Bacterial species and antimicrobial resistance differ between catheter and non-catheter-associated urinary tract infections: Data from a national surveillance network

OBJECTIVE To investigate clinically relevant microbiological characteristics of uropathogens and to compare patients with catheter-associated urinary tract infections (CAUTIs) to those with non-CAUTIs. METHODS All urine cultures from the calendar year 2019 of the Swiss Centre for Antibiotic Resistance database were analyzed. Group differences in the proportions of bacterial species and antibiotic-resistant isolates from CAUTI and non-CAUTI samples were investigated. RESULTS Data from 27,158 urine cultures met the inclusion criteria. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis together represented 70% and 85% of pathogens identified in CAUTI and non-CAUTI samples, respectively. Pseudomonas aeruginosa was significantly more often detected in CAUTI samples. The overall resistance rate for the empirically often-prescribed antibiotics ciprofloxacin (CIP), norfloxacin (NOR), and trimethoprim-sulfamethoxazole (TMP-SMX) was between 13% and 31%. Except for nitrofurantoin, E. coli from CAUTI samples were more often resistant (P ≤ .048) to all classes of antibiotics analyzed, including third-generation cephalosporines used as surrogate for extended-spectrum β-lactamase (ESBL). Significanty higher resistance proportions in CAUTI samples versus non-CAUTI samples were observed for CIP (P = .001) and NOR (P = .033) in K. pneumoniae, for NOR (P = .011) in P. mirabilis, and for cefepime (P = .015), and piperacillin-tazobactam (P = .043) in P. aeruginosa. CONCLUSION CAUTI pathogens were more often resistant to recommended empirical antibiotics than non-CAUTI pathogens. This finding emphasizes the need for urine sampling for culturing before initiating therapy for CAUTI and the importance of considering therapeutic alternatives

KIAA0319 influences cilia length, cell migration and mechanical cell-substrate interaction

Funding: This work was supported by Action Medical Research/ The Chief Scientist (CSO) Office, Scotland [GN 2614], Royal Society [RG160373], Carnegie Trust [50341], Wellcome Trust ISSF grant 105621/Z/14/Z, and RS Macdonald Charitable Trust grants to SP and Engineering and Physical Sciences Research Council [EP/P030017/1], Biotechnology and Biological Sciences Research Council [BB/P027148/1], and the European Research Council Starting Grant ABLASE [640012] grants to MCG. SP is a Royal Society University Research Fellow.Following its association with dyslexia in multiple genetic studies, the KIAA0319 gene has been extensively investigated in different animal models but its function in neurodevelopment remains poorly understood. We developed the first human cellular knockout model for KIAA0319 in RPE1 retinal pigment epithelia cells via CRISPR-Cas9n to investigate its role in processes suggested but not confirmed in previous studies, including cilia formation and cell migration. We observed in the KIAA0319 knockout increased cilia length and accelerated cell migration. Using Elastic Resonator Interference Stress Microscopy (ERISM), we detected an increase in cellular force for the knockout cells that was restored by a rescue experiment. Combining ERISM and immunostaining we show that RPE1 cells exert highly dynamic, piconewton vertical pushing forces through actin-rich protrusions that are surrounded by vinculin-rich pulling sites. This protein arrangement and force pattern has previously been associated to podosomes in other cells. KIAA0319 depletion reduces the fraction of cells forming these actin-rich protrusions. Our results suggest an involvement of KIAA0319 in cilia biology and cell–substrate force regulation.Publisher PDFPeer reviewe

Estimating antibiotic coverage from linked microbiological and clinical data from the Swiss Paediatric Sepsis Study to support empiric antibiotic regimen selection.

In light of rising antibiotic resistance, better methods for selection of empiric antibiotic treatment based on clinical and microbiological data are needed. Most guidelines target specific clinical infections, and variably adjust empiric antibiotic selection by certain patient characteristics. Coverage estimates reflect the probability that an antibiotic regimen will be active against the causative pathogen once confirmed and can provide an objective basis for empiric regimen selection. Coverage can be estimated for specific infections using a weighted incidence syndromic combination antibiograms (WISCAs) framework. However, no comprehensive data combining clinical and microbiological data for specific clinical syndromes are available in Switzerland. We therefore describe estimating coverage from semi-deterministically linked routine microbiological and cohort data of hospitalised children with sepsis. Coverage estimates were generated for each hospital and separately pooling data across ten contributing hospitals for five pre-defined patient risk groups. Data from 1,082 patients collected during the Swiss Paediatric Sepsis Study (SPSS) 2011-2015 were included. Preterm neonates were the most commonly represented group, and half of infants and children had a comorbidity. 67% of neonatal sepsis cases were hospital-acquired late-onset whereas in children 76% of infections were community-acquired. Escherichia coli, Coagulase-negative staphylococci (CoNS) and Staphylococcus aureus were the most common pathogens. At all hospitals, ceftazidime plus amikacin regimen had the lowest coverage, and coverage of amoxicillin plus gentamicin and meropenem were generally comparable. Coverage was improved when vancomycin was included in the regimen, reflecting uncertainty about the empirically targeted pathogen spectrum. Children with community-acquired infections had high coverage overall. It is feasible to estimate coverage of common empiric antibiotic regimens from linked data. Pooling data by patient risk groups with similar expected pathogen and susceptibility profiles may improve coverage estimate precision, supporting better differentiation of coverage between regimens. Identification of data sources, selection of regimens and consideration of pathogens to target for improved empiric coverage is important

PRAD1 (Cyclin D1): A Parathyroid Neoplasia Gene on 11q13

Hyperparathyroidism is a central component of multiple endocrine neoplasia type 1 (MEN 1), and both sporadic and familial forms of parathyroid disease may share certain pathogenetic features. We recently identified a gene that is clonally rearranged with the PTH locus in a subset of sporadic parathyroid adenomas. This candidate oncogene, PRAD1 (previously D11S287), appears to contribute to parathyroid tumorigenesis in a fashion analogous to activation of C-MYC or BCL-2 by rearrangement with tissue-specific enhancers of the immunoglobulin genes in B-lymphoid neoplasia. The PRAD1 gene maps to 11q13 and has been linked to the BCL-1 breakpoint locus, although not to the most tightly linked MEN 1 markers, by pulsed field gel electrophoresis. PRAD1 may, in fact, be the long-sought BCL-1 lymphoma oncogene. PRAD1 encodes a novel type of cyclin protein and thus may normally function in controlling the cell cycle, perhaps through direct interaction with cdc2 or a related kinase. PRAD1\u27s possible primary, or more likely secondary, involvement in the pathogenesis of MEN 1-related tumors is unknown and under investigation

Catheter-related infections: does the spectrum of microbial causes change over time? A nationwide surveillance study

Objectives To estimate the incidence and epidemiology of catheter-related bloodstream infections (CRBSIs) on a national scale by using prospective epidemiological data from the Swiss Antibiotic Resistance Surveillance System (ANRESIS). Design Observational study. Setting National surveillance from 2008 to 2015 of acute hospitals in Switzerland. Participants We included acute Swiss hospitals that sent blood cultures and catheter tip culture results on a regular basis during the entire study period to the ANRESIS database. Outcome measure A catheter-related bloodstream infection (termed ‘modified CRBSI’, mCRBSI) was defined as isolating the same microorganism with identical antibiogram from ≥1 blood cultures (performed ±7 days around the catheter removal) as the one recovered from the catheter tip. Incidence rates of mCRBSI were calculated per 1000 admissions. Results From 2008 to 2015, the mCRBSI incidence rate decreased from 0.83 to 0.58 episodes/1000 admissions (−6% per year, p<0.001). Coagulase-negative staphylococci, Staphylococcus aureus and fungi all exhibited decreasing trends, while rates of enterococci and Gram-negative bacteria remained stable. Conclusions The overall incidence of mCRBSI in Switzerland is decreasing; however, the incidence of mCRBSI due to Enterococci and Gram-negative micro-organisms did not change over time. These pathogens may grow in importance in catheter-related infections, which would have clinical implications for the choice of empirical treatment

The impact of public health interventions on the future prevalence of ESBL-producing Klebsiella pneumoniae: a population based mathematical modelling study.

BACKGROUND Future prevalence of colonization with extended-spectrum betalactamase (ESBL-) producing K. pneumoniae in humans and the potential of public health interventions against the spread of these resistant bacteria remain uncertain. METHODS Based on antimicrobial consumption and susceptibility data recorded during > 13 years in a Swiss region, we developed a mathematical model to assess the comparative effect of different interventions on the prevalence of colonization. RESULTS Simulated prevalence stabilized in the near future when rates of antimicrobial consumption and in-hospital transmission were assumed to remain stable (2025 prevalence: 6.8% (95CI%:5.4-8.8%) in hospitals, 3.5% (2.5-5.0%) in the community versus 6.1% (5.0-7.5%) and 3.2% (2.3-4.2%) in 2019, respectively). When overall antimicrobial consumption was set to decrease by 50%, 2025 prevalence declined by 75% in hospitals and by 64% in the community. A 50% decline in in-hospital transmission rate led to a reduction in 2025 prevalence of 31% in hospitals and no reduction in the community. The best model fit estimated that 49% (6-100%) of observed colonizations could be attributable to sources other than human-to-human transmission within the geographical setting. CONCLUSIONS Projections suggests that overall antimicrobial consumption will be, by far, the most powerful driver of prevalence and that a large fraction of colonizations could be attributed to non-local transmissions

Epidemiology of subsequent bloodstream infections in the ICU

Abstract Subsequent bloodstream infections (sBSI) occur with a delay after removal of the intravascular catheter (IVC) whose tip revealed microbial growth. Here we describe the epidemiology of sBSI in the intensive care setting. Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa, and yeast were the pathogens most frequently associated with sBSI. In contrast, Enterococci were rarely found in sBSI

Willin/FRMD6 influences mechanical phenotype and neuronal differentiation in mammalian cells by regulating ERK1/2 activity

This research was financially supported by an Engineering and Physical Sciences Research Council (EPSRC) Programme Grant (EP/P030017/1) and by the Biotechnology and Biological Sciences Research Council (BBSRC) Tools and Resources Development Fund (BB/P027148/1).Willin/FRMD6 is part of a family of proteins with a 4.1 ezrin-radixin-moesin (FERM) domain. It has been identified as an upstream activator of the Hippo pathway and, when aberrant in its expression, is associated with human diseases and disorders. Even though Willin/FRMD6 was originally discovered in the rat sciatic nerve, most studies have focused on its functional roles in cells outside of the nervous system, where Willin/FRMD6 is involved in the formation of apical junctional cell-cell complexes and in regulating cell migration. Here, we investigate the biochemical and biophysical role of Willin/FRMD6 in neuronal cells, employing the commonly used SH-SY5Y neuronal model cell system and combining biochemical measurements with Elastic Resonator Interference Stress Micropscopy (ERISM). We present the first direct evidence that Willin/FRMD6 expression influences both the cell mechanical phenotype and neuronal differentiation. By investigating cells with increased and decreased Willin/FRMD6 expression levels, we show that Willin/FRMD6 not only affects proliferation and migration capacity of cells but also leads to changes in cell morphology and an enhanced formation of neurite-like membrane extensions. These changes were accompanied by alterations of biophysical parameters such as cell force, the organization of actin stress fibers and the formation of focal adhesions. At the biochemical level, changes in Willin/FRMD6 expression inversely affected the activity of the extracellular signal-regulated kinases (ERK) pathway and downstream transcriptional factor NeuroD1, which seems to prime SH-SY5Y cells for retinoic acid (RA)-induced neuronal differentiation.Publisher PDFPeer reviewe

Estimating antibiotic coverage from linked microbiological and clinical data from the Swiss Paediatric Sepsis Study to support empiric antibiotic regimen selection

In light of rising antibiotic resistance, better methods for selection of empiric antibiotic treatment based on clinical and microbiological data are needed. Most guidelines target specific clinical infections, and variably adjust empiric antibiotic selection by certain patient characteristics. Coverage estimates reflect the probability that an antibiotic regimen will be active against the causative pathogen once confirmed and can provide an objective basis for empiric regimen selection. Coverage can be estimated for specific infections using a weighted incidence syndromic combination antibiograms (WISCAs) framework. However, no comprehensive data combining clinical and microbiological data for specific clinical syndromes are available in Switzerland. We therefore describe estimating coverage from semi-deterministically linked routine microbiological and cohort data of hospitalised children with sepsis. Coverage estimates were generated for each hospital and separately pooling data across ten contributing hospitals for five pre-defined patient risk groups. Data from 1,082 patients collected during the Swiss Paediatric Sepsis Study (SPSS) 2011-2015 were included. Preterm neonates were the most commonly represented group, and half of infants and children had a comorbidity. 67% of neonatal sepsis cases were hospital-acquired late-onset whereas in children 76% of infections were community-acquired. Escherichia coli, Coagulase-negative staphylococci (CoNS) and Staphylococcus aureus were the most common pathogens. At all hospitals, ceftazidime plus amikacin regimen had the lowest coverage, and coverage of amoxicillin plus gentamicin and meropenem were generally comparable. Coverage was improved when vancomycin was included in the regimen, reflecting uncertainty about the empirically targeted pathogen spectrum. Children with community-acquired infections had high coverage overall. It is feasible to estimate coverage of common empiric antibiotic regimens from linked data. Pooling data by patient risk groups with similar expected pathogen and susceptibility profiles may improve coverage estimate precision, supporting better differentiation of coverage between regimens. Identification of data sources, selection of regimens and consideration of pathogens to target for improved empiric coverage is important

Monoclonal antibody-based localization of major diagnostic antigens in metacestode tissue, excretory/secretory products, and extracellular vesicles of Echinococcus species

Alveolar (AE) and cystic echinococcosis (CE) are severe parasitic zoonoses caused by the larval stages of Echinococcus multilocularis and E. granulosus sensu lato, respectively. A panel of 7 monoclonal antibodies (mAbs) was selected against major diagnostic epitopes of both species. The binding capacity of the mAbs to Echinococcus spp. excretory/secretory products (ESP) was analyzed by sandwich-ELISA, where mAb Em2G11 and mAb EmG3 detected in vitro extravesicular ESP of both E. multilocularis and E. granulosus s.s. These findings were subsequently confirmed by the detection of circulating ESP in a subset of serum samples from infected hosts including humans. Extracellular vesicles (EVs) were purified, and the binding to mAbs was analyzed by sandwich-ELISA. Transmission electron microscopy (TEM) was used to confirm the binding of mAb EmG3 to EVs from intravesicular fluid of Echinococcus spp. vesicles. The specificity of the mAbs in ELISA corresponded to the immunohistochemical staining (IHC-S) patterns performed on human AE and CE liver sections. Antigenic small particles designated as ‘‘spems’’ for E. multilocularis and ‘‘spegs’’ for E. granulosus s.l. were stained by the mAb EmG3IgM, mAb EmG3IgG1, mAb AgB, and mAb 2B2, while mAb Em2G11 reacted with spems and mAb Eg2 with spegs only. The laminated layer (LL) of both species was strongly visualized by using mAb EmG3IgM, mAb EmG3IgG1, mAb AgB, and mAb 2B2. The LL was specifically stained by mAb Em2G11 in E. multilocularis and by mAb Eg2 in E. granulosus s.l. In the germinal layer (GL), including the protoscoleces, a wide staining pattern with all structures of both species was observed with mAb EmG3IgG1, mAb EmG3IgM, mAb AgB, mAb 2B2, and mAb Em18. In the GL and protoscoleces, the mAb Eg2 displayed a strong E. granulosus s.l. specific binding, while mAb Em2G11 exhibited a weak granular E. multilocularis specific reaction. The most notable staining pattern in IHC-S was found with mAb Em18, which solely bound to the GL and protoscoleces of Echinococcus species and potentially to primary cells. To conclude, mAbs represent valuable tools for the visualization of major antigens in the most important Echinococcus species, as well as providing insights into parasite-host interactions and pathogenesis