Background: Gram-negative bloodstream infections (BSI) are common complications after kidney transplantation. In this cohort study, we evaluated the long-term effect of Gram-negative BSI on allograft survival in kidney transplant recipients. Methods: Among a cohort of 1820 kidney recipients who were prospectively followed at the Mayo Clinic (Rochester, MN) from January 1, 1996, to December 31, 2007, we identified 120 patients with initial episodes of Gram-negative BSI before allograft failure. Multivariable Cox proportional hazard regression was used to examine the association between Gram-negative BSI, as a time-dependent covariate, and allograft and patient survival. Results: The median age of kidney recipients was 51 years (interquartile range, 39-61 years) and 58% were men. Among patients with Gram-negative BSI, 75% had a urinary tract source of infection and Escherichia coli was the most common microorganism (50%). Gram-negative BSI after transplantation was independently associated with allograft loss due to allograft failure or death (hazard ratio [HR], 2.52; 95% confidence intervals [CI], 1.83-3.47; P<0.001), allograft failure with death-censored (HR, 3.17; 95% CI, 2.11-4.76; P<0.001) and all-cause mortality (HR, 2.25; 95% CI, 1.55-3.26; P<0.001). Conclusions: Prevention and proper management of urinary tract infections in kidney recipients is essential to reduce the risk of more serious complications, including Gram-negative BSI, that are associated with reduced allograft and patient survival.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / We analyzed the association between antibiotic resistance and recurrent urinary tract infection (rUTI) by Escherichia coli. Susceptibility levels to 14 antimicrobial agents and the presence of extended-spectrum β-lactamases (ESBL) were established using MicroScan. Incidences of multidrug resistant (MDR), extensively drug resistant (XDR), and ESBL-producer isolates as well as rUTIs were estimated. The time to recurrence was established adjusted for number of antibiotic-resistant families and MDR as predictors of interest, respectively. Overall, 8,553 urinary tract infection (UTI) cases related to E. coli, including 963 rITU, were analyzed with levels of resistance >30% in all cases, except for amikacin, nitrofurantoin, and carbapenems. The incidence of rUTI was of 11.3%, being 46.5%, 24.3%, and 42.5% for MDR, XDR, and ESBLs, respectively. Bivariate analysis showed that rUTI was associated with age, gender, resistance to specific antimicrobials, MDR, and XDR. The number of antibiotic families tested as resistant, MDR, XDR, gender, and age were associated with time to recurrence when adjusted for number of antibiotic families, and MDR, gender, and age were related when adjusted for MDR. High rates of antibiotic resistance to the usual antibiotics was observed in E. coli causing UTI, with female sex, age, and antibiotic resistance being risk factors for the development of rUTI. / Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica / Revisión por pares

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Background 50% of antibiotic courses in long-term care facilities (LTCFs) are unnecessary, leading to increased risk of harm such as Clostridiodes difficile infection and antibiotic-resistant organisms. Antimicrobial Stewardship (AS) interventions plays an important role in optimizing antibiotic use. Most studies to improve antibiotic prescribing in LTCFs showed modest and unsustained results. We aimed to identify facilitators, barriers and strategies in implementing a urinary tract infection (UTI)-focused AS intervention at a LTCF with the secondary objective of exploring the pharmacist’s potential role(s) in this intervention. Methods A qualitative approach using conventional content analysis was used. Through purposeful sampling, we recruited different healthcare providers and administrators at Kensington Gardens. Interviewees attended focus groups or one-on-one interviews. Data were collected using a semi-structured interview guide. Data were analyzed inductively using a codebook modified in an iterative analytic process. Barrier and facilitator themes were identified from the transcripts and mapped using the COM-B (capability, opportunity, motivation and behaviour) model (Michie et al). Similarly, themes were identified from the transcripts regarding the pharmacist’s roles in this intervention. Results Sixteen participants were interviewed. Most barriers and facilitators mapped to the opportunities domain of the COM-B model. The main barrier themes were lack of access, lack of knowledge, ineffective communication, lack of resources and external factors while the main facilitator themes were education, effective collaboration, good communication, sufficient resources and access. For the pharmacist’s role, the barrier themes were ineffective collaboration and communication. Furthermore, the pharmacist can play a role in education and antibiotic selection. Conclusions A UTI-focused antimicrobial stewardship intervention in LTCF should consider strategies to improve access, knowledge, communication and collaboration in its design, having sufficient resources and addressing external factors in order to optimize the intervention’s success. Pharmacists can play a role in education and antibiotic selection. / Thesis / Master of Science (MSc) / Half of antibiotics prescribed in long-term care are not needed, leading to increased harm. It is unclear which strategies should be used to improve antibiotic prescribing. This project aims to identify facilitators, barriers and strategies in identifying and managing urinary tract infection in a long-term care facility as well as exploring the role of the pharmacist in this setting. We conducted focus groups and interviews to gather information and analyzed the transcripts to determine barrier and facilitator themes relating to urinary tract infection management and the role of the pharmacist. The main barrier themes were lack of access, lack of knowledge, ineffective communication, lack of resources and external factors while the main facilitator themes were education, effective collaboration, good communication, sufficient resources and access. For the pharmacist’s role, the barrier themes were ineffective collaboration and communication. In addition, the pharmacist can play a role in education and antibiotic selection.

The overall aim of this thesis was to evaluate methods for urinary catheter handling in patients undergoing hip surgery. The intention was to gain knowledge in order to provide optimal and cost- effective care regarding urinary catheterisation in this group of patients. In Study I , 45 of the 86 catheterised patients (52%) contracted nosocomial urinary tract infections (UTIs). Diabetes was a risk factor for developing UTI, and cloxacillin as a perioperative antibiotic prophylaxis seemed to offer a certain protection. Study II was a randomised controlled trial on the effect of clamping (n = 55) or not (n = 58) of the indwelling urinary catheter before removal. No significant differences were found between the groups with respect to time to normal bladder function, need for recatheterisation, or length of hospital stay. Study III was a randomised controlled trial among patients with hip fracture and hip arthroplasty, in which the patients were randomised to intermittent (n = 85) or indwelling (n = 85) urinary catheterisation. No significant differences in nosocomial UTIs (9% vs. 12%) or cost-effectiveness were shown. The patients in the intermittent group regained normal bladder function significantly sooner after surgery. Fourteen percent of the patients in the intermittent group did not need any catheterisation. In Study IV , 30 patients were interviewed about their experiences of bladder emptying and urinary catheterisation. The patients’ views were described through the main category ‘An issue but of varying impact’. Both bladder emptying through micturition and bladder emptying through catheterisation were described as convenient, but also as uncomfortable and an intrusion on dignity. The patients were aware of risks and complications of urinary catheterisation. In conclusion, this thesis indicates that UTI is common in hip surgery patients. Clamping of indwelling catheters seems not necessary. There is no preference for either intermittent or indwelling urinary catheterisation according to the results of this thesis, either for the development of nosocomial UTI or, for cost-effectiveness, or from the patient perspective. Nurses should be aware that catheterisation might make the patients feel exposed, and it is essential that their practice reflect the best available evidence.

Master of Science / Department of Industrial & Manufacturing Systems Engineering / Malgorzata Rys / Catheter associated urinary tract infections (CAUTIs) are a source of concern in the healthcare industry because they occur more frequently than other healthcare associated infections and the rates of CAUTI have not improved in recent years. The use of urinary catheters is common among patients; between 15 and 25 percent of all hospital patients will use a urinary catheter at some point during their hospitalization (CDC, 2016). The prevalence of urinary catheters in hospitalized patients and high CAUTI occurrence rates led to the application of human factors engineering to develop a tool to help hospitals reduce CAUTI rates. Human reliability analysis techniques are methods used by human factors engineers to quantify the probability of human error in a system. A human error during a catheter insertion has the opportunity to introduce bacteria into the patient’s system and cause a CAUTI; therefore, human reliability analysis techniques can be applied to catheter insertions to determine the likelihood of a human error. A comparison of three human reliability analysis techniques led to the selection of the Cognitive Reliability and Error Analysis Method (CREAM). To predict a patient’s probability of developing a CAUTI, the human error probability found from CREAM is incorporated with several health factors that affect the patient’s risk of developing CAUTI. These health factors include gender, duration, diabetes, and a patient’s use of antibiotics, and were incorporated with the probability of human error using fuzzy logic. Membership functions were developed for each of the health factors and the probability of human error, and the centroid defuzzification method is used to find a crisp value for the probability of a patient developing CAUTI. Hospitals that implement this tool can choose risk levels for CAUTI that places the patient into one of three zones: green, yellow, or red. The placement into the zones depends on the probability of developing a CAUTI. The tool also provides specific best practice interventions for each of the zones.

<p>Urinary tract infections (UTIs) are typically caused by bacteria that colonize different regions of the urinary tract, mainly the bladder and the kidney. Approximately 25% of women that suffer from UTIs experience a recurrent infection within 6 months of the initial bout, making UTIs a serious economic burden resulting in more than 10 million hospital visits and $3.5 billion in healthcare costs in the United States alone. Type-1 fimbriated Uropathogenic E. coli (UPEC) is the major causative agent of UTIs, accounting for almost 90 % of bacterial UTIs. The unique ability of UPEC to bind and invade the superficial bladder epithelium allows the bacteria to persist inside epithelial niches and survive antibiotic treatment. Persistent, intracellular UPEC are retained in the bladder epithelium for long periods, making them a source of recurrent UTIs. Hence, the ability of UPEC to persist in the bladder is a matter of major health and economic concern, making studies exploring the underlying mechanism of UPEC persistence highly relevant. </p><p>In my thesis, I will describe how intracellular Uropathogenic E.coli (UPEC) evade host defense mechanisms in the superficial bladder epithelium. I will also describe some of the unique traits of persistent UPEC and explore strategies to induce their clearance from the bladder. I have discovered that the UPEC virulence factor Alpha-hemolysin (HlyA) plays a key role in the survival and persistence of UPEC in the superficial bladder epithelium. In-vitro and in-vivo studies comparing intracellular survival of wild type (WT) and hemolysin deficient UPEC suggested that HlyA is vital for UPEC persistence in the superficial bladder epithelium. Further in-vitro studies revealed that hemolysin helped UPEC persist intracellularly by evading the bacterial expulsion actions of the bladder cells and remarkably, this virulence factor also helped bacteria avoid t degradation in lysosomes. </p><p>To elucidate the mechanistic basis for how hemolysin promotes UPEC persistence in the urothelium, we initially focused on how hemolysin facilitates the evasion of UPEC expulsion from bladder cells. We found that upon entry, UPEC were encased in “exocytic vesicles” but as a result of HlyA expression these bacteria escaped these vesicles and entered the cytosol. Consequently, these bacteria were able to avoid expulsion by the cellular export machinery. </p><p>Since bacteria found in the cytosol of host cells are typically recognized by the cellular autophagy pathway and transported to the lysosomes where they are degraded, we explored why this was not the case here. We observed that although cytosolic HlyA expressing UPEC were recognized and encased by the autophagy system and transported to lysosomes, the bacteria appeared to avoid degradation in these normally degradative compartments. A closer examination of the bacteria containing lysosomes revealed that they lacked V-ATPase. V-ATPase is a well-known proton pump essential for the acidification of mammalian intracellular degradative compartments, allowing for the proper functioning of degradative proteases. The absence of V-ATPase appeared to be due to hemolysin mediated alteration of the bladder cell F-actin network. From these studies, it is clear that UPEC hemolysin facilitates UPEC persistence in the superficial bladder epithelium by helping bacteria avoid expulsion by the exocytic machinery of the cell and at the same time enabling the bacteria avoid degradation when the bacteria are shuttled into the lysosomes. </p><p>Interestingly even though UPEC appear to avoid elimination from the bladder cell their ability to multiple in bladder cells seem limited.. Indeed, our in-vitro and in-vivo experiments reveal that UPEC survive in superficial bladder epithelium for extended periods of time without a significantly change in CFU numbers. Indeed, we observed these bacteria appeared quiescent in nature. This observation was supported by the observation that UPEC genetically unable to enter a quiescence phase exhibited limited ability to persist in bladder cells in vitro and in vivo, in the mouse bladder. </p><p>The studies elucidated in this thesis reveal how UPEC toxin, Alpha-hemolysin plays a significant role in promoting UPEC persistence via the modulation of the vesicular compartmentalization of UPEC at two different stages of the infection in the superficial bladder epithelium. These results highlight the importance of UPEC Alpha-hemolysin as an essential determinant of UPEC persistence in the urinary bladder.</p> / Dissertation

Properties of Escherichia coli considered to be of importance in overcoming host defence mechanisms against urinary tract infection (OTI) were investigated. These were: 1) 0 and H serotype 2) K antigen content 3) Sensitivity to the bactericidal activity of human serum 4) Haemolysin production 5) Fimbriae production 6) Fermentation of sucrose, salicin and dulcitol 7) Sensitivity to serine, spermine and urea 8) Growth requirements 9) Mucinase production Ecoli strains isolated from normal subjects and patients attending the Nephrourological Clinic at St. Bartholomew's Hospital because of known or suspected UTI, were studied. Strains isolated from urines more frequently belonged to 0 serogroups 2,4,6,8,18ab and 75, had high K antigen titres, were haemolytic and fimbriate, and fermented salicin than periurethral strains from normal subjects. These findings support the concept of "special pathogenicity", that certain strains are more invasive for the urinary tract than others. Strains rich in these "pathogenic properties" were rarely isolated from normal subjects but were significantly more frequently isolated from periurethral swabs of patients. Periurethral strains from symptomatic, abacteriuric (urethral syndrome) patients were similar to those from bacteriuric patients when they were between infections. Previous work has not implicated bacteria in the aetiology of most cases of this disease and this finding remains unexplained. Strains isolated from the upper tracts of patients undergoing localisation tests more frequently exhibited pathogenic properties than those isolated from only the lower tract, and this was considered to reflect the superior ability of these strains to reach the upper tract or better combat host defence mechanisms.

"Bacterial infections persist as a public threat due to the ease by which bacteria adapt to commonly used antibiotics. In addition, bacteria on surfaces develop protective communities called biofilms that hinder the ability of antibiotics to completely eliminate the pathogens. The rapid development of bacterial resistance to antibiotics has made pharmaceutical companies reluctant to fund new antibiotics research. Hence, novel approaches to prevent and treat infections are needed. The development of infections can be divided into three steps: adhesion, invasion and multiplication. Antibiotics target at the latter two step and are prone to bacterial resistance as passive strategies. Bacterial adhesion to host cells/implanted medical devices is the first step leading to following invasion and multiplication. However, fundamental understanding of bacterial adhesion process is still lacking. The current studies are aimed to systematically investigate biological interactions between pathogenic bacteria and host cell, proteins and biomaterials with both macro and micro scale approaches. The macro scale methods include bacterial adhesion assay, viability studies, and thermodynamic modeling. The micro scale methods include direct adhesion force measurements, ultra surface visualization via atomic force microscopy (AFM) and surface structure modeling. Our work combines experiments and modeling aimed at understanding the initial steps of the bacterial adhesion process, focusing on two case studies: 1) Mechanisms by which cranberry can prevent urinary tract infections through interfering with bacterial adhesion; and 2) Design of anti-adhesive and antimicrobial coatings for biomaterials. We make direct adhesion force measurements between bacteria and substrates with an atomic force microscope (AFM), and combine such experiments with thermodynamic calculations, in order to develop a set of tools that allows for the prediction of whether bacteria will attach to a given surface. These fundamental investigations of the bacterial adhesion process help elucidate the underlying mechanisms behind bacterial adhesion, thus leading to improved clinical outcomes for a number of biomedical applications. "

The aim of this study was to determine the prevalence of extended-spectrum b-lactamase (ESBL)- producing Klebsiella pneumoniae isolated from urinary tract and bloodstream infections in a rural hospital in Manhic¸a, Mozambique. ESBLs were investigated among ceftriaxone-non-susceptible K. pneumoniae clinical isolates recovered between 2004 and 2009. Characterisation of blaCTX-M, blaSHV, blaOXA and blaTEM genes was performed by PCR and sequencing. Epidemiological relationships were established by phylogenetic analysis, repetitive extragenic palindromic PCR (REP-PCR), pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST), whilst plasmid transferability was evaluated by conjugation. In addition,the presence of class 1 and 2 integrons was studied.A total of 19 K. pneumoniae were analysed. The blaCTX-M-15 gene was found in all strains. Other ESBL genes were found concomitantly, including blaSHV-5, blaSHV-2, blaSHV-2A, blaSHV-12 and blaSHV-38. In addition, other b-lactamases such as blaTEM-1 and blaOXA-30 were also detected. REP-PCR identified 15 different epidemiological profiles. MLST analysis also showed great variability of sequence types. The blaCTX-M-15 gene showed a high transfer capacity. The presence of class 1 integrons was high. High levels of multidrug resistance were also found. In conclusion, these data show the dominance of the CTX-M-type ESBL, particularly CTX-M-15, supporting its worldwide dissemination, including in areas with limited access to third-generation cephalosporins. This finding is a matter of concern for clinical management as third-generation cephalosporins are an alternative for treating severe cases of multidrug-resistant infections in this community. / Revisión por pares