Impact of infection status and cyclosporine on voriconazole pharmacokinetics in an experimental model of cerebral scedosporiosis

Cerebral Scedosporium infections usually occur in lung transplant recipients as well as in immunocompetent patients in the context of near-drowning. Voriconazole is the first-line treatment. The diffusion of voriconazole through the blood-brain barriers in the context of cerebral infection and cyclosporine administration is crucial and remains a matter of debate. To address this issue, the pharmacokinetics of voriconazole were assessed in the plasma, cerebrospinal fluid (CSF), and brain, in an experimental model of cerebral scedosporiosis in rats receiving or not cyclosporine. A single dose of voriconazole (30 mg/kg, i.v.) was administrated to six groups of rats randomized according to the infection status and the cyclosporine dosing regimen (no cyclosporine, a single dose or three doses 15 mg/kg each). Voriconazole concentrations in plasma, CSF, and brain samples were quantified using UPLC-MS/MS and HPLC-UV methods and documented up to 48 hours after administration. Pharmacokinetic parameters were estimated using a non-compartmental approach. Voriconazole pharmacokinetic profiles were similar for plasma, CSF, and the brain in all groups studied. Voriconazole Cmax and AUC0=>48h were significantly higher in the plasma than in the CSF (CSF/plasma ratio, median [range] = 0.5 [0.39-0.55] for AUC0=>48h and 0.47 [0.35 and 0.75] for Cmax). Cyclosporine administration was significantly associated with an increase in voriconazole exposure in the plasma, CSF, and brain. In the plasma but not in the brain, an interaction between the infection and cyclosporine administration reduced the positive impact of cyclosporine on voriconazole exposure. Together these results emphasize the impact of cyclosporine on the brain voriconazole exposure

DNA array analysis of Candida albicans gene expression in response to adherence to polystyrene.

Candidiasis is often initiated by the colonization of inert surfaces. In order to elucidate the mechanisms involved in this adherence process, DNA macroarrays were used to analyze the transcriptome of Candida albicans, the main causative agent of this mycoses, in a simple adherence model using germ tubes produced in polystyrene Petri dishes. Non-adherent germ tubes produced on glass surface were used as a control. Analysis of gene expression displayed 77 genes identified as statistically overexpressed in adherent germ tubes. Among these genes, some encoded enzymes participating in metabolism of lipids (such as LIP6), of proteins (such as SAP1) or of carbohydrates (like PGI1, PMI40 and PSA1. Some of these genes have already been reported as playing a role in pathogenesis of C. albicans. However, functions were unknown for a large part (45.5%) of the overexpressed genes which will be analyzed further in order to define their relationship with adherence

Draft Genome Sequence of the Human-Pathogenic Fungus Scedosporium boydii

The opportunistic fungal pathogen Scedosporium boydii is the most common Scedosporium species in French patients with cystic fibrosis. Here we present the first genome report for S. boydii, providing a resource which may enable the elucidation of the pathogenic mechanisms in this species

Pneumocystis jirovecii colonization among cystic fibrosis patients: A French prospective multicenter study

Pneumocystis carriage was detected in 12.5% of 104 cystic fibrosis (CF) patients during a prospective multicenter French study, with a prevalence of genotype 85C/248C and geographic variations. It was significantly associated with the absence of P. aeruginosa colonization and better FEV1 values. Results are discussed considering the natural history of CF

Desafíos políticos de los países de inmigración

13 págs.-- Publicado en "Confluencia XXI. Revista de Pensamiento Político" (México), nº 3 (Oct-Dic 2008) bajo el título monográfico "Migrantes: ¿Por qué se van? ¿Por qué se quedan?".Las migraciones, una práctica tan antigua como la propia condición humana, se han convertido en un factor estructural de primer orden, en uno de los macrofenómenos más definitorios de nuestra época y en un complejo reto para las sociedades contemporáneas. En prácticamente todos los países del mundo, todo lo que concierne a este complejo fenómeno ocupa un lugar destacado en la agenda política. La gestión, el control y la integración de los movimientos internacionales de personas se presentan como un policy field de creciente y prioritaria relevancia. No se trata, sin embargo, de una cuestión de mera moda: el número de países implicados de manera significativa en las migraciones internacionales ha aumentado considerablemente, hasta el punto de que resulta realmente difícil encontrar algún Estado que no sea bien un país de inmigración, bien un país de emigración o bien ambas cosas a la vez, cuando no al menos un país de tránsito. No ha de extrañar entonces que la mayoría de los gobiernos haya tomado conciencia de la necesidad de ofrecer una respuesta en términos legales e institucionales a un fenómeno de carácter permanente que puede llegar a alterar la estructura demográfica, social, cultural, económica y laboral de un país. Dada la complejidad de la cuestión, y por cuestiones de economía argumentativa, aquí se abordará de manera fundamental desde la perspectiva de los países receptores, que, por lo demás, es también la adoptada en forma habitual por los países europeos que registran mayor inmigración. Sin embargo, el fenómeno migratorio es fundamentalmente transnacional y tiene fehacientes repercusiones en los países de emigración.Peer reviewe

Antimykotische Therapie der invasiven pulmonalen Infektion durch Scedosporium und Pseudallescheria spp. bei Mukoviszidose

Autre titre : Antimykotische Therapie der pulmonalen Infektion durch Scedosporien bei MukoviszidoseInternational audienc

Combined antifungal therapy is superior to monotherapy in pulmonary scedosporiosis in cystic fibrosis

Cystic fibrosis (CF) is characterised by chronic airway infection with bacteria and fungi. Infections caused by Scedosporium/Lomentospora species can occur and are difficult to treat. Moulds belonging to the genus Scedosporium/Lomentospora are detected most frequently in respiratory samples of patients with CF, next to Aspergillus spp. Our aim was to define pulmonary fungal infections due to Scedosporium/Lomentospora in CF and to study the antimycotic treatment. In this multicentre study (12 centres; duration January 2008 to December 2014) 31 patients with a lung infection caused by moulds of the genus Scedosporium/Lomentospora were included. 36 courses of antifungal treatment were documented. Scedosporium apiospermum sensu stricto accounted for 48.4% of cases. In 20/31 patients a therapeutic response under antimycotics (median duration 3.9 months) was achieved. Triple and double therapy was significantly more effective compared to monotherapy regarding FEV1, radiology, and symptoms. This data suggests that combined treatment is superior to monotherapy in patients with CF

Enzymatic Mechanisms Involved in Evasion of Fungi to the Oxidative Stress: Focus on Scedosporium apiospermum

The airways of patients with cystic fibrosis (CF) are frequently colonized by various filamentous fungi, mainly Aspergillus fumigatus and Scedosporium species. To establish within the respiratory tract and cause an infection, these opportunistic fungi express pathogenic factors allowing adherence to the host tissues, uptake of extracellular iron, or evasion to the host immune response. During the colonization process, inhaled conidia and the subsequent hyphae are exposed to reactive oxygen species (ROS) and reactive nitrogen species (RNS) released by phagocytic cells, which cause in the fungal cells an oxidative stress and a nitrosative stress, respectively. To cope with these constraints, fungal pathogens have developed various mechanisms that protect the fungus against ROS and RNS, including enzymatic antioxidant systems. In this review, we summarize the different works performed on ROS- and RNS-detoxifying enzymes in fungi commonly encountered in the airways of CF patients and highlight their role in pathogenesis of the airway colonization or respiratory infections. The potential of these enzymes as serodiagnostic tools is also emphasized. In addition, taking advantage of the recent availability of the whole genome sequence of S. apiospermum, we identified the various genes encoding ROS- and RNS-detoxifying enzymes, which pave the way for future investigations on the role of these enzymes in pathogenesis of these emerging species since they may constitute new therapeutics targets

Etiologic Diagnosis of Lower Respiratory Tract Bacterial Infections Using Sputum Samples and Quantitative Loop-Mediated Isothermal Amplification

Etiologic diagnoses of lower respiratory tract infections (LRTI) have been relying primarily on bacterial cultures that often fail to return useful results in time. Although DNA-based assays are more sensitive than bacterial cultures in detecting pathogens, the molecular results are often inconsistent and challenged by doubts on false positives, such as those due to system- and environment-derived contaminations. Here we report a nationwide cohort study on 2986 suspected LRTI patients across P. R. China. We compared the performance of a DNA-based assay qLAMP (quantitative Loop-mediated isothermal AMPlification) with that of standard bacterial cultures in detecting a panel of eight common respiratory bacterial pathogens from sputum samples. Our qLAMP assay detects the panel of pathogens in 1047(69.28%) patients from 1533 qualified patients at the end. We found that the bacterial titer quantified based on qLAMP is a predictor of probability that the bacterium in the sample can be detected in culture assay. The relatedness of the two assays fits a logistic regression curve. We used a piecewise linear function to define breakpoints where latent pathogen abruptly change its competitive relationship with others in the panel. These breakpoints, where pathogens start to propagate abnormally, are used as cutoffs to eliminate the influence of contaminations from normal flora. With help of the cutoffs derived from statistical analysis, we are able to identify causative pathogens in 750 (48.92%) patients from qualified patients. In conclusion, qLAMP is a reliable method in quantifying bacterial titer. Despite the fact that there are always latent bacteria contaminated in sputum samples, we can identify causative pathogens based on cutoffs derived from statistical analysis of competitive relationship