Pharmacokinetics in vivo and pharmacodynamics ex vivo/in vitro of meropenem and cefpirome in the Yucatan micropig model: continuous infusion versus intermittent injection

ObjectiveTo investigate the pharmacodynamic disposition of two recently developed β-lactam antibiotics, meropenem and cefpirome, in the Yucatan micropig model, and to compare the bactericidal activity of these drugs against bacteria in this in vitro/ex vivo micropig model after administration by both intermittent injection and continuous infusion.MethodsCefpirome (1 g) was given to the micropig over a 12-h period by direct intravenous injection and 6-h continuous infusion (500 mg). Meropenem (250 mg) was administered either by 30-min intravenous and 8-h continuous infusion. The two drugs were assayed by HPLC. The pharmacodynamics of these drugs were evaluated by means of (1) serum killing curve against Klebsiella pneumoniae producing extended-spectrum β-lactamase, stably derepressed Enterobacter cloacae and methicillin-susceptible penicillinase-producing Staphylococcus aureus, and (2) calculations of index of surviving bacteria (ISB).ResultsThe bactericidal activity of meropenem against K. pneumoniae and E. cloacae in this in vitro/ex vivo model was excellent, with a 4 log decrease at peak concentrations. Meropenem produced a mixed concentration- and time-dependent, killing effect against E. cloacae and K. pneumoniae. The ISB value ranged from 25% to 30% for E. cloacae. With concentrations above MIC for S. aureus (1 mg/L), cefpirome has a time-dependent bactericidal activity, as shown by the ISB ranging from 20% to 80% after 4 h and between 20% and 40% after an 8-h drug exposure. For both antibiotics, the higher concentrations obtained just after intermittent injection had a rapid and strong killing effect against the strains tested, but the trough levels had no bactericidal activity. The continuous infusions produce consistent concentrations of antibiotic that can be maintained above the MIC, and the bactericidal activity of which ranges from 2 to 4 log10 decrease of inoculum.ConclusionsIn the present study the micropig has been shown to be an adequate model for the pharmacodynamic investigation of cefpirome and meropenem. In general, continuous infusion appears to optimize the pharmacodynamic profile of the two tested β-lactam antibiotics. However, against Gram-negative bacilli, the administration of a loading dose prior to continuous infusion of β-lactams would eliminate the only potential pharmacokinetic disadvantage of continuous infusion and ensure the rapid onset of antimicrobial activity

Fine Tuning of the Photoacoustic Generation Efficiency by Aggregation-Caused Quenching and Excitation Energy Transfer in Bodipy-Labeled Polylactide Nanoparticles

The relationship between the fluorescence decrease by Aggregation-Caused Quenching (ACQ) and the Photoacoustic Generation Efficiency in polylactide-Bodipy nanoparticles (PLA-Bodipy NPs) is demonstrated. PLA NPs with different PLA-Bodipy loading (from 2.5% to 50% by weight) were studied using a calibrated photoacoustic spectrophotometer. We demonstrate the presence of two photoacoustic emission regimes thanks to the determination of the Global PhotoAcoustic Efficiency (GPAE) which represents the averaged Photoacoustic Generation Efficiency (PGE) over the whole studied band (680-870 nm). In the monomer regime, below 10% by weight of PLA-Bodipy, the fluorescence emission from the Bodipy monomer limits the GPAE. Above 10% of PLA-Bodipy, in the ACQ regime, non-radiative deactivations from the aggregates are predominant and GPAE reaches a high value of 93%. We also introduce the photoacoustic brightness BPA, as the produce of the GPAE by the molar extinction coefficient of NPs. When Bodipy is aggregated, high nanoparticular extinction coefficients (2.4 x 108 L.mol-1.cm-1 for NP-50%) and high GPAE values are reached leading to ultrabright NPs (22 x 107 L.mol-1.cm-1). Finally, we show that high laser fluences (1-3.5 mJ.cm-2) can significantly reduce the photoacoustic signal by ground state depopulation at the band maximum excitation (-20% for NP-2.5%). This non-linear effect can be highly reduced with NPs in the ACQ regime. Above 10% PLA-Bodipy, NPs exhibit intense photoacoustic brightness and low signal loss by nonlinear effects. A mathematical fit of the absorption and photoacoustic excitation spectra allowed to introduce the Band PhotoAcoustic Efficiency (BPAE) to spectrally differentiate the averaged photoacoustic efficiency at the band maximum BPAEred and in the vibrational shoulder BPAEblue. The BPAEred highly depends on the laser fluence due to high ground state depopulation, whereas the BPAEblue does not change with the fluence thanks to a lower laser fluence saturation

Dynamiques et modalités du peuplement dans la vallée de la Loire, entre Orléans et Saint-Nazaire, de La Tène moyenne à la fin du règne d’Auguste

International audienceLoire constitutes, in its western part, a major element in the structuring of the landscape and the territories that it crosses in historical periods. This observation, which can be applied to the Iron Age according to the texts of Strabo and Caesar in particular, has only really started to be documented by archeology in recent years. The aim of this contribution is therefore to bring together largely unpublished documentation in order to provide information on three main questions: Development and management of the watercourse (bridges, fords, banks, wrecks) ; The status and organization of sites related to the Loire, in a 50 km wide strip; Cultural entities crossed by the river. Bringing together the results of numerous preventive archaeological interventions and recent academic work, the study demonstrates the Loire's significant attraction for the peoples concerned and its obvious role for long-distance exchanges. It also highlights the preeminent role of the Gallic populations in the human appropriation of the valley.La Loire constitue, dans sa portion occidentale, un élément majeur de la structuration du paysage et des territoires qu’elle traverse aux périodes historiques. Ce constat, que l’on peut appliquer à l’âge du Fer d’après les textes de Strabon et de César notamment, ne commence véritablement à être documenté par l’archéologie que depuis quelques années. Cette contribution a donc pour objectif de rassembler une documentation en grande partie inédite, afin de renseigner trois questions principales : Les aménagements et la gestion du cours d’eau (ponts, gués, berges, épaves) ; Le statut et l’organisation des sites en relation avec la Loire, dans une bande de 50 km de large ; Les entités culturelles traversées par le fleuve. Réunissant les résultats de nombreuses interventions d’archéologie préventives et de travaux universitaires récents, l’étude démontre l’attraction importante de la Loire pour les peuples concernés et son rôle manifeste pour les échanges à longue distance. Elle permet également de mettre en évidence le rôle prééminent des populations gauloises dans l’appropriation humaine du val

Dynamiques et modalités du peuplement dans la vallée de la Loire, entre Orléans et Saint-Nazaire, de La Tène moyenne à la fin du règne d’Auguste

International audienceLoire constitutes, in its western part, a major element in the structuring of the landscape and the territories that it crosses in historical periods. This observation, which can be applied to the Iron Age according to the texts of Strabo and Caesar in particular, has only really started to be documented by archeology in recent years. The aim of this contribution is therefore to bring together largely unpublished documentation in order to provide information on three main questions: Development and management of the watercourse (bridges, fords, banks, wrecks) ; The status and organization of sites related to the Loire, in a 50 km wide strip; Cultural entities crossed by the river. Bringing together the results of numerous preventive archaeological interventions and recent academic work, the study demonstrates the Loire's significant attraction for the peoples concerned and its obvious role for long-distance exchanges. It also highlights the preeminent role of the Gallic populations in the human appropriation of the valley.La Loire constitue, dans sa portion occidentale, un élément majeur de la structuration du paysage et des territoires qu’elle traverse aux périodes historiques. Ce constat, que l’on peut appliquer à l’âge du Fer d’après les textes de Strabon et de César notamment, ne commence véritablement à être documenté par l’archéologie que depuis quelques années. Cette contribution a donc pour objectif de rassembler une documentation en grande partie inédite, afin de renseigner trois questions principales : Les aménagements et la gestion du cours d’eau (ponts, gués, berges, épaves) ; Le statut et l’organisation des sites en relation avec la Loire, dans une bande de 50 km de large ; Les entités culturelles traversées par le fleuve. Réunissant les résultats de nombreuses interventions d’archéologie préventives et de travaux universitaires récents, l’étude démontre l’attraction importante de la Loire pour les peuples concernés et son rôle manifeste pour les échanges à longue distance. Elle permet également de mettre en évidence le rôle prééminent des populations gauloises dans l’appropriation humaine du val

Dynamiques et modalités du peuplement dans la vallée de la Loire, entre Orléans et Saint-Nazaire, de La Tène moyenne à la fin du règne d'Auguste

International audienceLoire constitutes, in its western part, a major element in the structuring of the landscape and the territories that it crosses in historical periods. This observation, which can be applied to the Iron Age according to the texts of Strabo and Caesar in particular, has only really started to be documented by archeology in recent years. The aim of this contribution is therefore to bring together largely unpublished documentation in order to provide information on three main questions : Development and management of the watercourse (bridges, fords, banks, wrecks) ; The status and organization of sites related to the Loire, in a 50 km wide strip; Cultural entities crossed by the river. Bringing together the results of numerous preventive archaeological interventions and recent academic work, the study demonstrates the Loire's significant attraction for the peoples concerned and its obvious role for long-distance exchanges. It also highlights the preeminent role of the Gallic populations in the human appropriation of the valley.La Loire constitue, dans sa portion occidentale, un élément majeur de la structuration du paysage et des territoires qu’elle traverse aux périodes historiques. Ce constat, que l’on peut appliquer à l’âge du Fer d’après les textes de Strabon et de César notamment, ne commence véritablement à être documenté par l’archéologie que depuis quelques années. Cette contribution a donc pour objectif de rassembler une documentation en grande partie inédite, afin de renseigner trois questions principales : Les aménagements et la gestion du cours d’eau (ponts, gués, berges, épaves) ; Le statut et l’organisation des sites en relation avec la Loire, dans une bande de 50 km de large ; Les entités culturelles traversées par le fleuve. Réunissant les résultats de nombreuses interventions d’archéologie préventives et de travaux universitaires récents, l’étude démontre l’attraction importante de la Loire pour les peuples concernés et son rôle manifeste pour les échanges à longue distance. Elle permet également de mettre en évidence le rôle prééminent des populations gauloises dans l’appropriation humaine du val