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Urinary tract infections (UTIs) are among the most prevalent microbial diseases and their financial burden on society is substantial. In the context of increasing antibiotic resistance, finding alternative treatments for UTIs is a top priority. We aimed to determine whether intravesical bacteriophage therapy with a commercial bacteriophage cocktail is effective in treating UTI. We did a randomised, placebo-controlled, clinical trial, at the Alexander Tsulukidze National Centre of Urology, Tbilisi, Georgia. Men older than 18 years of age, who were scheduled for transurethral resection of the prostate (TURP), with complicated UTI or recurrent uncomplicated UTI but no signs of systemic infection, were allocated by block randomisation in a 1:1:1 ratio to receive intravesical Pyo bacteriophage (Pyophage; 20 mL) or intravesical placebo solution (20 mL) in a double-blind manner twice daily for 7 days, or systemically applied antibiotics (according to sensitivities) as an open-label standard-of-care comparator. Urine culture was taken via urinary catheter at the end of treatment (ie, day 7) or at withdrawal from the trial. The primary outcome was microbiological treatment response after 7 days of treatment, measured by urine culture; secondary outcomes included clinical and safety parameters during the treatment period. Analyses were done in a modified intention-to-treat population of patients having received at least one dose of the allocated treatment regimen. This trial is registered with ClinicalTrials.gov, NCT03140085. Between June 2, 2017, and Dec 14, 2018, 474 patients were screened for eligibility and 113 (24%) patients were randomly assigned to treatment (37 to Pyophage, 38 to placebo, and 38 to antibiotic treatment). 97 patients (28 Pyophage, 32 placebo, 37 antibiotics) received at least one dose of their allocated treatment and were included in the primary analysis. Treatment success rates did not differ between groups. Normalisation of urine culture was achieved in five (18%) of 28 patients in the Pyophage group compared with nine (28%) of 32 patients in the placebo group (odds ratio [OR] 1·60 [95% CI 0·45–5·71]; p=0·47) and 13 (35%) of 37 patients in the antibiotic group (2·66 [0·79–8·82]; p=0·11). Adverse events occurred in six (21%) of 28 patients in the Pyophage group compared with 13 (41%) of 32 patients in the placebo group (OR 0·36 [95% CI 0·11–1·17]; p=0·089) and 11 (30%) of 37 patients in the antibiotic group (0·66 [0·21–2·07]; p=0·47). Intravesical bacteriophage therapy was non-inferior to standard-of-care antibiotic treatment, but was not superior to placebo bladder irrigation, in terms of efficacy or safety in treating UTIs in patients undergoing TURP. Moreover, the bacteriophage safety profile seems to be favourable. Although bacteriophages are not yet a recognised or approved treatment option for UTIs, this trial provides new insight to optimise the design of further large-scale clinical studies to define the role of bacteriophages in UTI treatment. Swiss Continence Foundation, the Swiss National Science Foundation, and the Swiss Agency for Development and Cooperation. For the Georgian and German translations of the abstract see Supplementary Materials section.

Recent advances in the analysis of microbial communities colonizing the human body have identified a resident microbial community in the human urinary tract (UT). Compared to many other microbial niches, the human UT harbors a relatively low biomass. Studies have identified many genera and species that may constitute a core urinary microbiome. However, the contribution of the UT microbiome to urinary tract infection (UTI) and recurrent UTI (rUTI) pathobiology is not yet clearly understood. Evidence suggests that commensal species within the UT and urogenital tract (UGT) microbiomes, such as Lactobacillus crispatus , may act to protect against colonization with uropathogens. Recent advances in the analysis of microbial communities colonizing the human body have identified a resident microbial community in the human urinary tract (UT). Compared to many other microbial niches, the human UT harbors a relatively low biomass. Studies have identified many genera and species that may constitute a core urinary microbiome. However, the contribution of the UT microbiome to urinary tract infection (UTI) and recurrent UTI (rUTI) pathobiology is not yet clearly understood. Evidence suggests that commensal species within the UT and urogenital tract (UGT) microbiomes, such as Lactobacillus crispatus , may act to protect against colonization with uropathogens. However, the mechanisms and fundamental biology of the urinary microbiome-host relationship are not understood. The ability to measure and characterize the urinary microbiome has been enabled through the development of next-generation sequencing and bioinformatic platforms that allow for the unbiased detection of resident microbial DNA. Translating technological advances into clinical insight will require further study of the microbial and genomic ecology of the urinary microbiome in both health and disease. Future diagnostic, prognostic, and therapeutic options for the management of UTI may soon incorporate efforts to measure, restore, and/or preserve the native, healthy ecology of the urinary microbiomes.

The use of long-term catheterisation to manage insensate bladders, often associated with spinal cord injury (SCI), increases the risk of microbial colonisation and infection of the urinary tract. Urinary tract infection (UTI) is typically diagnosed and treated based on the culturing of organisms from the urine, although this approach overlooks low titer, slow growing and non-traditional pathogens. Here, we present an investigation of the urinary tract microbiome in catheterised SCI individuals, using T-RFLP and metagenomic sequencing of the microbial community. We monitored three neurogenic patients over a period of 12 months, who were part of a larger study investigating the efficacy of probiotics in controlling UTIs, to determine how their urinary tract microbial community composition changed over time and in relation to probiotic treatment regimens. Bacterial biofilms adherent to urinary catheters were examined as a proxy for bladder microbes. The microbial community composition of the urinary tract differed significantly between individuals. Probiotic therapy resulted in a significant change in the microbial community associated with the catheters. The community also changed as a consequence of UTI and this shift in community composition preceded the clinical diagnosis of infection. Changes in the microbiota due to probiotic treatment or infection were transient, resolving to microbial communities similar to their pre-treatment communities, suggesting that the native community was highly resilient. Based on these results, we propose that monitoring a patient's microbial community can be used to track the health of chronically catheterized patients and thus, can be used as part of a health-status monitoring program.

In a trial involving infants with grade III, IV, or V vesicoureteral reflux and no previous UTI, continuous antibiotic prophylaxis for 2 years provided a small but significant benefit in preventing a first UTI.

New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23). Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Shionogi.

The objective is to review the literature related to lower urinary tract (LUT) conditions in children to conceptualize general practice guidelines for the general practitioner, pediatrician, pediatric urologist, and urologist. PubMed was searched for the last 15-year literature by the committee. All articles in peer-review journal-related LUT conditions (343) have been retrieved and 76 have been reviewed extensively. Prospective trials were few and the level of evidence was low. Most of the recommendations have been done by committee consensus after extensive discussion of literature reports. History taking is an integral part of evaluation assessing day- and nighttime urine and bowel control, urgency, and frequency symptoms. Exclusion of any neurogenic and organic cause is essential. Uroflowmetry and residual urine determination are recommended in all patients to evaluate bladder emptying. Urodynamic studies are reserved for refractory or complicated cases. Urotherapy that aims to educate the child and family about bladder and bowel function and guides them to achieve normal voiding and bowel habits should initially be employed in all cases except those who have urinary tract infections (UTI) and constipation. Specific medical treatment is added in the case of refractory overactive bladder symptoms and recurrent UTIs.Conclusion: Producing recommendations for managing LUTS in children based on high-quality studies is not possible. LUTS in children should be evaluated in a multimodal way by minimal invasive diagnostic procedures. Urotherapy is the mainstay of treatment and specific medical treatment is added in refractory cases.What is Known:• Symptoms of the lower urinary tract may have significant social consequences and sometimes clinical morbidities like urinary tract infections and vesicoureteral reflux. In many children, however, there is no such obvious cause for the incontinence, and they are referred to as having functional bladder problems.What is New:• This review aims to construct a practical recommendation strategy for the general practitioner, pediatrician, pediatric urologist, and urologist for LUTS in children. Producing recommendations for managing LUTS in children based on high-quality studies is not possible. LUTS in children should be evaluated in a multimodal way by minimal invasive diagnostic procedures. Urotherapy is the mainstay of treatment and specific medical treatment is added in refractory cases.

Key Points Urinary tract infections (UTIs) are some of the most common bacterial infections and are caused by both Gram-negative and Gram-positive species. UTIs are categorized into uncomplicated and complicated, and are a severe public health problem; this situation is being exacerbated by the rise in multidrug-resistant strains. Uropathogens carry multiple virulence factors involved in the pathophysiology of UTIs. These virulence factors are involved in invasion and colonization, as well as in mediating the subversion of host defences. Knowledge about the mechanism of action of these virulence factors is being used to develop new therapeutics against UTIs. Therapies that are currently in the initial stages of development include vaccines targeting bacterial factors that are essential for initial attachment and disease progression (such as adhesins, toxins, proteases and siderophores), and small-molecule inhibitors that prevent adhesin–receptor interactions. Urinary tract infections (UTIs) pose a severe public health problem and are caused by a range of pathogens. In this Review, Hultgren and colleagues discuss how basic science studies are elucidating the molecular mechanisms of UTI pathogenesis and how this knowledge is being used for the development of novel clinical treatments for UTIs. Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Enterococcus faecalis and Staphylococcus saprophyticus . High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the molecular details of the crosstalk that occurs at the host–pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs. We also describe current efforts to translate this knowledge into new clinical treatments for UTIs.

BackgroundWe present a consensus view from the International Children’s Continence Society (ICCS) on the evaluation and management of bladder bowel dysfunction (BBD) in children with urinary tract infection (UTI). The statement aims to highlight the importance of BBD in the development and recurrence of childhood UTI and its management to reduce its associated morbidity and sequelae.MethodsA systematic literature search was done on PubMed, Embase, and Scopus databases until August 15, 2016. Relevant publications concerning BBD and its relationship with UTI among children were reviewed and aggregated for statements of recommendation. Discussion by the ICCS Board and a multi-disciplinary core group of authors resulted in a document available on its website for all ICCS members to review. Insights and feedback were considered with consensus and agreement reached to finalize this position statement.ResultsBBD in children with UTI is summarized. Details regarding epidemiology, pathophysiology, and recommendations for general and family practitioners and pediatricians relating to the evaluation and management of this condition are presented.ConclusionsThis document serves as the position statement from ICCS, based on literature review and expert opinion providing our current understanding of BBD in children with UTI.

Selecting optimal therapeutic interventions for febrile urinary tract infection (f-UTI) is crucial to prevent complications such as kidney scarring. While current clinical guidelines provide risk-stratified imaging recommendations, they are largely based on Western populations and lack specific predictors for which children will ultimately require therapeutic interventions. This study aimed to establish risk stratification criteria for East Asian children with first-episode f-UTI. This retrospective single-center study analyzed patients aged 2–24 months with first-episode f-UTI. All patients underwent a standardized diagnostic and management protocol, including kidney–bladder ultrasound (KBUS) and voiding cystourethrography (VCUG), to ensure uniform evaluation. The primary outcome was “requirement for therapeutic intervention,” defined as one or more of the following: (1) urological surgery (2) antimicrobial prophylaxis (for vesicoureteral reflux grade ≥III) and (3) antimicrobial treatment for recurrent f-UTI. Multivariate logistic regression was performed to identify independent predictors associated with the interventions. A total of 216 patients were included (median age: 4 months). Overall, 59 patients required therapeutic interventions. Non- Escherichia coli infection (OR 3.3, 95% CI 1.3–8.7) and abnormal KBUS findings (OR 5.3, 95% CI 2.7–10.6) were identified as independent predictors. The sensitivity and specificity of the factors for predicting therapeutic intervention were 64.4% and 73.2%, respectively. This study identified non- E. coli infection and abnormal KBUS findings as key predictors for therapeutic interventions in East Asian children with first-episode f-UTI. These findings suggest that a more targeted approach based on these factors may optimize risk stratification and patient selection for VCUG, improving clinical decision-making.

Women with uncomplicated urinary tract infection (UTI) symptoms are commonly treated with empirical antibiotics, resulting in overuse of antibiotics, which promotes antimicrobial resistance. Available diagnostic tools are either not cost-effective or diagnostically sub-optimal. Here, we identified clinical and urinary immunological predictors for UTI diagnosis. We explored 17 clinical and 42 immunological potential predictors for bacterial culture among women with uncomplicated UTI symptoms using random forest or support vector machine coupled with recursive feature elimination. Urine cloudiness was the best performing clinical predictor to rule out (negative likelihood ratio [LR−] = 0.4) and rule in (LR+ = 2.6) UTI. Using a more discriminatory scale to assess cloudiness (turbidity) increased the accuracy of UTI prediction further (LR+ = 4.4). Urinary levels of MMP9, NGAL, CXCL8 and IL-1β together had a higher LR+ (6.1) and similar LR− (0.4), compared to cloudiness. Varying the bacterial count thresholds for urine culture positivity did not alter best clinical predictor selection, but did affect the number of immunological predictors required for reaching an optimal prediction. We conclude that urine cloudiness is particularly helpful in ruling out negative UTI cases. The identified urinary biomarkers could be used to develop a point of care test for UTI but require further validation.