Impact d'un traitement antifongique empirique par échinocandine chez les patients de réanimation à haut risque de candidose invasive (l'expérience dijonnaise)

DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Geometrical and material parameters to assess the macroscopic mechanical behaviour of fresh cranial bone samples

The present study aims at providing quantitative data for the personalisation of geometrical and 21 mechanical characteristics of the adult cranial bone to be applied to head FE models. A set of 351 22 cranial bone samples, harvested from 21 human skulls, were submitted to three-point bending tests 23 at 10 mm/min. For each of them, an apparent elastic modulus was calculated using the beam's 24 theory and a density-dependant beam inertia. Thicknesses, apparent densities and percentage of ash 25 weight were also measured. Distributions of characteristics among the different skull bones show 26 their symmetry and their significant differences between skull areas. A data analysis was 27 performed to analyse potential relationship between thicknesses, densities and the apparent elastic 28 modulus. A specific regression was pointed out to estimate apparent elastic modulus from the 29 product of thickness by apparent density. These results offer quantitative tools in view of 30 personalising head FE models and thus improve definition of local injury criteria for this body part

Linezolid and atorvastatin impact on pneumonia caused by Staphyloccocus aureus in rabbits with or without mechanical ventilation.

Pneumonia may involve methicillin-resistant Staphylococcus aureus (MRSA), with elevated rates of antibiotics failure. The present study aimed to assess the effect of statins given prior to pneumonia development. Spontaneously breathing (SB) or mechanically ventilated (MV) rabbits with pneumonia received atorvastatin alone, linezolid (LNZ) alone, or a combination of both (n = 5 in each group). Spontaneously breathing and MV untreated infected animals (n = 11 in each group), as well as uninfected animals (n = 5 in each group) were used as controls. Microbiological features and inflammation were evaluated. Data are presented as medians (interquartile range). Linezolid alone tended to reduce pulmonary MRSA load in both SB and MV rabbits, but failed to prevent bacteremia (59%) in the latter. Linezolid alone dampened TNF-α lung production in both SB and MV rabbits (e.g., 2226 [789] vs. 11478 [10251] pg/g; p = 0.022). Statins alone did the same in both SB and MV animals (e.g., 2040 [133]; p = 0.016), and dampened systemic inflammation in the latter, possibly through TLR2 down-regulation within the lung. However, the combination of LNZ and statin led to an increased rate of bacteremia in MV animals up to 75%. Statins provide an anti-inflammatory effect in rabbits with MRSA pneumonia, especially in MV ones. However, dampening the systemic inflammatory response with statins could impede blood defenses against MRSA

Mechanical ventilation alters the development of staphylococcus aureus pneumonia in rabbit

Ventilator-associated pneumonia (VAP) is common during mechanical ventilation (MV). Beside obvious deleterious effects on muco-ciliary clearance, MV could adversely shift the host immune response towards a pro-inflammatory pattern through toll-like receptor (TLRs) up-regulation. We tested this hypothesis in a rabbit model of Staphylococcus aureus VAP. Pneumonia was caused by airway challenge with S. aureus, in either spontaneously breathing (SB) or MV rabbits (n = 13 and 17, respectively). Pneumonia assessment regarding pulmonary and systemic bacterial burden, as well as inflammatory response was done 8 and 24 hours after S. aureus challenge. In addition, ex vivo stimulations of whole blood taken from SB or MV rabbits (n = 7 and 5, respectively) with TLR2 agonist or heat-killed S. aureus were performed. Data were expressed as mean +/- standard deviation. After 8 hours of infection, lung injury was more severe in MV animals (1.40 +/- 0.33 versus [vs] 2.40 +/- 0.55, p = 0.007), along with greater bacterial concentrations (6.13 +/- 0.63 vs. 4.96 +/- 1.31 colony forming units/gram, p = 0.002). Interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha serum concentrations reached higher levels in MV animals (p = 0.010). Whole blood obtained from MV animals released larger amounts of cytokines if stimulated with TLR2 agonist or heat-killed S. aureus (e.g., TNF-alpha: 1656 +/- 166 vs. 1005 +/- 89; p = 0.014). Moreover, MV induced TLR2 overexpression in both lung and spleen tissue. MV hastened tissue injury, impaired lung bacterial clearance, and promoted a systemic inflammatory response, maybe through TLR2 overexpression

Pulmonary and systemic bacterial burden of <i>S</i>. <i>aureus</i>.

<p>Pulmonary bacterial clearance expressed as the median (IQR) ratio between the amounts of bacteria recovered from the lung culture and the initial <i>Staphylococcus aureus</i> inoculum 24 hours after bacterial challenge in either spontaneously breathing or mechanically ventilated animals. Pulmonary-to-systemic bacterial translocation expressed as the spleen positive cultures rate 24 hours after bacteria instillation according to the experimental group in either spontaneously breathing or mechanically ventilated animals with <i>Staphylococcus aureus</i> pneumonia. Values are presented as percentages <i>(right)</i>. Kruskall-Wallis test with Dunn correction for multiple comparisons or Fisher exact test was used as appropriate for intergroup comparisons. CFU: colony forming unit; MRSA: methicillin-resistant S. aureus; LNZ: linezolid; SB: spontaneously breathing; MV: mechanical ventilation; IQR: interquartile range.</p

Toll-like receptor 2 gene expression.

<p>TLR2 gene expression was measured in both lung (<i>left</i>) and spleen (<i>right</i>) homogenates in either spontaneously breathing rabbits (SB) or animals subjected to mechanical ventilation (MV) with or without atorvastatin pre-treatment (n = 5 in each group). All values are reported as fold increases compared with SB rabbits. Results are expressed as mean±standard deviation. Kolmogorov-Smirnov test was used for all intergroup comparisons.</p

Time course of serum inflammatory cytokine concentrations during experiment.

<p>Serum concentrations of interleukin (IL)-8 and tumor necrosis factor (TNF)-α expressed as % of the mean baseline value measured by enzyme-linked immune-sorbent assay at baseline (100%; 24 hours before bacterial airway challenge), just before intra-tracheal instillation of 10⁹ CFU of <i>S</i>. <i>aureus</i> (H0), and then 8 (H8) and 24 hours (H24) after instillation, in the spontaneously breathing (A) and the mechanically ventilated animals (B). Concentrations measured in non-infected controls are shown in panel C. Variables were compared at each time-point with Mann-Whitney U test and p values were adjusted for multiple comparisons. (A): (<i>left</i>) * denotes p = 0.014 between rabbits treated with atorvastatin vs. untreated animals, and ** denotes p = 0.027 between rabbits treated with LNZ+atorvastatin vs. untreated animals; (<i>right</i>) * denotes p = 0.049 between rabbits treated with LNZ vs. untreated animals, and ** denotes p = 0.006 between rabbits treated with LNZ+atorvastatin vs. untreated animals. (B): (<i>left</i>) * denotes p = 0.004 between rabbits treated with atorvastatin vs. untreated animals, ** denotes p = 0.003 between rabbits treated with LNZ vs. untreated animals, and *** denotes p = 0.014 between rabbits treated with LNZ+atorvastatin vs. untreated animals; (<i>right</i>) * denotes p = 0.034 between rabbits treated with atorvastatin vs. untreated animals, ** denotes p = 0.013 between rabbits treated with LNZ vs. untreated animals, and *** denotes p = 0.002 between rabbits treated with LNZ+atorvastatin vs. untreated animals. CFU: colony forming unit; MRSA: methicillin-resistant <i>S</i>. <i>aureus</i>; LNZ: linezolid; SB: spontaneously breathing; MV: mechanical ventilation. CFU: colony forming unit; MRSA: methicilline-resistant S. aureus; LNZ: linezolid; SB: spontaneously breathing; MV: mechanical ventilation; IQR: interquartile range.</p

Inflammatory cytokines in the lung and in the spleen of rabbits in various experimental conditions.

<p>Inflammatory cytokines (interleukin [IL]-8 and tumor necrosis factor [TNF]-α) concentrations in lung (A) and spleen (B) homogenates 24 hours after tracheal instillation of saline (controls) 10⁹ CFU of <i>Staphylococcus aureus</i> in either spontaneously breathing rabbits or animals subjected to mechanical ventilation with various treatment combinations. Values are presented as means (SD). 2-way ANOVA test was used for all intergroup comparisons with Tukey’s adjustment for multiple comparisons. CFU: colony forming unit; MRSA: methicilline-resistant S. aureus; LNZ: linezolid; SB: spontaneously breathing; MV: mechanical ventilation; SD: standard deviation.</p

Inflammatory cytokines in whole blood stimulated <i>ex vivo</i> by <i>S</i>. <i>aureus</i> in various conditions.

<p>Interleukin (IL)-8 and tumor necrosis factor (TNF)-α mean levels (SD) in the supernatant of whole blood from either spontaneously breathing rabbits or animals subjected to mechanical ventilation. Atorvastatin was added to the medium (“statin”) or given to the rabbit prior to blood sampling (“Premed”). Values are presented as means (SD). 2-way ANOVA test was used for all intergroup comparisons with Tukey’s adjustment for multiple comparisons. One missing [IL-8] and one missing [TNF-α] value in the Whole blood+MRSA and in the Whole blood+MRSA+statin groups. MRSA: methicillin-resistant <i>S</i>. <i>aureus</i>; SB: spontaneously breathing; MV: mechanical ventilation; SD: standard deviation.</p