Le sepsis sévère est l’une des causes de mortalité les plus fréquentes à travers le monde. L’étiologie la plus fréquente étant des infections causées par des bactéries, le traitement repose sur l’administration rapide d’un traitement antibiotique adapté. Toutefois, la diminution de la sensibilité des bactéries observée au cours des dernières années nous pousse à repenser notre utilisation des antibiotiques. Parmi les options envisageables, on retrouve l’utilisation de nouveaux antibiotiques et l’optimisation des posologies d’antibiotiques couramment utilisés. Dans les deux cas, la modélisation pharmacocinétique est un outil indispensable pour caractériser la pharmacocinétique des agents antimicrobiens et ainsi guider les posologies. Les études pharmacocinétiques comportent toutefois de nombreux défis en pédiatrie. Afin de les contourner, nous avons utilisé des méthodes à risques minimaux pour étudier deux molécules chez les enfants : le linézolide, un nouvel antibiotique de la classe des oxazolidinones, qui a été administré chez des nouveau-nés prématurés, et la pipéracilline-tazobactam, une bêta-lactamine fréquemment utilisée en pédiatrie, qui a été administrée en utilisant une nouvelle posologie sous forme d’infusions prolongées. Premièrement, nous avons effectué une étude pharmacocinétique rétrospective du linézolide aux soins intensifs néonataux du CHU Sainte-Justine. Le linézolide est un antibiotique qui peut être utilisé pour traiter les infections causées par le staphylocoque à coagulase négative chez les nouveau-nés prématurés. Il s’agit d’une pratique relativement nouvelle et un programme de surveillance des concentrations plasmatiques avait été instauré il y a quelques années pour encadrer l’utilisation du linézolide dans cette population. Nous avons utilisé les données de ce programme et construit un modèle pharmacocinétique de population en utilisant des méthodes de modélisation non-linéaire à effets mixtes. Nous avons ainsi pu démontrer que les posologies utilisées chez les 26 nouveau-nés inclus dans notre étude atteignaient la cible préalablement déterminée (aire sous la courbe/concentration minimale inhibitrice [ASC/CMI 0-24] > 80), et qu’elles étaient donc probablement efficaces. De plus, nous avons observé que le linézolide semblait sécuritaire dans cette population. Nous nous sommes ensuite intéressés aux infusions prolongées de pipéracilline-tazobactam en pédiatrie. Déjà bien décrite dans la population adulte, l’utilisation d’infusions prolongées permet d’optimiser l’efficacité des bêta-lactamines puisque cette dernière dépend du temps où les concentrations plasmatiques sont supérieures à la concentration minimale inhibitrice (ƒt > CMI). Comme aucune posologie n’était établie en pédiatrie, nous avons d’abord effectué une étude de simulation où nous avons déterminé les posologies dites « optimales » en utilisant les paramètres pharmacocinétiques décrits en pédiatrie. Nous avons par la suite effectué une étude pharmacocinétique prospective où les posologies préalablement établies ont été administrées à 89 enfants de deux mois à six ans, duquel 79 ont eu des prélèvements sanguins pour déterminer les concentrations plasmatiques. Deux modèles pharmacocinétiques de population distincts (pipéracilline et tazobactam) ont été développés en utilisant la modélisation non-linéaire à effets mixtes. Des simulations ont par la suite été effectuées en utilisant le modèle final de la pipéracilline pour déterminer les posologies optimales selon l’âge. Pour des bactéries avec une CMI à 16 mg/L, nous avons observé que des infusions prolongées étaient nécessaires pour atteindre notre cible préalablement déterminée (ƒt > CMI > 50%) chez les enfants de six mois à six ans (130 mg/kg/dose toutes les 8 heures administré sur 4 heures), alors que des durées d’infusion standard de trente minutes étaient suffisantes chez les nourrissons de deux à six mois (75 mg/kg/dose toutes les 4 heures administré sur 30 minutes). Notre étude supporte également la faisabilité et l’innocuité des infusions prolongées en pédiatrie. / Severe sepsis remains one of the most important causes of pediatric mortality around the world. Bacterial infections represent the most common cause, and effective treatment depends on the prompt administration of antibiotics. However, we observe a concerning decrease in susceptibility to antibiotics over the last decades, prompting us to reevaluate our antibiotics use. New antibiotics or novel ways of administering currently available antibiotics more efficiently are the two main alternatives when facing increased antibiotic resistance. In both cases, pharmacokinetic (PK) modeling represents an invaluable tool to guide dosing. However, PK studies in children are challenging. We used minimal risk methods to study two different antibiotics in children: Linezolid, a new oxazolidinone antibiotic that was administered to premature neonates, and piperacillin-tazobactam, a frequently used beta-lactam that we administered in a novel way using extended infusions. First, we conducted a single-center retrospective PK study of linezolid in premature neonates in the neonatal intensive care unit of the CHU Sainte-Justine. We built a population PK model using nonlinear mixed-effects modeling with plasmatic concentrations collected for therapeutic drug monitoring per standard of care. We were able to demonstrate that the dosing regimens used in the 26 neonates included in our study reached our established target (area under the curve over the minimal inhibitory concentration [AUC/MIC 0-24] > 80), and, therefore, were deemed efficient. Moreover, we collected adverse events and found that linezolid administration appeared safe in this population. We then focused on piperacillin-tazobactam extended infusions in children. Beta-lactams efficacy depends on the fraction of time that concentrations are above the MIC (ƒt > MIC). Extended infusions are a simple way to achieve higher ƒt > MIC and are well studied in adults. Based on published piperacillin-tazobactam PK parameters in children, we first conducted a simulation PK study to establish optimal extended infusions dosing in children. We then conducted a single-center prospective PK study where the established dosing regimens were administered to 89 children from two months to six years old. Of those, 79 children contributed plasma PK samples. Two PK models (piperacillin and tazobactam) were developed using nonlinear mixed-effects modeling. Simulations were conducted using our final piperacillin model, allowing us to determine optimal dosing regimens according to age. For bacteria with MICs up to 16 mg/L, extended infusions (130 mg/kg/dose every 8 hours infused over 4 hours) were needed in children six months to six years old to reach our established target (ƒt > MIC > 50%), whereas standard 30 minutes infusion (75 mg/kg/dose every 4 hours infused over 30 minutes) were adequate in infants two months to six months old. Our study also supported the feasibility and safety of extended infusions in young children.

Sepsis represents a serious medical problem accounting for numerous deaths of critically ill patients in intensive care units (ICUs). An early, sensitive, and specific diagnosis is considered a key element for improving the outcome of sepsis patients. In addition to classical laboratory markers, ICU scoring systems and serum miRNAs are discussed as potential sepsis biomarkers. In the present prospective observational study, the suitability of miRNAs in sepsis diagnosis was tested based on proper validated and normalized data (i.e., absolute quantification by means of Droplet Digital PCR (ddPCR)) in direct comparison to classical sepsis markers and ICU scores within the same patient cohort. Therefore, blood samples of septic intensive care patients (n = 12) taken at day of admission at ICU were compared to non-septic intensive care patients (n = 12) and a healthy control group (n = 12). Our analysis indicates that all tested biomarkers have only a moderate informative power and do not allow an unequivocal differentiation between septic and non-septic ICU patients. In conclusion, there is no standalone laboratory parameter that enables a reliable diagnosis of sepsis. miRNAs are not superior to classical parameters in this respect. It seems recommendable to measure multiple parameters and scores and to interpret them with regard to the clinical presentation.

Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) (n = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n = 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro blood culture experiments and in vivo experiments in mouse models were performed to assess biological plausibility. A low serum IFNg/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies in vitro revealed that IFNg/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an in silico analysis of published IFNg and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNg/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNg/IL10 may become a suitable theranostic marker for an urging clinical need.

The liver regulates inflammation during sepsis, and most liver functions are carried out by hepatocytes. Bacterial lipids, including lipopolysaccharide (LPS) and lipoteichoic acid (LTA), can be cleared by hepatocytes, but the underlying mechanisms are uncertain. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates uptake of LPS by hepatocytes, but it is unknown whether LTA uptake is similarly regulated. Therefore, our objectives were to characterize the PCSK9-regulated pathway of bacterial lipid uptake by hepatocytes by identifying whether low-density lipoprotein (LDL) receptor (LDLR) and LDLR-related protein 1 (LRP1) are the target receptors, and by determining which lipoproteins are involved. To study this pathway, we assessed the uptake of fluorescently-labeled LPS or LTA by human HepG2 hepatocytes using flow cytometry. We pre-treated HepG2 cells with PCSK9, alone or in combination with anti-LDLR or anti-LRP1 antibodies, in order to identify the PCSK9-regulated receptors that are involved, and utilized media containing normal serum or lipoprotein-deficient serum to investigate the lipoprotein- dependence of this pathway. We also determined the roles of LDL and HDL in bacterial lipid uptake through a series of add-back experiments to lipoprotein-deficient serum, and blocked LDLR to confirm that LDLR mediates LDL-dependent uptake. The HepG2 cell response to variable degrees of bacterial lipid uptake was also assessed in a subset of experiments by measuring several cytokines and extracellular alanine aminotransferase (ALT) activity in the cell culture supernatant. We found that PCSK9 regulates LDLR-mediated uptake of both LPS and LTA through an LDL-dependent mechanism, while LRP1 is not involved. Increased bacterial lipid uptake did not result in any hepatocellular injury or cytokine production, as measured by ALT activity and interleukin (IL)-6, IL-8, IL-10, and IL-17 concentrations. In conclusion, we completed our objective of characterizing the PCSK9-regulated pathway of bacterial lipid uptake, and provide supporting evidence for targeting PCSK9 as a novel therapeutic avenue in sepsis. / Thesis / Master of Science (MSc) / Bacterial compounds stimulate inflammation that can be overwhelming during sepsis. Understanding the processes behind uptake and clearance of these compounds may lead to better sepsis treatments. Therefore, our goal was to understand how uptake of two bacterial compounds, lipopolysaccharide and lipoteichoic acid, occurs by liver cells called hepatocytes. Hepatocytes are naturally equipped to clear foreign compounds, so understanding their role in clearing bacterial compounds is important. Another goal was to identify the role of the protein PCSK9 in this uptake process, as treatments targeting PCSK9 could be applied to sepsis once we understand its role in this disease. Our research demonstrates the negative role of PCSK9 in regulating uptake of lipopolysaccharide and lipoteichoic acid through a lipoprotein receptor called LDLR, and identifies the role of lipoproteins in this process. These findings further our understanding of the hepatocyte response to bacterial compounds in relation to sepsis, and identify PCSK9 as a potential target for new sepsis therapies.

Sepsis is life-threatening organ dysfunction produced by a dysregulated host response to infection in which neutrophils release neutrophil extracellular traps (NETs). NETs consist of DNA, histones, and antimicrobial peptides which kill pathogens. However, DNA and histones also exert damage by activating the intrinsic pathway of coagulation and inducing endothelial cell death, respectively. AADH, a 15kDa non-anticoagulant unfractionated heparin (UFH), prevents histone-mediated cytotoxicity in vitro and improves survival in septic mice. We explored the effectiveness of Vasoflux, a 5.5kDa low-molecular-weight-heparin as an anti-sepsis treatment as compared to enoxaparin and UFH. Vasoflux has reduced anticoagulant functions and hence reduces the risk of bleeding as compared to enoxaparin or UFH. We showed that UFH, enoxaparin, or Vasoflux at concentrations of up to 13.3uM, 40uM, or 40uM, neutralize histone-mediated cytotoxicity. These results suggest that these glycosaminoglycans (GAGs) are able to neutralize histone-mediated cytotoxicity independent of the AT-binding pentasaccharide. To quantitate the binding affinity between GAGs and histones, surface plasmon resonance was conducted. UFH is a more potent inhibitor of histone-mediated cytotoxicity compared to Vasoflux as UFH has a 10-fold greater binding affinity to histones compared to Vasoflux. To translate our in vitro findings to in vivo, Vasoflux, enoxaparin, and UFH were administered in a murine model of sepsis. Vasoflux at 8mg/kg - 50mg/kg reduced survival and exhibited damage in the lung, liver, and kidney in septic mice compared to 10 mg/kg of UFH or 8mg/kg of enoxaparin. This may be due to Vasoflux and UFH disrupting the DNA-histone complex, thereby releasing free procoagulant DNA. This is evident by our gel electrophoresis experiments, where addition of 1uM Vasoflux or 3.3uM UFH to DNA-histone complexes lead to histone dissociation from DNA. UFH bound to histones may be able to inhibit DNA-mediated thrombin generation, as it retains its anticoagulant properties, demonstrated by UFH-histone complexes attenuating DNA and TF-mediated thrombin generation. In contrast, Vasoflux may not neutralize the procoagulant DNA leading to a hypercoagulable state in the mice. Our study may have important clinical implications as there is an ongoing trial, HALO, which will administer intravenous UFH to patients suspected to have septic shock to reduce mortality. Based on our results, future clinical trials should consider the antithrombin-dependent anticoagulant activity of UFH being used as a sepsis treatment. / Thesis / Master of Science (MSc) / Sepsis is a life threatening condition caused by the body’s extreme response to microbial infection of the blood, whereby neutrophils release traps composed of cell-free DNA (cfDNA), histones, and antimicrobial proteins. In addition to fighting off infections, these traps also exert harmful effects like triggering clotting and killing host cells. Currently, no specific anti-septic drugs exist. Studies have shown that DNase1 (a recombinant protein that digests double stranded cfDNA) or a modified form of heparin (neutralizes histones) improves survival in septic mice. Our goal was to explore the protective effects of Vasoflux, (a non-anticoagulant heparin) and DNase1 in a mouse model of sepsis. We hypothesize that the combined therapy of DNase1 and Vasoflux will improve survival. We found that Vasoflux has minimal blood thinning activity and can prevent histones from killing cells. However, Vasoflux administered into septic mice worsened organ damage and decreased survival. We hypothesize that this damage may be due to Vasoflux’s ability to displace histones from histone-DNA complexes, thereby releasing free DNA, which promotes excessive blood clotting in sepsis.

Bakgrund: Sepsis är en livshotande överreaktion i immunförsvaret som kan uppstå av en infektion. Tidig identifiering av sepsis är fundamentalt för att tillhandahålla snabb och effektiv vård. Detta skapar goda förutsättningar för patientens överlevnad. Syfte: Att kartlägga faktorer som påverkar sjuksköterskans identifiering av sepsis. Metod: För att sammanfatta och skapa en bild av det nuvarande kunskapsläget har en litteraturöversikt med kvantitativ design genomförts. Polit och Becks 9-stegs flödesschema utgjorde strukturen för skapandet av litteraturöversikten. Sökningar i databaserna CINAHL, MEDLINE och PsycINFO resulterade i 14 artiklar till resultatet, publicerade mellan 2012–2023. Resultat: I resultatet framkom att faktorer som påverkar sjuksköterskans identifiering av sepsis var sjuksköterskans kunskap, genomgången utbildning, hjälpmedel vid sepsisidentifiering samt bristande arbetsförhållanden. Bland annat framkom att sepsisidentifiering försenades på grund av bristande kunskap om sepsissymtom samt hög arbetsbelastning, och främjades av utbildning om sepsis och användning av screeningverktyg. Slutsats: Litteraturöversikten kartlägger faktorer som främjar och hindrar sjuksköterskans identifiering av sepsis. Detta möjliggör tidig adekvat behandling som skapar goda förutsättningar för överlevnad. Kärnkompetensen samverkan i team är grundläggande för samordning av vårdens resurser för en god och säker vård. / Background: Sepsis is a life-threatening overreaction in the immune system that can arise from an infection. Early identification of sepsis is fundamental to provide prompt and effective care. This creates good prerequisites for the patient's survival. Purpose: To map factors that influence the nurse's identification of sepsis. Method: To summarize and create a picture of the current state of knowledge a literature review with a quantitative design was conducted. Polit and Beck's 9-step flow chart formed the structure for the creation of the literature review. Searches in the databases CINAHL, MEDLINE and PsycINFO resulted in 14 articles used in the result, published between 2012-2023. Results: The result showed that factors influencing the nurse's identification of sepsis were the nurse's knowledge, completed training, aids for sepsis identification and lacking working conditions. Among other things, it appeared that sepsis identification was delayed due to a lack of knowledge about sepsis symptoms and high workload and was improved by education about sepsis and the use of screening tools. Conclusion: This literature review identifies factors that promote and impede the nurse’s identification of sepsis. This enables early adequate treatment which creates good conditions for survival. The core competency of collaboration in teams is fundamental for coordinating care resources for good and safe care.

Yes / Objectives: To develop a logistic regression model to predict the risk of sepsis following emergency medical admission using the patient’s first, routinely collected, electronically recorded vital signs and blood test results and to validate this novel computer-aided risk of sepsis model, using data from another hospital. Design: Cross-sectional model development and external validation study reporting the C-statistic based on a validated optimized algorithm to identify sepsis and severe sepsis (including septic shock) from administrative hospital databases using International Classification of Diseases, 10th Edition, codes. Setting: Two acute hospitals (York Hospital - development data; Northern Lincolnshire and Goole Hospital - external validation data). Patients: Adult emergency medical admissions discharged over a 24-month period with vital signs and blood test results recorded at admission. Interventions: None. Main Results: The prevalence of sepsis and severe sepsis was lower in York Hospital (18.5% = 4,861/2,6247; 5.3% = 1,387/2,6247) than Northern Lincolnshire and Goole Hospital (25.1% = 7,773/30,996; 9.2% = 2,864/30,996). The mortality for sepsis (York Hospital: 14.5% = 704/4,861; Northern Lincolnshire and Goole Hospital: 11.6% = 899/7,773) was lower than the mortality for severe sepsis (York Hospital: 29.0% = 402/1,387; Northern Lincolnshire and Goole Hospital: 21.4% = 612/2,864). The C-statistic for computer-aided risk of sepsis in York Hospital (all sepsis 0.78; sepsis: 0.73; severe sepsis: 0.80) was similar in an external hospital setting (Northern Lincolnshire and Goole Hospital: all sepsis 0.79; sepsis: 0.70; severe sepsis: 0.81). A cutoff value of 0.2 gives reasonable performance. Conclusions: We have developed a novel, externally validated computer-aided risk of sepsis, with reasonably good performance for estimating the risk of sepsis for emergency medical admissions using the patient’s first, electronically recorded, vital signs and blood tests results. Since computer-aided risk of sepsis places no additional data collection burden on clinicians and is automated, it may now be carefully introduced and evaluated in hospitals with sufficient informatics infrastructure. / Health Foundation

Le cytosquelette se compose de microfilaments (polymères d'actine), de microtubules (polymères de tubuline) et de filaments intermédiaires (polymères de desmine, de lamines ...). Le sepsis défini par une infection associée à une réaction inflammatoire systémique est responsable de dysfonctions myocardiques de mauvais pronostique. Cette cardiomyopathie apparait dans les premières heures du sepsis et guérit en moins de deux semaines chez les survivants. Même si certaines études démontrent l'implication d'éléments du cytosquelette dans la cardiomyopathie septique, les rôles des microfilaments et des microtubules ne sont pas clairement établis.Macrophage migration inhibitory factor (MIF) est une cytokine pro-inflammatoire sécrétée en excès dans le sepsis qui serait responsable d'un ralentissement de la récupération myocardique. Dans un premier temps, notre travail a consisté à caractériser l'implication des microtubules dans la dysfonction musculaire cardiaque induite par MIF. Dans un modèle de trabécules auriculaires droites humaines nous avons démontré que MIF induit une hyperpolymérisation des microtubules responsable d'une hyperviscosité intracellulaire, d'une dysfonction mitochondriale et d'une dysfonction contractile. Nos résultats suggèrent qu'une hyperpolymérisation des microtubules induite par MIF pourrait être responsable d'un ralentissement de la récupération myocardique à la phase tardive de la myocardiopathie septique. Dans un second temps, nous avons évalué l'implication des microfilaments dans un modèle murin de dysfonction myocardique inflammatoire induite par l'injection d'une endotoxine bactérienne, le lipopolysaccharide. Nos résultats suggèrent qu'à la phase précoce de la cardiomyopathie inflammatoire il existe une hyperpolymérisation des microfilaments responsable de dysfonctions contractile et mitochondriale.Les connaissances fondamentales acquises au cours de ce travail de thèse suggèrent une implication directe des microtubules et des microfilaments dans la physiopathologie des cardiomyopathies inflammatoires.

Bacterial infections are a major cause of morbidity and mortality in both the community and nosocomial settings, particularly among the elderly and chronically ill. Sepsis is the body’s response to antigens and toxins released by the invasive pathogenic organisms that cause infection. When infection is not effectively controlled, sepsis may develop and progress to severe sepsis and septic shock. Early diagnosis and treatment is pivotal for survival in severe sepsis and particularly, septic shock. Our research focuses on developing a novel treatment strategy for septic shock by using single, ultra-high doses of aminoglycosides. In this project, the effect of a single, ultra-high dose of gentamicin in clearing bacteria from the blood and reducing the bacterial burden in vital organs was evaluated in a rat model of E. coli (Bort strain) induced peritonitis with severe sepsis/septic shock. Serum cytokine levels and serum lactate levels were serially measured. Further, the potential adverse effects of ultra-high dosing of aminoglycoside antibiotics in a short-term (9 h) invasive study and long term (180 days) non-invasive study were assessed. Neuromuscular paralyses due to ultra-high doses of aminoglycosides were assessed. In addition, renal injury markers such as serum creatinine and urinary Neutrophil Gelatinase Associated Lipocalin (NGAL) were assayed. The auditory and vestibular function was also assessed after ultra-high dosing of aminoglycoside in the long-term study. We conclude that animals can tolerate ultra-high doses of aminoglycosides with appropriate support. Animals were under neuromuscular paralysis for 28 – 50 minutes and were on ventilator support after single ultra-high doses (80 and 160 mg/kg) of aminoglycoside antibiotics (gentamicin and tobramycin). There was no significant acute or delayed renal or ototoxicity associated with the single, ultra-high dose aminoglycoside therapy. Histology studies of the kidneys and the cochlea of single, ultra-high aminoglycoside dosed animals and untreated control animals were performed after 180 days (6 months). Results indicated that there were no morphological differences between the treated and untreated control animals. Terminal deoxy-nucleotidyl transferase dUTP nick end labeling (TUNEL) assay of kidney tissue indicated that there was no apoptosis of endothelial cells in the tubular and glomerular regions with single, ultra- high dose of aminoglycosides consistent with an absence of ultrahigh dose induced nephrotoxicity. In the septic shock model, the E. coli Bort was below the limit of detection from the blood of the animals within minutes after single, ultra-high dose aminoglycoside administration. After necropsy, bacterial load was determined from all the vital organs and peritoneal fluid (site of infection). The bacterial levels were below the detection limit from the kidneys and there was a significant reduction in bacterial counts from all the remaining organs compared to the infected control animals. A decrease in serum cytokine and serum lactate levels compared to baseline was observed after ultra-high doses of aminoglycosides in the septic shock animals. Our studies have indicated that the ultra-high dose gentamicin is well tolerated by rats. It is highly effective in clearing E. coli Bort from the blood and reducing the bacterial burden in the organs in an experimental model of bacterial peritonitis/septic shock. Further studies in larger animals such as rabbits, sheep, pigs or dogs are required to confirm these results. If these findings are replicated in larger animals, this therapy may be developed further from ‘lab to bedside’ to treat septic shock patients in intensive care units (ICUs). / October 2015

Résumé Introduction: Les infections urinaires (IU) sont les infections bactériennes les plus fréquentes chez les patients hospitalisés. Cette étude décrit les tendances temporelles d'admission et de mortalité liées aux hospitalisations pour les IU, ainsi que le fardeau économique associé. Les prédicteurs de mauvaise évolution clinique et de mortalité sont examinés par la suite. Méthodes: Les données ont été extraites à partir de la base de données du NIS entre le 1er janvier 1998 et le 31 décembre 2010. 1,717,181 hospitalisations liées aux IU ont été retenues. L'incidence et la mortalité ont été calculées et stratifiées selon le sexe, l'âge et la présence de sepsis. Les frais médians et totaux pour les hospitalisations sont calculés et ajustés pour l'inflation. Finalement, les prédicteurs d'avoir un sepsis induit par les IU et de mortalité sont examinés avec une analyse par régression logistique multivariée. Résultats: L'incidence globale d'hospitalisation et la mortalité associées aux IU voit une croissance annuel estimé (EAPC) de +4.764 et +4.610 respectivement (p<0.0001). L'augmentation d'incidence est le plus marquée pour les patients âgés de 55 à 64 ans (EAPC = +7.805; p<0.0001). Les frais médians par hospitalisation ont augmenté de $10 313 en 1998 à $21 049 en 2010 (EAPC +9.405; p<0.0001). Les frais globaux pour les hospitalisations des IU ont augmenté de $8.9 milliard en 1998 à $33.7 milliard en 2010 (EAPC +0.251; p<0.0001). Les patients âgés, de sexe masculin, de race afro-américaine, ainsi que les patients assurés par Medicaid ou ceux sans assurance, et les patients soignés à des centres non-académiques sont à risque plus important de mortalité (p<0.0001). Conclusion: L'incidence et la mortalité associées aux IU ont augmenté au cours de la dernière décennie. Les frais médians ajustés pour l'inflation ainsi que les frais globaux ont augmenté progressivement au cours de la période d'étude. Dans la cohorte étudiée, les patients âgés, de sexe masculin, de race afro-américaine, ainsi que les patients assurés par Medicaid ou ceux sans assurance, et les patients soignés à des centres non-académiques sont à risque plus important de mortalité. Ces données représentent des indicateurs de qualité de soins qui pourraient permettre d'adapter certaines politiques de soins de santé aux besoins des sous-populations plus vulnérables. / Abstract Introduction: Urinary tract infections (UTIs) are the most common bacterial infections in hospitalized patients. This study describes the temporal trends of admissions and mortality, as well as the economic burden of UTI-associated hospitalizations. Predictors of having severe disease as well as predictors of mortality were also examined. Methods: Data were retrieved from the Nationwide Inpatient Sample between 1998 and 2010, yielding a weighted sample of 1,717,181 UTI-associated admissions. Incidence and mortality rates were calculated and stratified according to gender, age, and the presence of sepsis. The median and total charges of hospitalization were calculated and adjusted for inflation. Finally, predictors of UTI induced sepsis and mortality were examined using logistic regression models. Results: The overall incidence and mortality of UTI-admissions has been increasing with an EAPC of +4.764 and +4.610 respectively (p<0.0001). The increase of UTI-admissions is most remarkable for patients aged 55-64 years (EAPC = +7.805; p<0.0001). Median cost per hospitalization has increased from $10,313 in 1998 to $21,049 (EAPC +9.405; p<0.0001). Overall total inpatient yearly cost rose from $8.9 billion in 1998 to $33.7 billion in 2010 (EAPC +0.251; p<0.0001). Increasing age, male gender, African-American race, patients with Medicaid or no insurance and those treated at non-academic centers are at increased risk of UTI-associated inpatient mortality (p<0.0001). Conclusion: The incidence and mortality of UTI-associated hospitalization has increased over the last decade. The inflation-adjusted median cost of UTI-hospitalization as well as the total overall annual associated cost have been steadily increasing. In these patients, male gender, African-American race, those with Medicaid or no insurance and those treated in non-academic hospitals represent attributes associated with higher risk of mortality. These findings represent candidate quality indicators to adapt health care policy for particularly vulnerable sub-populations.