Validation of bladder health scales and function indices for women's research.

BACKGROUND: Existing bladder-specific measures lack the ability to assess the full range of bladder health, from poor to optimal health. OBJECTIVE: This study aimed to report evidence of validity of the self-administered, multidimensional bladder health scales and function indices for research in adult women. STUDY DESIGN: A cross-sectional population-based validation study with random assignment to paper or electronic administration was conducted using national address-based probability sampling supplemented by purposive sampling of women with lower urinary tract symptoms in 7 clinical research centers. Construct validity of the bladder health scales and function indices was guided by a multitrait-multimethod approach using health and condition-specific questionnaires, bladder diaries, expert ratings of bladder health, and noninvasive bladder function testing. Internal dimensional validity was evaluated using factor analysis; internal reliability was assessed using paired t-tests and 2-way mixed-effects intraclass correlation coefficient models. Chi-square, Fisher exact, or t-tests were used for mode comparisons. Convergent validity was evaluated using Pearson correlations with the external construct measures, and known-group validity was established with comparison of women known and unknown to be symptomatic of urinary conditions. RESULTS: The sample included 1072 participants. Factor analysis identified 10 scales, with Cronbach's alpha ranging from 0.74 to 0.94. Intraclass correlation coefficients of scales ranged from 0.55 to 0.94. Convergent validity of the 10 scales and 6 indices ranged from 0.52 to 0.83. Known-group validity was confirmed for all scales and indices. Item distribution was similar by mode of administration. CONCLUSION: The paper and electronic forms of the bladder health scales and function indices are reliable and valid measures of bladder health for use in women's health research.

Survey of lower urinary tract symptoms in United States women using the new lower urinary tract dysfunction research Network-Symptom Index 29 (LURN-SI-29) and a national research registry.

PURPOSE: An online bladder health survey was administered to national registry volunteers to: (1) determine the feasibility of using ResearchMatch for studying lower urinary tract symptoms (LUTS); (2) pilot the new, comprehensive Lower Urinary Tract Dysfunction Research Network Symptom Index-29 (LURN-SI-29) and determine its ability to detect known associations with LUTS; and (3) explore novel areas of bladder health in community-based women. METHODS: A cross-sectional web-based survey was administered to a random sample of ResearchMatch adult female, transgender and non-binary volunteers. Participant demographics, health characteristics, the LURN-SI-29, and LUTS-related experiences were collected. RESULTS: A total of 1725 ReseachMatch volunteers with a mean age of 44.0 years completed the study and were eligible for the analysis. Participants were primarily white, cisgendered, highly educated, nulliparous, and premenopausal. The median LURN-SI-29 score was 17 (interquartile range: 11-26). More than half the sample reported urinary urgency (71.0%), nocturia (65.7%), and stress incontinence (52.3%) a "few times" or more in the last 7 days. Approximately half reported sensation of incomplete bladder emptying (49.6%) with one-third reporting urgency incontinence (37.6%); notably, 52.6% of respondents reported being at least "somewhat" bothered by LUTS. LURN-SI-29 scores increased with age, body mass index, decrements in self-reported health, medical comorbidity, parity, menopausal status, and urinary symptom bother, providing evidence of convergent validity. LURN-SI-29 scores varied by race and education, with the lowest scores in Asian and highly educated women. CONCLUSION: Overall, the prevalence and spectrum of LUTS in an online research registry of women volunteers were high and comparable to other population-based samples. The new LURN-SI-29 demonstrated its ability to detect expected associations with demographic and health characteristics in a nonclinical population.

Asymptomatic Bacteriuria and Pyuria in Premenopausal Women.

BACKGROUND: Asymptomatic bacteriuria and pyuria in healthy women often trigger inappropriate antimicrobial treatment, but there is a paucity of data on their prevalence and persistence. METHODS: To evaluate the prevalence and persistence of asymptomatic bacteriuria and pyuria in women at high risk of recurrent urinary tract infection, we conducted an observational cohort study in 104 healthy premenopausal women with a history of recurrent urinary tract infection with daily assessments of bacteriuria, pyuria, and urinary symptoms over a 3-month period. RESULTS: The mean age of participants was 22 years, and 74% were white. Asymptomatic bacteriuria events (urine cultures with colony count ≥105 CFU/mL of a uropathogen on days with no symptomatic urinary tract infection diagnosed) occurred in 45 (45%) women on 159 (2.5%) of 6283 days. Asymptomatic bacteriuria events were most commonly caused by Escherichia coli, which was present on 1.4% of days, with a median duration of 1 day (range, 1-10). Pyuria occurred in 70 (78%) of 90 evaluable participants on at least 1 day and 25% of all days on which no symptomatic urinary tract infection was diagnosed. The positive predictive value of pyuria for E. coli asymptomatic bacteriuria was 4%. CONCLUSIONS: In this population of healthy women at high risk of recurrent urinary tract infection, asymptomatic bacteriuria is uncommon and, when present, rarely lasts more than 2 days. Pyuria, on the other hand, is common but infrequently associated with bacteriuria or symptoms. These data strongly support recommendations not to screen for or treat asymptomatic bacteriuria or pyuria in healthy, nonpregnant women.

Response to Persistent ER Stress in Plants: A Multiphasic Process That Transitions Cells from Prosurvival Activities to Cell Death.

The unfolded protein response (UPR) is a highly conserved response that protects plants from adverse environmental conditions. The UPR is elicited by endoplasmic reticulum (ER) stress, in which unfolded and misfolded proteins accumulate within the ER. Here, we induced the UPR in maize (Zea mays) seedlings to characterize the molecular events that occur over time during persistent ER stress. We found that a multiphasic program of gene expression was interwoven among other cellular events, including the induction of autophagy. One of the earliest phases involved the degradation by regulated IRE1-dependent RNA degradation (RIDD) of RNA transcripts derived from a family of peroxidase genes. RIDD resulted from the activation of the promiscuous ribonuclease activity of ZmIRE1 that attacks the mRNAs of secreted proteins. This was followed by an upsurge in expression of the canonical UPR genes indirectly driven by ZmIRE1 due to its splicing of Zmbzip60 mRNA to make an active transcription factor that directly upregulates many of the UPR genes. At the peak of UPR gene expression, a global wave of RNA processing led to the production of many aberrant UPR gene transcripts, likely tempering the ER stress response. During later stages of ER stress, ZmIRE1's activity declined, as did the expression of survival modulating genes, Bax inhibitor1 and Bcl-2-associated athanogene7, amid a rising tide of cell death. Thus, in response to persistent ER stress, maize seedlings embark on a course of gene expression and cellular events progressing from adaptive responses to cell death.

Analysis validation has been neglected in the Age of Reproducibility.

Increasingly complex statistical models are being used for the analysis of biological data. Recent commentary has focused on the ability to compute the same outcome for a given dataset (reproducibility). We argue that a reproducible statistical analysis is not necessarily valid because of unique patterns of nonindependence in every biological dataset. We advocate that analyses should be evaluated with known-truth simulations that capture biological reality, a process we call "analysis validation." We review the process of validation and suggest criteria that a validation project should meet. We find that different fields of science have historically failed to meet all criteria, and we suggest ways to implement meaningful validation in training and practice.

Escherichia coli Resistance to Fluoroquinolones in Community-Acquired Uncomplicated Urinary Tract Infection in Women: a Systematic Review.

Antibiotic resistance is a threat to public health, and uncomplicated urinary tract infections (uUTIs) are an example of this concern. This systematic review (International Prospective Register of Systematic Reviews [PROSPERO] ID: CRD42020156674) is the first to determine the prevalence of Escherichia coli resistance to fluoroquinolones in women with community-acquired uUTI. PubMed and Embase searches were conducted; 38 studies fulfilled eligibility criteria and were included in the systematic review. Within Europe, ciprofloxacin resistance in E. coli isolates varied between countries and increased in some from 2006 to 2008 and 2014 to 2016, specifically in the United Kingdom (0.5% to 15.3%), Germany (8.7% to 15.1%), and Spain (22.9% to 30.8%), although methodologies and settings were often not comparable. In Asia, there was a substantial increase in ciprofloxacin resistance during 2008 to 2014 from 25% to more than 40%. In North America, resistance to ciprofloxacin also increased between 2008 and 2017, from 4% to 12%. Data exploring different age groups did not show a consistent relationship with resistance, whereas two studies found that fluoroquinolone resistance was higher in postmenopausal women than premenopausal women. One study indicated a link between fluoroquinolone resistance and uUTI recurrence. These findings may have implications for the empirical treatment of uUTI with fluoroquinolones globally, but more data are needed to fully understand regional situations and impact patient management.

A Bayesian multivariate meta-analysis of prevalence data.

When conducting a meta-analysis involving prevalence data for an outcome with several subtypes, each of them is typically analyzed separately using a univariate meta-analysis model. Recently, multivariate meta-analysis models have been shown to correspond to a decrease in bias and variance for multiple correlated outcomes compared with univariate meta-analysis, when some studies only report a subset of the outcomes. In this article, we propose a novel Bayesian multivariate random effects model to account for the natural constraint that the prevalence of any given subtype cannot be larger than that of the overall prevalence. Extensive simulation studies show that this new model can reduce bias and variance when estimating subtype prevalences in the presence of missing data, compared with standard univariate and multivariate random effects models. The data from a rapid review on occupation and lower urinary tract symptoms by the Prevention of Lower Urinary Tract Symptoms Research Consortium are analyzed as a case study to estimate the prevalence of urinary incontinence and several incontinence subtypes among women in suspected high risk work environments.

Treatment and Prevention of Recurrent Lower Urinary Tract Infections in Women: A Rapid Review with Practice Recommendations.

PURPOSE: Recurrent lower urinary tract infections in women are a highly prevalent and burdensome condition for which best practice guidelines for treatment and prevention that minimize harm and optimize well-being are greatly needed. To inform development of practice recommendations, a rapid literature review of original research, systematic reviews, meta-analyses and practice guidelines was conducted. MATERIALS AND METHODS: PubMed®, Embase®, Opus, Scopus®, Google Scholar, The Cochrane Library and the U.S. National Guideline Clearinghouse electronic databases were searched from inception to September 22, 2017. Articles and practice guidelines were included if they were in English, were peer reviewed, included women, involved treatment or prevention strategies for recurrent urinary tract infection and reported an outcome related to recurrence rates of urinary tract infection. Critical appraisal of original studies was conducted using the Cochrane risk of bias tool, and of systematic reviews using the AMSTAR 2 tool. RESULTS: Of 1,582 citations identified 74 met our study inclusion criteria. These comprised 49 randomized controlled trials, 23 systematic reviews (16 with meta-analyses) and 2 practice guidelines. No study reported a multi-targeted treatment approach. There was a lack of high quality studies and systematic reviews evaluating prevention strategies for recurrent urinary tract infection. CONCLUSIONS: We recommend an algorithmic approach to care that includes education on lifestyle and behavioral modifications, and addresses specific populations of women with antimicrobial based and nonantibiotic alternatives. This approach includes the use of vaginal estrogen with or without lactobacillus containing probiotics in postmenopausal women, low dose post-coital antibiotics for recurrent urinary tract infection associated with sexual activity in premenopausal women, low dose daily antibiotic prophylaxis in premenopausal women with infections unrelated to sexual activity, and methenamine hippurate and/or lactobacillus containing probiotics as nonantibiotic alternatives. Future research should involve consistent use of terminology, validated instruments to assess response to interventions and patient perspectives on care. Our treatment algorithm is based on the best available evidence, and fills a gap in the literature and practice regarding effective strategies to prevent recurrent urinary tract infection in women.

Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine.

In human urinary tract infections, host cells release the antimicrobial protein siderocalin (SCN; also known as lipocalin-2, neutrophil gelatinase-associated lipocalin, or 24p3) into the urinary tract. By binding to ferric catechol complexes, SCN can sequester iron, a growth-limiting nutrient for most bacterial pathogens. Recent evidence links the antibacterial activity of SCN in human urine to iron sequestration and metabolomic variation between individuals. To determine whether these metabolomic associations correspond to functional Fe(III)-binding SCN ligands, we devised a biophysical protein binding screen to identify SCN ligands through direct analysis of human urine. This screen revealed a series of physiologic unconjugated urinary catechols that were able to function as SCN ligands of which pyrogallol in particular was positively associated with high urinary SCN activity. In a purified, defined culture system, these physiologic SCN ligands were sufficient to activate SCN antibacterial activity against Escherichia coli In the presence of multiple SCN ligands, native mass spectrometry demonstrated that SCN may preferentially combine different ligands to coordinate iron, suggesting that availability of specific ligand combinations affects in vivo SCN antibacterial activity. These results support a mechanistic link between the human urinary metabolome and innate immune function.

Human Urinary Composition Controls Antibacterial Activity of Siderocalin.

During Escherichia coli urinary tract infections, cells in the human urinary tract release the antimicrobial protein siderocalin (SCN; also known as lipocalin 2, neutrophil gelatinase-associated lipocalin/NGAL, or 24p3). SCN can interfere with E. coli iron acquisition by sequestering ferric iron complexes with enterobactin, the conserved E. coli siderophore. Here, we find that human urinary constituents can reverse this relationship, instead making enterobactin critical for overcoming SCN-mediated growth restriction. Urinary control of SCN activity exhibits wide ranging individual differences. We used these differences to identify elevated urinary pH and aryl metabolites as key biochemical host factors controlling urinary SCN activity. These aryl metabolites are well known products of intestinal microbial metabolism. Together, these results identify an innate antibacterial immune interaction that is critically dependent upon individualistic chemical features of human urine.

Voided midstream urine culture and acute cystitis in premenopausal women.

BACKGROUND: The cause of acute uncomplicated cystitis is determined on the basis of cultures of voided midstream urine, but few data guide the interpretation of such results, especially when gram-positive bacteria grow. METHODS: Women from 18 to 49 years of age with symptoms of cystitis provided specimens of midstream urine, after which we collected urine by means of a urethral catheter for culture (catheter urine). We compared microbial species and colony counts in the paired specimens. The primary outcome was a comparison of positive predictive values and negative predictive values of organisms grown in midstream urine, with the presence or absence of the organism in catheter urine used as the reference. RESULTS: The analysis of 236 episodes of cystitis in 226 women yielded 202 paired specimens of midstream urine and catheter urine that could be evaluated. Cultures were positive for uropathogens in 142 catheter specimens (70%), 4 of which had more than one uropathogen, and in 157 midstream specimens (78%). The presence of Escherichia coli in midstream urine was highly predictive of bladder bacteriuria even at very low counts, with a positive predictive value of 10(2) colony-forming units (CFU) per milliliter of 93% (Spearman's r=0.944). In contrast, in midstream urine, enterococci (in 10% of cultures) and group B streptococci (in 12% of cultures) were not predictive of bladder bacteriuria at any colony count (Spearman's r=0.322 for enterococci and 0.272 for group B streptococci). Among 41 episodes in which enterococcus, group B streptococci, or both were found in midstream urine, E. coli grew from catheter urine cultures in 61%. CONCLUSIONS: Cultures of voided midstream urine in healthy premenopausal women with acute uncomplicated cystitis accurately showed evidence of bladder E. coli but not of enterococci or group B streptococci, which are often isolated with E. coli but appear to rarely cause cystitis by themselves. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Performance of a New Rapid Immunoassay Test Kit for Point-of-Care Diagnosis of Significant Bacteriuria.

Urinary tract infections (UTIs) are frequently encountered in clinical practice and most commonly caused by Escherichia coli and other Gram-negative uropathogens. We tested RapidBac, a rapid immunoassay for bacteriuria developed by Silver Lake Research Corporation (SLRC), compared with standard bacterial culture using 966 clean-catch urine specimens submitted to a clinical microbiology laboratory in an urban academic medical center. RapidBac was performed in accordance with instructions, providing a positive or negative result in 20 min. RapidBac identified as positive 245/285 (sensitivity 86%) samples with significant bacteriuria, defined as the presence of a Gram-negative uropathogen or Staphylococcus saprophyticus at ≥10(3) CFU/ml. The sensitivities for Gram-negative bacteriuria at ≥10(4) CFU/ml and ≥10(5) CFU/ml were 96% and 99%, respectively. The specificity of the test, detecting the absence of significant bacteriuria, was 94%. The sensitivity and specificity of RapidBac were similar on samples from inpatient and outpatient settings, from male and female patients, and across age groups from 18 to 89 years old, although specificity was higher in men (100%) compared with that in women (92%). The RapidBac test for bacteriuria may be effective as an aid in the point-of-care diagnosis of UTIs especially in emergency and primary care settings.

The siderophore yersiniabactin binds copper to protect pathogens during infection.

Bacterial pathogens secrete chemically diverse iron chelators called siderophores, which may exert additional distinctive functions in vivo. Among these, uropathogenic Escherichia coli often coexpress the virulence-associated siderophore yersiniabactin (Ybt) with catecholate siderophores. Here we used a new MS screening approach to reveal that Ybt is also a physiologically favorable Cu(II) ligand. Direct MS detection of the resulting Cu(II)-Ybt complex in mice and humans with E. coli urinary tract infections demonstrates copper binding to be a physiologically relevant in vivo interaction during infection. Ybt expression corresponded to higher copper resistance among human urinary tract isolates, suggesting a protective role for this interaction. Chemical and genetic characterization showed that Ybt helps bacteria resist copper toxicity by sequestering host-derived Cu(II) and preventing its catechol-mediated reduction to Cu(I). Together, these studies reveal a new virulence-associated function for Ybt that is distinct from iron binding.

Evaluation of infectious morbidity due to BTK inhibitors in indolent B-cell lymphomas: latest research findings and systematic analysis.

INTRODUCTION: Randomized clinical trials (RCTs) have suggested that BTK inhibitors (BTKis) might increase infectious disease (ID) risk. Systematic analysis of this topic as derived from RCTs and clinical practice is needed. AREAS COVERED: An extensive Medline, Embase, and Cochrane search of peer-reviewed sources reporting on ID morbidity in patients on BTKis was performed (1 January 2014 - 31 December 2013). Contribution of intrinsic immune defects in indolent B-cell lymphomas to this morbidity was carefully considered. EXPERT OPINION: Patients with indolent B-cell lymphomas display a wide range of innate and adaptive immune defects. In addition, BTKi use is linked with an increased signal of upper respiratory tract infections (URTIs) and pneumonias, mainly grade 1-2. These agents also increase the risk of rare invasive fungal infections (IFIs), mainly due to Cryptococcus and Aspergillus spp. with a peak within several months after the start of therapy. More than half of these IFIs are fatal. Research suggests a similar ID risk across 1st, 2nd and 3rd generations of BTKis, all causing B-cell dysfunction due to BTK inhibition, along with off-target functional neutrophil/macrophage alterations. Expanding the knowledge base on ID morbidity in patients on BTKis would facilitate timely diagnosis and treatment, and improve clinical outcomes.

The type 1 pili regulator gene fimX and pathogenicity island PAI-X as molecular markers of uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC) fall within a larger group of isolates producing extraintestinal disease. UPEC express type 1 pili as a critical virulence determinant mediating adherence to and invasion into urinary tract tissues. Type 1 pili expression is under regulation by a family of site-specific recombinases, including FimX, which is encoded from a genomic island called PAI-X for pathogenicity island of FimX. Using a new multiplex PCR, fimX and the additional PAI-X genes were found to be highly associated with UPEC (144/173 = 83.2 %), and more prevalent in UPEC of lower urinary tract origin (105/120 = 87.5 %) than upper urinary tract origin (39/53 = 74 %; P<0.05) or commensal isolates (28/78 = 36 %; P≤0.0001). The Fim-like recombinase gene fimX is the only family member that has a significant association with UPEC compared to commensal isolates. Our results indicate PAI-X genes, including the type 1 pili regulator gene fimX, are highly prevalent among UPEC isolates and have a strong positive correlation with genomic virulence factors, suggesting a potential role for PAI-X in the extraintestinal pathogenic E. coli lifestyle.

Escherichia coli isolates that carry vat, fyuA, chuA, and yfcV efficiently colonize the urinary tract.

Extraintestinal Escherichia coli (ExPEC), a heterogeneous group of pathogens, encompasses avian, neonatal meningitis, and uropathogenic E. coli strains. While several virulence factors are associated with ExPEC, there is no core set of virulence factors that can be used to definitively differentiate these pathotypes. Here we describe a multiplex of four virulence factor-encoding genes, yfcV, vat, fyuA, and chuA, highly associated with uropathogenic E. coli strains that can distinguish three groups of E. coli: diarrheagenic and animal-associated E. coli strains, human commensal and avian pathogenic E. coli strains, and uropathogenic and neonatal meningitis E. coli strains. Furthermore, human intestinal isolates that encode all four predictor genes express them during exponential growth in human urine and colonize the bladder in the mouse model of ascending urinary tract infection in higher numbers than human commensal strains that do not encode the four predictor genes (P = 0.02), suggesting that the presence of the predictors correlates with uropathogenic potential.

Cefpodoxime vs ciprofloxacin for short-course treatment of acute uncomplicated cystitis: a randomized trial.

CONTEXT: Although fluoroquinolones remain the most reliable urinary antimicrobial, resistance rates have increased and effective fluoroquinolone-sparing antimicrobials are needed. OBJECTIVE: To determine whether cefpodoxime is noninferior to ciprofloxacin for treatment of acute cystitis. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind trial of 300 women aged 18 to 55 years with acute uncomplicated cystitis comparing ciprofloxacin (n = 150) with cefpodoxime (n = 150); patients were from a student health center in Seattle, Washington, and a referral center in Miami, Florida. The study was conducted from 2005 to 2009 and outcomes were assessed at 5 to 9 days and 28 to 30 days after completion of therapy. Intent-to-treat and per-protocol analyses were performed; 15 women in the ciprofloxacin group and 17 women in the cefpodoxime group were lost to follow-up. INTERVENTIONS: Patients were given 250 mg of ciprofloxacin orally twice daily for 3 days or 100 mg of cefpodoxime proxetil orally twice daily for 3 days. MAIN OUTCOME MEASURES: Overall clinical cure (defined as not requiring antimicrobial treatment during follow-up) at the 30-day follow-up visit. Secondary outcomes were clinical and microbiological cure at the first follow-up visit and vaginal Escherichia coli colonization at each follow-up visit. The hypothesis that cefpodoxime would be noninferior to ciprofloxacin by a 10% margin (ie, for the difference in the primary outcome for ciprofloxacin minus cefpodoxime, the upper limit of the confidence interval would be <10%) was formulated prior to data collection. RESULTS: The overall clinical cure rate at the 30-day visit with the intent-to-treat approach in which patients lost to follow-up were considered as having clinical cure was 93% (139/150) for ciprofloxacin compared with 82% (123/150) for cefpodoxime (difference of 11%; 95% CI, 3%-18%); and for the intent-to-treat approach in which patients lost to follow-up were considered as having not responded to treatment, the clinical cure rate was 83% (124/150) for ciprofloxacin compared with 71% (106/150) for cefpodoxime (difference of 12%; 95% CI, 3%-21%). The microbiological cure rate was 96% (123/128) for ciprofloxacin compared with 81% (104/129) for cefpodoxime (difference of 15%; 95% CI, 8%-23%). At first follow-up, 16% of women in the ciprofloxacin group compared with 40% of women in the cefpodoxime group had vaginal E coli colonization. CONCLUSIONS: Among women with uncomplicated cystitis, a 3-day regimen of cefpodoxime compared with ciprofloxacin did not meet criteria for noninferiority for achieving clinical cure. These findings, along with concerns about possible adverse ecological effects associated with other broad-spectrum ß-lactams, do not support the use of cefpodoxime as a first-line fluoroquinolone-sparing antimicrobial for acute uncomplicated cystitis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00194532.

Fimbrial profiles predict virulence of uropathogenic Escherichia coli strains: contribution of ygi and yad fimbriae.

Escherichia coli, a cause of ∼90% of urinary tract infections (UTI), utilizes fimbrial adhesins to colonize the uroepithelium. Pyelonephritis isolate E. coli CFT073 carries 12 fimbrial operons, 5 of which have never been studied. Using multiplex PCR, the prevalence of these 12 and 3 additional fimbrial types was determined for a collection of 303 E. coli isolates (57 human commensal, 32 animal commensal, 54 asymptomatic bacteriuria, 45 complicated UTI, 38 uncomplicated cystitis, and 77 pyelonephritis). The number of fimbrial types per E. coli isolate was distributed bimodally: those with low (3.2 ± 1.1) and those with high (8.3 ± 1.3) numbers of fimbrial types (means ± standard errors of the means). The fimbrial genes ygiL, yadN, yfcV, and c2395 were significantly more prevalent among urine isolates than human commensal isolates. The effect of deletion of Ygi and Yad fimbrial operons on growth, motility, biofilm formation, adherence to immortalized human epithelial cells, and pathogenesis in the mouse model of UTI was examined. Yad fimbriae were necessary for wild-type levels of adherence to a bladder epithelial cell line and for biofilm formation. Deletion of these fimbrial genes increased motility. Ygi fimbriae were necessary for wild-type levels of adherence to a human embryonic kidney cell line, biofilm formation, and in vivo fitness in the urine and kidneys. Complementation of each fimbrial mutant restored wild-type levels of motility, biofilm formation, adherence and, for ygi, in vivo fitness. A double deletion strain, Δygi Δyad, was attenuated in the urine, bladder, and kidneys in the mouse model, demonstrating that these fimbriae contribute to uropathogenesis.

Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection.

BACKGROUND: Urinary tract infections (UTIs) are common among women and frequently recur. Depletion of vaginal lactobacilli is associated with UTI risk, which suggests that repletion may be beneficial. We conducted a double-blind placebo-controlled trial of a Lactobacillus crispatus intravaginal suppository probiotic (Lactin-V; Osel) for prevention of recurrent UTI in premenopausal women. METHODS: One hundred young women with a history of recurrent UTI received antimicrobials for acute UTI and then were randomized to receive either Lactin-V or placebo daily for 5 d, then once weekly for 10 weeks. Participants were followed up at 1 week and 10 weeks after intervention and for UTIs; urine samples for culture and vaginal swabs for real-time quantitative 16S ribosomal RNA gene polymerase chain reaction for L. crispatus were collected. RESULTS: Recurrent UTI occurred in 7/48 15% of women receiving Lactin-V compared with 13/48 27% of women receiving placebo (relative risk [RR], .5; 95% confidence interval, .2-1.2). High-level vaginal colonization with L. crispatus (≥10(6) 16S RNA gene copies per swab) throughout follow-up was associated with a significant reduction in recurrent UTI only for Lactin-V (RR for Lactin-V, .07; RR for placebo, 1.1; P < .01). CONCLUSIONS: Lactin-V after treatment for cystitis is associated with a reduction in recurrent UTI. Larger efficacy trials of this novel preventive method for recurrent UTI are warranted. CLINICAL TRIALS REGISTRATION. NCT00305227.