Concentrations of Cefuroxime in Brain Tissue of Neurointensive Care Patients

ABSTRACT Effective concentrations of antibiotics in brain tissue are essential for antimicrobial therapy of brain infections. However, data concerning cerebral penetration properties of antibiotics for treatment or prophylaxis of central nervous system infections are rare. Six patients suffering subarachnoid hemorrhage and requiring cerebral microdialysis for neurochemical monitoring were included in this study. Free interstitial concentrations of cefuroxime after intravenous application of 1,500 mg were measured by microdialysis in brain tissue, as well as in plasma at steady-state (n = 6) or after single-dose administration (n = 1). At steady state, free area under the concentration-time curve from 0 to 24 h (AUC0–24) values of 389.0 ± 210.3 mg/liter·h and 131.4 ± 72.8 mg/liter·h were achieved for plasma and brain, respectively, resulting in a brain tissue penetration ratio (AUC0–24 brain/AUC0–24 free plasma) of 0.33 ± 0.1. Plasma and brain tissue concentrations at individual time points correlated well (R = 0.59, P = 0.001). At steady-state time over MIC (t>MIC) values of >40% of dosing interval were achieved up to an MIC of 16 mg/liter for plasma and 4 mg/liter for brain tissue. Although MIC90 values could not be achieved in brain tissue for relevant bacteria, current dosing strategies of cefuroxime might be sufficient to treat pathogens with MIC values up to 4 mg/liter. The activity of cefuroxime in brain tissue might be overestimated when relying exclusively on plasma levels. Although currently insufficient data after single dose administration exist, lower brain-plasma ratios observed after the first dose might warrant a loading dose for treatment and perioperative prophylaxis.

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

ABSTRACT Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 ± 12.1 μg · h/ml and 13.3 ± 3.5 μg · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor = 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CLlung) was added to the model for these animals (CLlung = 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

Imine-linked micron-network polymers with high polyethylene glycol uptake for shaped-stabilized phase change materials

Micron-network polymers with high free interstitial space show high adsorption of PEG (up to 85 wt%) for shape-stabilized phase change materials with high energy storage density.

Influence of Cooling Rate on Free Interstitial Concentration in Type 430 Ferritic Stainless Steel

In ferritic steels, the amount of free C and N should be as low as possible to avoid the formation of Cottrell atmospheres and their associated discontinuous yielding and Lüders bands during forming. During the post-annealing cooling of ferritic stainless steel, carbides and nitrides of the type MX and M23C6precipitate. The volume fraction of the precipitates is determined by chemical composition, microstructure and the cooling path. In some cases, precipitation might not be sufficient to remove all free interstitials from the matrix, in which case, the process parameters or composition of the steel should be reconsidered. Here, thermodynamic and kinetic calculations using Thermo-calc and TC Prisma software have been made to investigate the precipitation of C and N as a function of total interstitial content and cooling rate. According to the calculations, decreasing the cooling rate would result in a more efficient precipitation and hence, less free C and N in the matrix, but the amount is not sufficient to remove the upper yield point. Furthermore, changing the C and N content of the steel was found to have insignificant influence. However, the free C and N could possible be bound through a more complex cooling.

Intracoronary administration of FGF-2: a computational model of myocardial deposition and retention

This study uses a computational model to characterize the myocardial deposition and retention of basic fibroblast growth factor (FGF-2) at the cellular level after intracoronary (IC) administration of exogenous FGF-2. The model is applied to the in situ conditions present within the myocardium of a dog for which the plasma pharmacokinetics resulting from IC injection of FGF-2 were recorded. Our estimates show that the processes involved in FGF-2 signaling are not diffusion limited; rather, the response time is determined by the reaction time of FGF-2 binding to cell surface receptors. Additionally, the processes of receptor secretion and internalization are found to play crucial roles in the FGF-2 dynamics; future experiments are required to quantify these processes. The model predictions obtained in this study suggest that IC administration of FGF-2 via either a single bolus or repetitive injections causes a transient increase (time scale of hours) in myocardial FGF-2 concentration if the endogenous level of free interstitial FGF-2 is low enough to allow permeation of FGF-2 molecules from the microvascular to the interstitial spaces. The model shows that the majority (64%) of the extracellular FGF-2 ligands are located within the interstitium, and similar fractions are found in the basement membrane and extracellular matrix. Among the FGF-2 molecules found within the interstitium, 2% are free and 98% are bound to interstitial heparan sulfate proteoglycans. These results support the theory of extracellular control of the bioavailability of FGF-2 via dynamic storage of FGF-2 within the basement membrane and extracellular matrix.

Thermal Evolution of Extrinsic Defects in Ion Implanted Silicon: Current Understanding and Modelling

We present an extensive study of the thermal evolution of the extended defects found in ion implanted Si as a function of annealing conditions. We will first review their structure and energetics and show that the defect kinetics can be described by an Ostwald ripening process whereby the defects exchange Si atoms and evolve in size and type to minimise their formation energy. Finally, we will present a physically based model to predict the evolution of extrinsic defects during annealing through the calculation of defect densities, size distributions, number of clustered interstitials and free-interstitial supersaturation. We will show some successful applications of our model to a variety of experimental conditions and give an example of its predictive capabilities at ultra low implantation energies.

A Physically Based Modeling of Boron TED in Amorphised Si

We have developed a physically based modeling of TED of implanted boron in amorphised Si. The simulation starts with a supersaturation of Si free interstitials located below the amorphous/crystalline interface which, upon annealing, tend to diffuse out or to precipitate in the form of extended defects (clusters, {113}s, dislocation loops). The modeling of the nucleation and growth of these defects is divided into three distinct stages: the nucleation, the “pure growth” and the Ostwald ripening. This system can interact with a surface (characterized by a given recombination velocity for Si interstitials) only after the SPE regrowth is completed. Implementation of this model into a process simulator allows to describe the isothermal and isochronal evolutions of the sizes and of the densities of dislocation loops in agreement with TEM observations. Assuming that boron diffusion is caused by the concomitant time and space variations of the free interstitial supersaturation in the wafer, TED can be accurately predicted for a variety of experimental conditions.