under acidified conditions than under control conditions. Thus, the carbonate system dynamics of A. poculata's calcifying fluid appear to be most consistent with the fixed [H+]E/[H+]I end-member scenario. Similar microelectrode experiments performed on additional taxa are required to assess the model's general applicability.

Seawater carbonate chemistry and trace element accumulation during experiments with common cuttlefish, Sepia officinalis, 2009

Cephalopods play a key role in many marine trophic networks and constitute alternative fisheries resources, especially given the ongoing decline in finfish stocks. Along the European coast, the eggs of the cuttlefish Sepia officinalis are characterized by an increasing permeability of the eggshell during development, which leads to selective accumulation of essential and non-essential elements in the embryo. Temperature and pH are two critical factors that affect the metabolism of marine organisms in the coastal shallow waters. In this study, we investigated the effects of pH and temperature through a crossed (3?2; pH 8.1 (pCO2, 400 ppm), 7.85 (900 ppm) and 7.6 (1400 ppm) at 16 and 19°C, respectively) laboratory experiment. Seawater pH showed a strong effect on the egg weight and non-significant impact on the weight of hatchlings at the end of development implying an egg swelling process and embryo growth disturbances. The lower the seawater pH, the more 110 mAg was accumulated in the tissues of hatchlings. The 109Cd concentration factor (CF) decreased with decreasing pH and 65Zn CF reached maximal values pH 7.85, independently of temperature. Our results suggest that pH and temperature affected both the permeability properties of the eggshell and embryonic metabolism. To the best of our knowledge, this is one of the first studies on the consequences of ocean acidification and ocean warming on metal uptake in marine organisms, and our results indicate the need to further evaluate the likely ecotoxicological impact of the global change on the early-life stages of the cuttlefish.

The role of glass modifiers in the solubility of Tm3+ ions in As2S3 glasses

Au cours des années une variété des compositions de verre chalcogénure a été étudiée en tant qu’une matrice hôte pour les ions Terres Rares (TR). Pourtant, l’obtention d’une matrice de verre avec une haute solubilité des ions TR et la fabrication d’une fibre chalcogénure dopée au TR avec une bonne qualité optique reste toujours un grand défi. La présente thèse de doctorat se concentre sur l’étude de nouveaux systèmes vitreux comme des matrices hôtes pour le dopage des ions TR, ce qui a permis d’obtenir des fibres optiques dopées au TR qui sont transparents dans l’IR proche et moyenne. Les systèmes vitreux étudiés ont été basés sur le verre de sulfure d’arsenic (As2S3) co-dopé aux ions de Tm3+ et aux différents modificateurs du verre. Premièrement, l’addition de Gallium (Ga), comme un co-dopant, a été examinée et son influence sur les propriétés d’émission des ions de Tm a été explorée. Avec l’incorporation de Ga, la matrice d’As2S3 dopée au Tm a montré trois bandes d’émission à 1.2 μm (1H5→3H6), 1.4 μm (3H4→3F4) et 1.8 μm (3F4→3H6), sous l’excitation des longueurs d’onde de 698 nm et 800 nm. Les concentrations de Tm et de Ga ont été optimisées afin d’obtenir le meilleur rendement possible de photoluminescence. À partir de la composition optimale, la fibre Ga-As-S dopée au Tm3+ a été étirée et ses propriétés de luminescence ont été étudiées. Un mécanisme de formation structurale a été proposé pour ce système vitreux par la caractérisation structurale des verres Ga-As-S dopés au Tm3+, en utilisant la spectroscopie Raman et l’analyse de spectrométrie d’absorption des rayons X (EXAFS) à seuil K d’As, seuil K de Ga et seuil L3 de Tm et il a été corrélé avec les caractéristiques de luminescence de Tm. Dans la deuxième partie, la modification des verres As2S3 dopés au Tm3+, avec l’incorporation d’halogénures (Iode (I2)), a été étudiée en tant qu’une méthode pour l’adaptation des paramètres du procédé de purification afin d’obtenir une matrice de verre de haute pureté par distillation chimique. Les trois bandes d’émission susmentionnées ont été aussi bien observées pour ce système sous l’excitation à 800 nm. Les propriétés optiques, thermiques et structurelles de ces systèmes vitreux ont été caractérisées expérimentalement en fonction de la concentration d’I2 et de Tm dans le verre, où l’attention a été concentrée sur deux aspects principaux: l’influence de la concentration d’I2 sur l’intensité d’émission de Tm et les mécanismes responsables pour l’augmentation de la solubilité des ions de Tm dans la matrice d’As2S3 avec l’addition I2.