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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.

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.

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.

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.

Purpose To test whether d -mannose powder is effective for recurrent urinary tract infection (UTI) prevention. Materials and methods After initial antibiotic treatment of acute cystitis, 308 women with history of recurrent UTI and no other significant comorbidities were randomly allocated to three groups. The first group ( n  = 103) received prophylaxis with 2 g of d -mannose powder in 200 ml of water daily for 6 months, the second ( n  = 103) received 50 mg Nitrofurantoin daily, and the third ( n  = 102) did not receive prophylaxis. Results Overall 98 patients (31.8 %) had recurrent UTI: 15 (14.6) in the d -mannose group, 21 (20.4) in Nitrofurantoin group, and 62 (60.8) in no prophylaxis group, with the rate significantly higher in no prophylaxis group compared to active groups ( P  < 0.001). Patients in d -mannose group and Nitrofurantoin group had a significantly lower risk of recurrent UTI episode during prophylactic therapy compared to patients in no prophylaxis group (RR 0.239 and 0.335, P  < 0.0001). In active groups, 17.9 % of patients reported side effects but they were mild and did not require stopping the prophylaxis. Patients in d -mannose group had a significantly lower risk of side effects compared to patients in Nitrofurantoin group (RR 0.276, P  < 0.0001), but the clinical importance of this finding is low because Nitrofurantoin was well tolerated. Conclusions In our study, d -mannose powder had significantly reduced the risk of recurrent UTI which was no different than in Nitrofurantoin group. More studies will be needed to validate the results of this study, but initial findings show that d -mannose may be useful for UTI prevention.

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.

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 adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82–1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

OBJECTIVE To describe antimicrobial resistance patterns for healthcare-associated infections (HAIs) that occurred in 2011-2014 and were reported to the Centers for Disease Control and Prevention's National Healthcare Safety Network. METHODS Data from central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonias, and surgical site infections were analyzed. These HAIs were reported from acute care hospitals, long-term acute care hospitals, and inpatient rehabilitation facilities. Pooled mean proportions of pathogens that tested resistant (or nonsusceptible) to selected antimicrobials were calculated by year and HAI type. RESULTS Overall, 4,515 hospitals reported that at least 1 HAI occurred in 2011-2014. There were 408,151 pathogens from 365,490 HAIs reported to the National Healthcare Safety Network, most of which were reported from acute care hospitals with greater than 200 beds. Fifteen pathogen groups accounted for 87% of reported pathogens; the most common included Escherichia coli (15%), Staphylococcus aureus (12%), Klebsiella species (8%), and coagulase-negative staphylococci (8%). In general, the proportion of isolates with common resistance phenotypes was higher among device-associated HAIs compared with surgical site infections. Although the percent resistance for most phenotypes was similar to earlier reports, an increase in the magnitude of the resistance percentages among E. coli pathogens was noted, especially related to fluoroquinolone resistance. CONCLUSION This report represents a national summary of antimicrobial resistance among select HAIs and phenotypes. The distribution of frequent pathogens and some resistance patterns appear to have changed from 2009-2010, highlighting the need for continual, careful monitoring of these data across the spectrum of HAI types. Infect Control Hosp Epidemiol 2016;1-14.

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.