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Nijmegen, Netherlands

Muller A.E.,RadboudUMC | Punt N.,Medimatics | Moutona J.W.,Erasmus Medical Center
Antimicrobial Agents and Chemotherapy

The percentage of the dosing interval that the non-protein-bound plasma concentration is above the MIC (%fT>MIC) for cephalosporins has been shown to correlate with microbiological outcomes in preclinical studies. However, clinical data are scarce. Using data from a randomized double-blind phase 3 clinical trial, we explored the relationship of ceftobiprole exposure with microbiological and clinical outcomes in patients with nosocomial pneumonia. The individual ceftobiprole exposure was determined for different pharmacokinetic (PK)/pharmacodynamic (PD) indices using individual pharmacokinetic data and a previously published population model. The MICs used in the analysis were the highest MICs for any bacterium cultured at baseline or the end of treatment (EOT). Outcomes were microbiological cure at EOT and clinical cure at test of cure (TOC). Multiple logistic regression (MLR) and classification and regression tree (CART) analyses were applied to determine the relationships among exposure, patient characteristics, and outcomes. MLR indicated that the%fT>MIC of ceftobiprole was the best predictor for both microbiological eradication and clinical cure. CART analysis showed a breakpoint value of 51.1% (n=159; P=0.0024) for clinical cure, whereas it was 62.2% (n=251; P<0.0001) for microbiological eradication. Other factors also contributed, particularly to clinical outcome. These included the difference between VAP and non-VAP patients, systemic inflammatory response syndrome (SIRS), creatinine clearance, the use of anti-Pseudomonas combination therapy, and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score. There is a strong correlation between microbiological eradication and clinical cure with exposure to ceftobiprole. The%fT>MIC required to result in a favorable clinical outcome is>51% of the dosing interval, which is in line with the values found for microbiological eradication, the comparator ceftazidime, and preclinical models. © 2014, American Society for Microbiology. Source

Seyedmousavi S.,Erasmus MC | Verweij P.E.,RadboudUMC | Mouton J.W.,Erasmus MC
Expert Review of Anti-Infective Therapy

The prodrug isavuconazonium sulfate (BAL8557) is an extended-spectrum water-soluble triazole, developed for the treatment of severe invasive and life-threatening fungal diseases. Its active moiety, BAL4815, is a potent inhibitor of ergosterol biosynthesis, resulting in the disruption of fungal membrane structure and function. The active compound shows broad-spectrum of activity and potency against all major opportunistic fungi, such as Aspergillus spp., Candida spp., Cryptococcus spp., Mucorales, Black yeasts and their filamentous relatives and the true pathogenic fungi, including Histoplasma capsulatum and Blastomyces dermatitidis. It is currently in Phase III clinical development for treatment of aspergillosis, candidiasis and mucormycosis, as well as other rare fungi infections. We reviewed the pharmacokinetic and pharmacodynamic characteristics of isavuconazole, and its microbiological and clinical investigation progress in advanced stages of development. © Informa UK, Ltd. Source

Lepor H.,New York University | Llukani E.,New York University | Sperling D.,Sperling Prostate Cancer Center | Futterer J.J.,RadboudUMC
European Urology

From April 2013 to July 2014, 25 consecutive men participated in a longitudinal outcomes study following in-bore magnetic resonance imaging (MRI)-guided focal laser ablation (FLA) of prostate cancer (PCA). Eligibility criteria were clinical stage T1c and T2a disease; prostate-specific antigen (PSA) <10 ng/ml; Gleason score <8; and cancer-suspicious regions (CSRs) on multiparametric MRI harboring PCA. CSRs harboring PCA were ablated using a Visualase cooled laser applicator system. Tissue temperature was monitored throughout the ablation cycle by proton resonance frequency shift magnetic resonance thermometry from phase-sensitive images. There were no significant differences between baseline and 3-mo mean American Urological Association Symptom Score or Sexual Health Inventory in Men scores. No man required pads at any time. Overall, the mean PSA decrease between baseline and 3 mo was 2.3 ng/ml (44.2%). Of 28 sites subjected to target biopsy after FLA, 26 (96%) showed no evidence of PCA. Our study provides encouraging evidence that excellent early oncologic control of significant PCA can be achieved following FLA, with virtually no complications or adverse impact on quality of life. Longer follow-up is required to show that oncologic control is durable. Patient summary Early results for focal laser ablation of prostate cancer are very encouraging. Until long-term oncologic control is demonstrated, focal laser ablation must be considered an investigational treatment option. © 2015 European Association of Urology. Source

Sobbi S.C.,RadboudUMC | Van den Boogaard M.,RadboudUMC
Critical Care

The pathophysiological mechanism of the serious and frequently occurring disorder delirium is poorly understood. Inflammation and sepsis are known risk factors for ICU delirium and therefore these patients are highly susceptible to delirium. Several studies have been performed to determine which cytokines are most associated with delirium but the results are inconclusive. Also, new biomarkers associated with brain dysfunction and cognitive impairment are still recognized and need to be studied to determine their relation with delirium. In this commentary we address some limitations concerning an interesting new study that warrants directions for future studies. © 2014 Cheheili Sobbi and van den Boogaard; licensee BioMed Central Ltd. Source

Weinreb J.C.,Yale University | Barentsz J.O.,RadboudUMC | Choyke P.L.,U.S. National Institutes of Health | Cornud F.,University of Paris Descartes | And 8 more authors.
European Urology

The Prostate Imaging - Reporting and Data System Version 2 (PI-RADS™ v2) is the product of an international collaboration of the American College of Radiology (ACR), European Society of Uroradiology (ESUR), and AdMetech Foundation. It is designed to promote global standardization and diminish variation in the acquisition, interpretation, and reporting of prostate multiparametric magnetic resonance imaging (mpMRI) examination, and it is based on the best available evidence and expert consensus opinion. It establishes minimum acceptable technical parameters for prostate mpMRI, simplifies and standardizes terminology and content of reports, and provides assessment categories that summarize levels of suspicion or risk of clinically significant prostate cancer that can be used to assist selection of patients for biopsies and management. It is intended to be used in routine clinical practice and also to facilitate data collection and outcome monitoring for research. © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. Source

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