The objectives of this thesis are : 1) To provide a review of the literature on the significance, pathogenesis, diagnosis and management of secondary infections in the Intensive Care Unit. 2) To present the findings of a study of the technique of selective parenteral and enteral antisepsis regimen (SPEAR) in the patient population of the Respiratory ICU at Groote Schuur Hospital, aimed at reducing the incidence of secondary infection and, further to evaluate the study in terms of the effect of SPEAR on the incidence of secondary infection and its influence on the mortality due to secondary infection. 3) To present the findings of the effect of SPEAR on patient bacterial colonisation in the ICU, and to evaluate its longterm influence on the microbial flora of the ICU.

Patients with cancer who receive bone marrow transplants (BMT) are at increased risk for central line-associated blood stream infections (CLABSI), a serious complication leading to increased costs, length of stay, and even death. Recognition of an increased CLABSI rate at one BMT unit in the southwestern United States prompted development of an evidence-based staff development education program to improve nurses’ knowledge of central line maintenance and CLABSI prevention practices. Guided by Lewin change theory, the program was developed based on a nurse-led analysis and synthesis of the evidence, and a formative evaluation of the educational program conducted by a 3-member expert panel made up of the BMT director, a BMT clinical nurse specialist and vascular access team member. The review confirmed the lack of standardized evidence-based guidelines for central venous catheter care, that any patient who has a central line is at risk for CLABSI, and BMT patients are at particular risk due to frequency of catheter manipulation. Findings reinforced the need for the recommendations to educate nurses in BMT settings on evidence-based central line practices, evaluate knowledge gained, and audit practice techniques post education. The social change implication of this DNP project will be the potential decrease in healthcare costs, length of stay, and mortality associated with central line infections when nursing staff are provided an educational program that aims to improve their knowledge and skills of evidence-based central line care and CLABSI prevention practices.

Les nourrissons âgés de moins de trois mois ont la particularité d’être à relativement haut risque d’infections bactériennes sévères (IBS), majoritairement représentées par les infections urinaires et en particulier celles plus invasives (IBI) que sont les méningites et les bactériémies. On ne dispose actuellement pas d’outil suffisamment fiable et d’un rapport coût-bénéfice bien évalué pour différencier les nourrissons fébriles porteurs d’une affection virale banale de ceux porteurs d’une infection bactérienne.Le travail doctoral avait pour objectifs d’évaluer l’épidémiologie et les pratiques de prise en charge françaises des infections bactériennes de l’enfant fébrile âgé de moins de trois mois admis aux urgences pédiatriques ainsi que des outils diagnostiques, tels que la bandelette urinaire et la procalcitonine dans cette population. Plus de 2000 nourrissons ont été inclus dans une étude prospective observationnelle multicentrique (PRONOUR) sur une période de trente mois d’octobre 2008 à Mars 2011.Nous avons dans un premier temps décrit les modalités de prise en charge de ces jeunes nourrissons fébriles et montré que les pratiques étaient hétérogènes entre les centres participants et variaient par rapport aux recommandations existantes.Nous avons dans un second temps, étudié les pratiques de dépistage des infections urinaires, IBS la plus fréquente dans cette tranche d’âge, et en particulier les performances de la bandelette urinaire. La majorité des urines étaient prélevées par poche collectrice et la bandelette urinaire avait une sensibilité pour la détection d’infection urinaire comparable à celle de l’analyse par microscopie avec cette méthode de recueil.Puis, nous avons réévalué les performances des algorithmes décisionnels existants pour la détection des enfants à faible risque d’IBS dans une nouvelle population (PRONOUR). Nous avons montré qu’ils avaient une valeur prédictive négative satisfaisante comme précédemment décrit, mais une faible valeur prédictive positive pour la distinction des enfants porteurs ou non d’une IBS.Enfin, les performances de la procalcitonine (PCT) dans la détection des IBS et IBI ont été calculées et comparées avec celles d’autres marqueurs inflammatoires usuels. La capacité discriminative de la PCT était excellente pour le diagnostique d’IBI et meilleure que celles des autres marqueurs inflammatoires. Pour la détection d’une IBS, la PCT avait des performances similaires à celles de la C-réactive protein.La prise en charge des nourrissons fébriles âgés de moins de trois mois est hétérogène et pourrait être améliorée par de nouveaux outils prédictifs La prise en charge des nourrissons fébriles âgés de moins de trois mois est hétérogène et pourrait être améliorée par de nouveaux outils prédictifs tels que l’utilisation de la procalcitonine et de la bandelette urinaire dans cette tranche d’âge. / The prevalence of severe bacterial infections (SBI),mainly represented by urinary tract infections is relatively high in infants less than three months of age and particularly those more invasive (IBI) that are meningitis and bacteremia. Current strategies to distinguish young infants with SBIs from those with viral infections are not absolutely reliable and their cost-effectiveness and the associated iatrogenic morbidity have not been extensively evaluated.The purposes of the study were to characterize the spectrum of disease, clinical outcomes and management of febrile infants aged three months or younger admitted to pediatric emergency department in France and to evaluate the performances of diagnostics tests that are urinary dipstick test and procalcitonin assay in this population. A prospective multicenter cohort study was conducted in 15 French pediatric emergency departments over a period of 30 months between October 2008 and March 2011(PRONOUR). More than 2000 infants were enrolled.First, we have described the management of these young febrile infants. We have showed that practices were heterogeneous between the participating centers and varied from the current guidelines.We have analyzed screening strategies of urinary tract infection, the most common SBI in this age group, and in particular we aimed to assess the test performances of urine dipstick test. Most of urine specimens were collected by bag. Dipstick tests on bag urine samples detected urinary tract infections in infants aged 7 to 92 days similarly to microscopy.Then, we have re-evaluated the performances of current strategies for identifying infants at low risk for SBI in a new population (PRONOUR). We have showed that current protocols maintained their good previously reported negative predictive values but have low positive predictive values to detect young infants with SBIs.Finally, the performances parameters of procalcitonine (PCT) for detecting SBI and IBI in this population were calculated and compared with usual biomarkers. Procalcitonin has better diagnostic accuracy than CRP for detecting IBI. The two tests perform similarly for identifying SBI in febrile infants aged 7 to 91 days.The management of febrile infants less than three months of age varied between centers should be improved by new predictive tests. The performance of PCT testing should encourage the development of decision-making rules incorporating PCT and urinary dipstick test.

Nosokomiale Infektionen (NKI) gehören zu den häufigsten Komplikationen eines Krankenhausaufenthaltes, insbesondere auf Intensivstationen mit einer Prävalenz von rund 18,65%. Die Folgen sind eine längere Verweildauer, erhöhte Morbidität und Letalität sowie höhere Kosten für das Gesundheitssystem. Die Erfassung NKI stellt einen wichtigen Qualitäts- Parameter für Intensivstationen dar. Ziel dieser Arbeit war es, die Übereinstimmung von nur nach KISS (Krankenhaus-InfektionsSurveillance System)- Definitionen erfassten Infektionen mit der klinisch diagnostizierten nosokomialen Infektion zu prüfen und den Zusammenhang zwischen ärztlicher Diagnose und den laborchemischen und klinisch erhobenen Kriterien darzustellen. Hierfür wurden auf einer interdisziplinären operativen Intensivstation nosokomiale Infektionen sowohl nach ITS- KISS (VAP, ZVK- assoziierte Infektionen und HWI), als auch nach ärztlicher Diagnose plus Beginn oder Eskalation einer Antibiotikatherapie erfasst. Zusätzlich zu den KISS-Parametern wurden laborchemische Entzündungsparameter (CRP und PCT) registriert. Es traten 32 Infektionen nach ITS- KISS und 69 Infektionen nach ärztlicher Diagnose auf. Acht Infektionen wurden ausschließlich nach KISS und 45 ausschließlich nach der ärztlichen Diagnose erfasst. Die Infektionsrate nach KISS für VAP lag bei 20,6, für ZVK bei 5,9 und für HWI bei 2 Infektionen, jeweils pro 1000 Devicetage. Spezifität und positiv prädiktiver Wert hinsichtlich der Vorhersage einer ärztlich diagnostizierten Infektion waren gering. Auch durch Kombination verschiedener Parameter wurden keine höheren prädiktiven Werte erreicht. Die geringe Übereinstimmung der beiden Methoden legt nahe, dass KISS die klinisch relevanten Infektionen nicht wesentlich erfasst und relevante Infektfoci nicht berücksichtigt werden, beispielsweise abdominelle Infektionen. Zudem erlauben die erfassten Laborparameter keine zuverlässige Diagnose bzw. Prädiktion einer nosokomialen Infektion. Die ärztliche Diagnose in Verbindung mit dem Beginn oder der Eskalation einer Antibiotikatherapie könnte eine vereinfachte Methode zur Surveillance nosokomialer Infektionen darstellen.

Background: More than 90 % of anal cancers are caused by high-risk human papillomavirus (HR HPV) infection and a history of cervical intraepithelial neoplasia (CIN) and cervical cancer is established as possible risk factor. The aim of this study was to demonstrate relationship between anal and cervical HPV infection in women with different grades of CIN and microinvasive cervical cancer and to determinate potential risk factors for concurrent cervical-anal HPV infection. Methods: A total of 272 women were enrolled in the study. The study group included 172 women who underwent conization for high-grade CIN or microinvasive cervical cancer. The control group consisted of 100 women with non-neoplastic gynecologic diseases or biopsy- confirmed CIN 1. All participants completed a questionnaire detailing their medical history and sexual risk factors and were subjected to anal and cervical HPV genotyping using Lynear array test (Roche). Results: Cervical, anal, and concurrent cervical-anal HPV infections were detected in 82.6 %, 48.3 % and 42.4 % of women in the study group, and in 28.0 %, 26.0 % and 8.0 % of women in the control group, respectively. The prevalence of the HR HPV genotypes was higher in the study group and significantly increased with the severity of cervical lesion. Concurrent infections...

The aim of this study was to assess the prevalence and predictive factors of secondary infectionsin patients with coronavirus disease 2019 (COVID-19) and compare with influenza. A retrospective cohort study which included COVID-19 and influenza patients with samples processed at Karolinska University Hospital Laboratory between 1st March 2020 to 1st January2021 and 1st January 2015 to 1st January 2021 respectively. Blood, urine and respiratory culture results from 7 days before and 7 days after the primary diagnosis collected from laboratory information system. Chi-square and Mann-Whitney U test used for descriptive comparison. Predictive factors of secondary infections analyzed using logistic regression. Data includes 16,354 patients:7470 COVID-19 and 8884 influenza. Secondary infections were significantly fewer in COVID-19 patients (26.6%) compared to influenza patients (30%) p<0.01. Lower proportion of episodes with growth (EWG) in blood culture of COVID-19 patients (1.8%) compared to influenza (2.9%) p<0.001. Lower proportion of EWG in respiratory tract cultures of COVID-19 patients (11.1%) compared to influenza patients (24.5%) p<0.001. Higher proportionof EWG in urinary tract cultures of COVID-19 patients (24.5%) compared to influenza (20.1%)p<0.001. Staphylococcus aureus were common bacteria in blood and respiratory tract in both cohorts. Escherichia coli were the most common bacteria in urine in both cohorts. Fungi were least common with unspecified yeast being the most frequent. Likelihood of secondary infection lower in males compared to females AOR 0.70 (95%CI 0.66-0.76)), lower in other clinicalsettings AOR 0.65 (95%CI 0.56-0.76) and increased with age in both COVID-19 and influenza patients (AOR 1.03(95%CI 1.02-1.04)). Higher probability of secondary infections in young influenza patients compared to young COVID-19 patients. A lower prevalence of secondary infections in blood, respiratory tract cultures of COVID-19 patients compared to influenza. Olderage, female sex, intensive care were predictive factors for secondary infections. Findings important for planning of treatment protocols.

Under stress, chlamydiae can enter a non-infectious but viable state termed persistence. In the absence of a tractable genetic system, persistence induction provides an important experimental tool with which to study these fascinating organisms. This review will discuss examples of: i) persistence studies that have illuminated critical chlamydiae/host interactions; and ii) novel persistence models that will do so in the future.

Central line-associated bloodstream infections (CLABSI) are usually attributable to suboptimal line insertion, care, or maintenance and are associated with poor patient outcomes. Nursing plays a pivotal role in preventing CLABSI, because nurses are generally responsible for the routine care and maintenance of central lines. The purpose of this project was to determine if CLABSI nursing education and demonstration-based competency could improve nurses' knowledge on a neurology unit as compared to current practice of an annual e-learning module as the sole source of nurse education. This project was informed by Lewin's planned change theory and involved changing behaviors, attitudes, and practices of nurses via a conducive approach consisting of three phases: unfreezing, movement, and refreezing. To have a foundation in evidence, expert literature supports the project. Participating nurses attended an educational session consisting of a presentation and demonstration-based competency of central line dressing change technique. A pre- and post-test were administered; the mean pretest score was 72.1% and the mean posttest score was 94.1%. Comparison of pre- and post-test scores reflect a 22% increase in test scores, therefore, this program increased knowledge. This project can contribute to positive social change by improving nursing practice through increasing nurses' knowledge of proper care and maintenance of central lines, which can translate into evidence-based practice changes and improve patient outcomes.

Les enzymes de la famille Mur (MurA-MurG) sont essentielles pour la survie bactérienne, car elles catalysent les étapes cytoplasmiques de la biosynthèse du peptidoglycane, la principale composante de la paroi cellulaire. En outre, les Murs métabolisent des molécules qui sont absentes chez les eucaryotes, et ces enzymes sont structurellement et biochimiquement tractables. Cependant, malgré le fait que nombreux inhibiteurs anti-Mur ont été développés, un nombre tres réduit de ces molécules ont montré une activité antibactérienne prometteuse, ce qui a incité l'hypothèse selon laquelle, dans le cytoplasme bactérien, les enzymes Mur peuvent exister dans un complexe où les sites actifs sont à proximité, bloquant donc l'accès de petites molécules venant de l'extérieur. Cette hypothèse est soutenue par l'observation selon laquelle, dans de nombreux organismes, les gènes codant pour les enzymes Mur sont présents dans un seul opéron, souvent dans le même ordre; en outre, souvent des paires de gènes sont fusionnées pour générer un seul polypeptide, préconisant la possibilité que des complexes entre ces enzymes pourraient être formés dès qu'ils sont synthétisés. Nous avons obtenu les premières informations structurales et fonctionnelles sur la forme fusionnée MurE-MurF, présente dans le pathogène humain Bordetella pertussis, et nous avons montré qu'elle interagit avec la glycosyltransférase périphérique MurG, ce qui suggère la présence d'un complexe enzymatique ternaire. De façon intéressante, nous avons constaté que MurG de B. pertussis est capable de s'associer avec elle-même et de former différentes espèces oligomériques. Cette découverte pourrait renforcer le rôle de MurG en tant que protéine agissant comme une plateform capable d'ancrer d'autres enzymes Mur à la face interne de la membrane cytoplasmique bactérienne. Nos resultats pourront également être explorés pour comprendre le rôle potentiel de MurG en tant que régulateur de l'activité des enzymes de synthèse du PG. Ces résultats passionnants ouvriront le chemin vers la compréhension du mecanisme d’interaction des enzymes Mur dans le cytoplasme bactérien et pourraient permettre l'emploi éventuel des Murs comme cibles de facto pour développer de nouveaux antibiotiques. / Enzymes of the Mur family (MurA-MurG) are essential for bacteria, since they catalyse the cytoplasmic steps of peptidoglycan biosynthesis, the major component of bacterial cell wall; they metabolize molecules that do not exist in eukaryotes, and are structurally and biochemically tractable. However, despite the fact that many anti-Mur inhibitors have been developed, few of these molecules have shown promising antibacterial activity, which has prompted the hypothesis that within the bacterial cytoplasm Mur enzymes may exist in a complex where the active sites are in closed proximity, blocking small molecule access from the outside. This suggestion is supported by the observation that in many organisms, genes encoding Mur enzymes are present in a single operon, often in the same order, and often pairs of genes are fused to generate a single polypeptide, advocating the possibility that complexes between these enzymes could be formed as soon as they are synthesized. We have obtained the first structural and functional information on the MurE-MurF fused form, present in the human pathogen Bordetella pertussis, and shown that it interacts with the peripheral glycosyltransferase MurG, suggesting the presence of a ternary enzymatic complex. Interestingly, we have found that B. pertussis MurG is able to self-associate and form different oligomeric species. This finding could strengthen the hypothesis of MurG as a scaffold protein capable of anchoring other Murs to the inner face of bacterial inner membrane, but could be also further explored to understand its potential role as a regulator of the activity of PG synthesis enzymes. These exciting results will open the path towards the understanding of how Mur enzymes interact within the bacterial cytoplasm, and could permit the eventual employment of Mur enzymes as de facto targets for novel antibiotic development.

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