High-throughput Identification of Bacteria Repellent Polymers for Medical Devices.

Medical devices are often associated with hospital-acquired infections, which place enormous strain on patients and the healthcare system as well as contributing to antimicrobial resistance. One possible avenue for the reduction of device-associated infections is the identification of bacteria-repellent polymer coatings for these devices, which would prevent bacterial binding at the initial attachment step. A method for the identification of such repellent polymers, based on the parallel screening of hundreds of polymers using a microarray, is described here. This high-throughput method resulted in the identification of a range of promising polymers that resisted binding of various clinically relevant bacterial species individually and also as multi-species communities. One polymer, PA13 (poly(methylmethacrylate-co-dimethylacrylamide)), demonstrated significant reduction in attachment of a number of hospital isolates when coated onto two commercially available central venous catheters. The method described could be applied to identify polymers for a wide range of applications in which modification of bacterial attachment is important.

Fortified interpenetrating polymers - bacteria resistant coatings for medical devices.

Infections arising from contaminated medical devices are a serious global issue, contributing to antibiotic resistance and imposing significant strain on healthcare systems. Since the majority of medical device-associated infections are biofilm related, efforts are being made to generate either bacteria-repellent or antibacterial coatings aimed at preventing bacterial colonisation. Here, we utilise a nanocapsule mediated slow release of a natural antimicrobial to improve the performance of a bacteria repellent polymer coating. Poly(lauryl acrylate) nanocapsules containing eugenol (4-allyl-2-methoxyphenol) were prepared and entrapped within a interpenetrating network designed to repel bacteria. When coated on a catheter and an endotracheal tube, this hemocompatible system allowed slow-release of eugenol, resulting in notable reduction in surface-bound Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus.

Bacteria repelling poly(methylmethacrylate-co-dimethylacrylamide) coatings for biomedical devices†Electronic supplementary information (ESI) available: Polymer microarray screening, including analysis of bacterial adhesion by fluorescence microscopy and SEM, and chemical composition of bacteria repelling polymers identified in the screen; polymer synthesis and characterisation; preparation of catheter pieces and solvent studies, and details for confocal imaging/analysis. See DOI: 10.1039/c4tb01129eClick here for additional data file.

Nosocomial infections due to bacteria have serious implications on the health and recovery of patients in a variety of medical scenarios. Since bacterial contamination on medical devices contributes to the majority of nosocomical infections, there is a need for redesigning the surfaces of medical devices, such as catheters and tracheal tubes, to resist the binding of bacteria. In this work, polyurethanes and polyacrylates/acrylamides, which resist binding by the major bacterial pathogens underpinning implant-associated infections, were identified using high-throughput polymer microarrays. Subsequently, two 'hit' polymers, PA13 (poly(methylmethacrylate-co-dimethylacrylamide)) and PA515 (poly(methoxyethylmethacrylate-co-diethylaminoethylacrylate-co-methylmethacrylate)), were used to coat catheters and substantially shown to decrease binding of a variety of bacteria (including isolates from infected endotracheal tubes and heart valves from intensive care unit patients). Catheters coated with polymer PA13 showed up to 96% reduction in bacteria binding in comparison to uncoated catheters.

An integrated model for developing research skills in an undergraduate medical curriculum: appraisal of an approach using student selected components.

Student selected components (SSCs), at that time termed special study modules, were arguably the most innovative element in Tomorrow's Doctors (1993), the document from the General Medical Council that initiated the modernization of medical curricula in the UK. SSCs were proposed to make up one-third of the medical curriculum and provide students with choice, whilst allowing individual schools autonomy in how SSCs were utilized. In response, at the University of Edinburgh the undergraduate medical curriculum provides an integrated and sequential development and assessment of research skill learning outcomes, for all students in the SSC programme. The curriculum contains SSCs which provide choice to students in all 5 years. There are four substantial timetabled SSCs where students develop research skills in a topic and speciality of their choice. These SSCs are fully integrated and mapped with core learning outcomes and assessment, particularly with the 'Evidence-Based Medicine and Research' programme theme. These research skills are developed incrementally and applied fully in a research project in the fourth year. One-third of students also perform an optional intercalated one-year honours programme between years 2 and 3, usually across a wide range of honours schools at the biomedical science interface. Student feedback is insightful and demonstrates perceived attainment of research competencies. The establishment of these competencies is discussed in the context of enabling junior graduate doctors to be effective and confident at utilizing their research skills to effectively practice evidence-based medicine. This includes examining their own practice through clinical audit, developing an insight into the complexity of the evidence base and uncertainty, and also gaining a view into a career as a clinical academic.

Reducing ventilator-associated pneumonia in intensive care: impact of implementing a care bundle.

OBJECTIVES: Ventilator-associated pneumonia is the most common intensive care unit-acquired infection. Although there is widespread consensus that evidenced-based interventions reduce the risk of ventilator-associated pneumonia, controversy has surrounded the importance of implementing them as a "bundle" of care. This study aimed to determine the effects of implementing such a bundle while controlling for potential confounding variables seen in similar studies. DESIGN: A before-and-after study conducted within the context of an existing, independent, infection surveillance program. SETTING: An 18-bed, mixed medical-surgical teaching hospital intensive care unit. PATIENTS: All patients admitted to intensive care for 48 hrs or more during the periods before and after intervention. INTERVENTIONS: A four-element ventilator-associated pneumonia prevention bundle, consisting of head-of-bed elevation, oral chlorhexidine gel, sedation holds, and a weaning protocol implemented as part of the Scottish Patient Safety Program using Institute of Health Care Improvement methods. MEASUREMENTS AND MAIN RESULTS: Compliance with head-of-bed elevation and chlorhexidine gel were 95%-100%; documented compliance with "wake and wean" elements was 70%, giving overall bundle compliance rates of 70%. Compared to the preintervention period, there was a significant reduction in ventilator-associated pneumonia in the postintervention period (32 cases per 1,000 ventilator days to 12 cases per 1,000 ventilator days; p<.001). Statistical process control charts showed the decrease was most marked after bundle implementation. Patient cohorts staying ≥6 and ≥14 days had greater reduction in ventilator-associated pneumonia acquisition and also had reduced antibiotic use (reduced by 1 and 3 days; p=.008/.007, respectively). Rates of methicillin-resistant Staphylococcus aureus acquisition also decreased (10% to 3.6%; p<.001). CONCLUSIONS: Implementation of a ventilator-associated pneumonia prevention bundle was associated with a statistically significant reduction in ventilator-associated pneumonia, which had not been achieved with earlier ad hoc ventilator-associated pneumonia prevention guidelines in our unit. This occurred despite an inability to meet bundle compliance targets of 95% for all elements. Our data support the systematic approach to achieving high rates of process compliance and suggest systematic introduction can decrease both infection incidence and antibiotic use, especially for patients requiring longer duration of ventilation.

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients.

Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kδ. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection.

Diagnostic importance of pulmonary interleukin-1beta and interleukin-8 in ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is the most commonly fatal nosocomial infection. Clinical diagnosis of VAP remains notoriously inaccurate. The hypothesis was tested that significantly augmented inflammatory markers distinguish VAP from conditions closely mimicking VAP. METHODS: A prospective, observational cohort study was carried out in two university hospital intensive care units recruiting 73 patients with clinically suspected VAP, and a semi-urban primary care practice recruiting a reference group of 21 age- and sex-matched volunteers. Growth of pathogens at >10(4) colony-forming units (cfu)/ml of bronchoalveolar lavage fluid (BALF) distinguished VAP from "non-VAP". Inflammatory mediators were quantified in BALF and serum. Mediators showing significant differences between patients with and without VAP were analysed for diagnostic utility by receiver operator characteristic (ROC) curves. RESULTS: Seventy-two patients had recoverable lavage-24% had VAP. BALF interleukin-1beta (IL-1beta), IL-8, granulocyte colony-stimulating factor and macrophage inflammatory protein-1alpha were significantly higher in the VAP group (all p<0.005). Using a cut-off of 10 pg/ml, BALF IL-1beta generated negative likelihood ratios for VAP of 0.09. In patients with BALF IL-1beta <10 pg/ml the post-test probability of VAP was 2.8%. Using a cut-off value for IL-8 of 2 ng/ml, the positive likelihood ratio was 5.03. There was no difference in cytokine levels between patients with sterile BALF and those with growth of <10(4) cfu/ml. CONCLUSIONS: BALF IL-1beta and IL-8 are amongst the strongest markers yet identified for accurately demarcating VAP within the larger population of patients with suspected VAP. These findings have potential implications for reduction in unnecessary antibiotic use but require further validation in larger populations.