Sepsis related mortality of extremely low gestational age newborns after the introduction of colonization screening for multi-drug resistant organisms

Background: In 2013 German infection surveillance guidelines recommended weekly colonization screening for multidrug-resistant (MDRO) or highly epidemic organisms for neonatal intensive care units (NICUs) and extended hygiene measures based on screening results. It remains a matter of debate whether screening is worth the effort. We therefore aimed to evaluate sepsis related outcomes before and after the guideline update. Methods: The German Neonatal Network (GNN) is a prospective cohort study including data from extremely preterm infants between 22 + 0 and 28 + 6 gestational weeks born in 62 German level III NICUs. Results: Infants treated after guideline update (n = 8.903) had a lower mortality (12.5% vs. 13.8%, p = 0.036), reduced rates for clinical sepsis (31.4 vs. 42.8%, p < 0.001) and culture-proven sepsis (14.4% vs. 16.5%, p = 0.003) as compared to infants treated before update (n = 3.920). In a multivariate logistic regression analysis, nine pathogens of cultureproven sepsis were associated with sepsis-related death, e.g. Pseudomonas aeruginosa [OR 59 (19–180), p < 0.001)]. However, the guideline update had no significant effect on pathogen-specific case fatality, total sepsis-related mortality and culture-proven sepsis rates with MDRO. While the exposure of GNN infants to cefotaxime declined over time (31.1 vs. 40.1%, p < 0.001), the treatment rate with meropenem was increased (31.6 vs. 26.3%, p < 0.001). Conclusions: The introduction of weekly screening and extended hygiene measures is associated with reduced sepsis rates, but has no effects on sepsis-related mortality and sepsis with screening-relevant pathogens. The high exposure rate to meropenem should be a target of antibiotic stewardship programs

Characterization of the Channel Constriction Allowing the Access of the Substrate to the Active Site of Yeast Oxidosqualene Cyclase

In oxidosqualene cyclases (OSCs), an enzyme which has been extensively studied as a target for hypocholesterolemic or antifungal drugs, a lipophilic channel connects the surface of the protein with the active site cavity. Active site and channel are separated by a narrow constriction operating as a mobile gate for the substrate passage. In Saccharomyces cerevisiae OSC, two aminoacidic residues of the channel/constriction apparatus, Ala525 and Glu526, were previously showed as critical for maintaining the enzyme functionality. In this work sixteen novel mutants, each bearing a substitution at or around the channel constrictions, were tested for their enzymatic activity. Modelling studies showed that the most functionality-lowering substitutions deeply alter the H-bond network involving the channel/constriction apparatus. A rotation of Tyr239 is proposed as part of the mechanism permitting the access of the substrate to the active site. The inhibition of OSC by squalene was used as a tool for understanding whether the residues under study are involved in a pre-catalytic selection and docking of the substrate oxidosqualene

Sepsis related mortality of extremely low gestational age newborns after the introduction of colonization screening for multi-drug resistant organisms

Background!#!In 2013 German infection surveillance guidelines recommended weekly colonization screening for multidrug-resistant (MDRO) or highly epidemic organisms for neonatal intensive care units (NICUs) and extended hygiene measures based on screening results. It remains a matter of debate whether screening is worth the effort. We therefore aimed to evaluate sepsis related outcomes before and after the guideline update.!##!Methods!#!The German Neonatal Network (GNN) is a prospective cohort study including data from extremely preterm infants between 22 + 0 and 28 + 6 gestational weeks born in 62 German level III NICUs.!##!Results!#!Infants treated after guideline update (n = 8.903) had a lower mortality (12.5% vs. 13.8%, p = 0.036), reduced rates for clinical sepsis (31.4 vs. 42.8%, p &amp;lt;  0.001) and culture-proven sepsis (14.4% vs. 16.5%, p = 0.003) as compared to infants treated before update (n = 3.920). In a multivariate logistic regression analysis, nine pathogens of culture-proven sepsis were associated with sepsis-related death, e.g. Pseudomonas aeruginosa [OR 59 (19-180), p &amp;lt;  0.001)]. However, the guideline update had no significant effect on pathogen-specific case fatality, total sepsis-related mortality and culture-proven sepsis rates with MDRO. While the exposure of GNN infants to cefotaxime declined over time (31.1 vs. 40.1%, p &amp;lt;  0.001), the treatment rate with meropenem was increased (31.6 vs. 26.3%, p &amp;lt;  0.001).!##!Conclusions!#!The introduction of weekly screening and extended hygiene measures is associated with reduced sepsis rates, but has no effects on sepsis-related mortality and sepsis with screening-relevant pathogens. The high exposure rate to meropenem should be a target of antibiotic stewardship programs