New research

Possible role of L-form switching in recurrent urinary tract infection
Nature Communications 2019
Katarzyna M. Mickiewicz, Yoshikazu Kawai, Lauren Drage, Margarida C. Gomes, Frances Davison, Robert Pickard, Judith Hall, Serge Mostowy, Phillip D. Aldridge & Jeff Errington

Scientists have confirmed for the first time that bacteria can change form to avoid being detected by antibiotics in the human body. Studying samples from 30 elderly patients from Newcastle Freeman Hospital with recurring urinary tract infections, the Newcastle University team used state-of-the art techniques to identify that a bacteria can lose its cell wall – the common target of many groups of antibiotics. This altered shape made the bugs flimsy and weaker, however, some were better able to survive. Interestingly, once the antibiotics had been removed, the scientists filmed the bacteria reverting back to their original shape over five hours.

Direct Detection of Tissue-Resident Bacteria and Chronic Inflammation in the Bladder Wall of Postmenopausal Women with Recurrent Urinary Tract Infection
Journal of Molecular Biology 2019
Nicole J. De Nisco , Michael Neugent, Jason Mull, Luming Chen, Amy Kuprasertkul, Marcela de Souza Santos, Kelli L. Palmer, Philippe Zimmern and Kim Orth

A new finding by researchers at The University of Texas at Dallas and UT Southwestern Medical Center shows that several species of bacteria reside in bladder tissue of postmenopausal women who experience recurrent urinary tract infections (RUTIs). Their study findings offer further understanding of the interaction between bacteria and host tissue, which the authors hope may lead to more effective treatment strategies for those suffering recurrent and chronic UTI.

Reassessment of routine midstream culture in diagnosis of urinary tract infection
The Journal of Clinical Microbiology 2018
Sanchutha Sathiananthamoorthy, James Malone-Lee, Kiren Gill, Anna Tymon, Trang K. Nguyen, Shradha Gurung, Linda Collins, Anthony S. Kupelian, Sheela Swamy, Rajvinder Khasriya, David A. Spratt, Jennifer L. Rohn

Midstream urine culture (MSU) are still widely seen as the gold standard diagnostic test for acute UTIs. But this research found that MSUs

  • miss a wide variety of bacteria
  • can’t distinguish between infected patients from normal controls.

Cross over data supporting long term antibiotic treatment in patients with painful lower urinary tract symptoms, pyuria and negative urinalysis 2018
The International Urogynecology Journal 2018
Sheela Swamy & Anthony S. Kupelian & Rajvinder Khasriya & Dhanuson Dharmasena & Hristina Toteva & Tara Dehpour & Linda Collins & Jennifer L. Rohn & James Malone-Lee

This paper examines the results of an unplanned, sudden cessation of treatment in 2015 for an unselected group of 221 patients with chronic painful LUTS managed with long term antibiotic treatment at the Lower Urinary Tract Symptoms Clinic, Whittington Hospital London. It concludes that 199 patients (90%; female = 188; male = 9) reported deterioration. Eleven patients required hospital care in association with recurrence of infection, including acute urinary tract infection (UTI) and urosepsis and support’s the clinic’s protocol of treating patients with painful lower urinary tract symptoms with long-term antimicrobial courses, despite negative urine culture.

Recalcitrant chronic bladder pain and recurrent cystitis but negative urinalysis: What should we do?
International Urogynecology Journal March 2018
Sheela Swamy, William Barcella, Maria De Iorio, Kiren Gill, Rajvinder Khasriya, Anthony S. Kupelian, Jennifer L. Rohn, James Malone-Lee.

This research study looked at how lower urinary tract symptoms may be associated with chronic urinary tract infection undetected by routine diagnostic tests. Antimicrobial therapy might confer benefit for these patients.

A blinded observational cohort study of the microbiological ecology associated with pyuria and overactive bladder symptoms
International Urogynecology Journal 2018
Kiren Gill, Ryoon Kang, Sanchutha Sathiananthamoorthy, Rajvinder Khasriya, James Malone-Lee

This study supports the need to re-examine the OAB phenotype given this association with microbial colonisation.

Biofilms

Importance of Biofilms in Urinary Tract Infections: New Therapeutic Approaches
Advances in Biology 2014
Sara M. Soto.

This paper looks specifically at the issue of bacterial forming biofilms within the urinary tract , the difficulty of eradication due to the presence of persistent cells within the urinary epithelium and a review of new therapeutic tools that are necessary. It concludes that new antimicrobial drugs that inhibit bacterial virulence and biofilm formation are needed.

Dr. Bill Costerton: Diagnosing and Treating Biofilm Infections
Awarded the nicknames, ‘Father of Biofilms’ and ‘The King of Slime’, Dr Costerton saw microbial life as a community of microorganisms with the ability to attach to hydrated surfaces. He realized not only the importance of biofilms, but also their uniqueness displayed by microorganisms within biofilms, such as antibiotic tolerance or slow growth rate.
Watch Dr Bill Costerton on YouTube

Bacterial Biofilms: Development, dispersal, and therapeutic strategies in the dawn of the postantibiotic era
Cold Spring Harbour Perspectives in Medicine April 2013
Kostakioti M, Hadjifrangiskou M & Hultgren SJ

This paper discusses the various bacterial methods of attachment and then biofilm formation on surfaces and within cells, highlighting several medically important pathogens, and discusses recent advances for new strategies aimed at biofilm prevention and/or dissolution.

Microbial Biofilms in Urinary Tract Infections and Prostatitis- Etiology, Pathogenicity, and Combating strategies
Pathogens December 2016
Cristina Delcaru, Ionela Alexandru, Paulina Podgoreanu, Mirela Grosu, Elisabeth Stavropoulos, Mariana Carmen Chifiriuc and Veronica Lazar

A short paper evaluating the role of microbial biofilms in the development of female UTI and different male prostatitis syndromes, their consequences, as well as the challenges for therapy.

Implication of biofilm formation in the persistence of urinary tract infection caused by uropathogenic Escherichia coli
Clinical Microbiology and Infection 2006
S.M.Soto, A.Smithson, J.P.Horcajada, J.A.Martinez, J.P.Mensa, J.Vila

Escherichia coli is the most frequent bacteria involved in urinary tract infection. An acute e coli UTI can lead to recurrent infection. In this study, E. coli strains causing relapse and re-infection were analysed. The production of biofilm in these e-coli was significantly more frequent among strains causing relapse. It concludes that Biofilm testing may be helpful for patients to help formulate an approach to eradicate persistent biofilm-forming E. coli strains and prevent subsequent relapses.

Biofilm Formation
The International Journal of Health Research and Medical Sciences 2014
Dardi Charan Kaur G, Maral Sanjivani S

This study observed the ability of urinary pathogens to form biofilms and their antimicrobial resistant patterns. Biofilm forming pathogens showed higher antimicrobial resistance as compared to non-biofilm bacteria. They concluded that urinary pathogens should be routinely screened for biofilm formation.

Intracellular bacterial communities

Intracellular lifestyles and immune evasion strategies of uropathogenic Escherichia coli.
The Annual Review of Microbiology 2010
Hunstad DA & Justice SS

This paper looks beyond the traditional view of the extracellular colonisation of the bladder surface and notes that pathogenic bacteria invade the epithelium’s deeper layers becoming intracellular and thus creating a haven away from host defences and antimicrobial treatment. This leads to biofilm formation and bacterial expansion. Cells are routinely shed from the bladder surface but there remains a chronic intracellular community leading to episodes of recurrent cystitis and chronicity of symptoms. It reviews the ongoing scientific advances into the knowledge around the development of these cUTI.

Intracellular Bacterial Communities: A Potential Etiology for Chronic Lower Urinary Tract Symptoms
Urology 2015
Scott VC, Haake DA, Churchill BM, Justice SS, Kim JH

A review of emerging evidence for a role of intracellular bacterial communities. The authors review the potential role of occult infection in OAB and IC/BPS, the evidence for intracellular bacterial community (IBC) formation in human bladder infections, and discuss the possible role of IBCs in recurrent UTIs. They finish with a discussion around current treatment methods which fail patients because of IBC and note that education around IBC and new approaches for targeting these infections, capable of eradication of intracellular biofilms, will be necessary leading to more successful diagnostic and treatment strategies for these patients.

Detection of Intracellular Bacterial Communities in Human Urinary Tract Infection
PLOS Medicine 2007
David A Rosen, Thomas M Hooton,Walter E Stamm, Peter A Humphrey & Scott J Hultgren

The authors in this study sought to analyse whether evidence of an IBC pathway could be found in urine specimens from women with acute UTI. The researchers collected urine from 80 young women with cystitis and from 20 women with no symptoms who had had cystitis previously. None of the women without cystitis had IBCs or filamentous bacteria such as uropathogenic E coli in their sample, but IBCs were found in nearly 1 in 5, and filamentous bacteria were in nearly half, of urine samples from the women with cystitis. All the urine samples that contained IBCs also contained filamentous bacteria. All of the women with IBCs and most of them with filamentous bacteria had E coli infections. Finally, the women with IBCs and filamentous bacteria in their urine had higher bacterial counts in their urine and had symptoms of cystitis for slightly longer than those without. They conclude that additional studies are needed to examine whether there are any associations between the presence of IBCs and filamentous bacteria and current treatment methods and rates of recurrence and the mechanisms within the bladder during the process of infection.

Detection of intracellular bacterial communities in a child with Escherichia coli recurrent urinary tract infections.
Pathogens and Disease 2013
Luciana Robino, Paola Scavone, Lucia Araujo, Gabriela Algorta, Pablo Zunino & Rafael Vignoli

This study confirms the presence of IBC in children with UTI, as it has been described before in women. Working with a child suffering from recurrent infections, the authors noted the presence of IBC in uroepithelial cells. The urine samples obtained from the paediatric patient were analyzed by light and confocal laser scanning microscopy (CLSM) and noted clear Escherichia coli UTI intracellular formation.

Host subversion by formation of intracellular bacterial communities in the urinary tract
Microbes and Infection October 2004
Gregory G. Anderson, Steven M. Martin, Scott J. Hultgren

The study highlights the unique immune evasion and suppression strategies of uropathogenic E coli (UPEC) and suggests pathways for further study; by understanding the molecular mechanisms of these infections, improved diagnostic and treatment regimes can be developed. They further note that host inflammation during a UTI may actually represent a false positive. Whilst inflammatory response is essential for controlling UTI an overly exuberant inflammatory response during acute cystitis may be associated with increased tissue damage, predisposing the host to developing chronic forms of infection. Further, they go on to advise that in murine models, after chronic cystitis has become established, despite an intense, ongoing leukocyte response, an effective immune response could not be provided and restoration of the exfoliated transitional epithelium was inhibited. This inflamed situation may allow UPEC access to more protected niches and deeper cell layers.

How to make it in the Urinary Tract
PLOS Pathogens 2012
Ine Jorgensen, Patrick C. Seed

This study notes that 25% of women with acute cystitis experience a second UTI within six months. They advise that failure to mount a protective immune response may be due to host genetic factors, antibiotic use, the ability of the intestinal uropathogenic ecoli to adapt and suppress the host immune system and its ability to reside within protected, dormant reservoirs in the cells of the bladder wall. This review highlights the different stages of the E Coli developmental cycle in the host bladder tissue, and describes the strategies employed to gain the upper hand.

Enterococcus faecalis Subverts and Invades the Host Urothelium in Patients with Chronic Urinary Tract Infection
Plos Pathogens 2013
Harry Horsley, James Malone-Lee, David Holland, Madeleine Tuz, Andrew Hibbert, Michael Kelsey, Anthony Kupelian & Jennifer L. Rohn

The authors of this paper specifically studied E.faecalis harvesting urothelial cells shed in response to inflammation and, using advanced imaging techniques, inspected them for signs of bacterial pathology and invasion. They discovered strong evidence of intracellular E. faecalis harboured within urothelial cells shed from the bladder of patients with lower urinary tract symptoms. In contrast, no evidence of cellular invasion by E. coli in the patient cells or the culture model system was found. The study concludes that whilst most attention has been directed to E. coli in studies, E.Faecilis is also a major cause of urinary tract infections globally and has significant biofilm forming capabilities. Thus lower urinary tract symptoms may be caused by low-grade intracellular infection of the bladder by E. faecalis not just E Coli.

Bad bugs and beleaguered bladders: interplay between uropathogenic Escherichia coli and innate host defences
PNAS 2000
Mulvey MA, Schilling JD, Martinez JJ & Hultgren SJ

The authors of this paper reviews the studies carried out into the actions of Uropathogenic E Coli, which despite triggering a number of host responses, including cytokine production, inflammation, and the exfoliation of infected bladder epithelial cells and the usage of antibiotic treatments that can effectively sterilize the urine, these uropathogens can persist within the bladder tissue. It is in the underlying epithelial layers that UPEC may be able to persist for long intervals, hidden within host bladder epithelial cells, possibly in a dormant state and undetectable within the urine. These bacteria could potentially serve as a source for recurrent infections, one of the more vexing problems associated with UTIs.

Bacteria in the bladder wall of women with lower urinary tract symptoms: An interesting finding
Vijaya G, Dutta S, Singh A U, Bray R, Digesu A, Fernando R, Khullar V.

Published by Imperial College, London the objectives of this study were to investigate if bacteria are present in the bladder wall and are they associated with a positive urine culture and to determine if the bacteria in the bladder wall are associated with lower urinary tract symptoms or recurrent urinary tract infections. The authors noted that their study results support a link between LUTS and bacterial infection in the bladder wall not the urine.

Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection
FEMS Microbiology Review 2012
Hannan TJ, Totsika M, Mansfield KJ, Moore KH, Schembri MA & Hultgren SJ

The Hultgren Laboratory is one of the leading researchers into Uropathogenic Escherichia coli (UPEC) and this paper examines it’s behaviour in the urinary tract, the bladder epithelium (urothelium) and how UPEC bypass this barrier when they invade urothelial cells and form intracellular bacterial communities (IBCs). It advises that understanding of these is critical for ongoing knowledge of bladder infection and efforts to devise new therapeutic strategies.

Paediatrics

Absolute and relative accuracy of rapid urine tests
The Lancet Infectious Diseases 2010
Williams GJ, Macaskill P, Chan SF, Turner RM, Hodson E, Craig JC

This study undertook a literature review of 95 studies analysing the success of rapid urine tests, such as microscopy, for bacteria and white cells, and dipsticks, for leucocyte esterase and nitrites with the aim of establishing whether these tests were sufficiently sensitive to avoid urine culture in children with negative results. It also compared the accuracy of dipsticks with microscopy. The concluded that microscopy for white cells should not be used for the diagnosis of urinary tract infection because its accuracy is no better than that of dipstick, laboratory facilities are needed, and results are delayed. Rapid tests are negative in around 10% of children with a urinary tract infection and cannot replace urine culture. If resources allow, microscopy with Gram stain should be the single rapid test used.

Diagnosis of urinary tract infection in children
The Journal of Clinical Microbiology 2016
Christopher D. Doern and Susan E. Richardson

In this review the authors provide an analysis of issues relevant to the diagnosis of UTIs in children, particularly as they differ from those in adults. They analyse the literature to offer best practice for determining optimal laboratory testing for UTIs in children, from birth to adulthood and use the available evidence to explore controversial areas in diagnostic testing. They conclude that the optimal diagnosis of urinary tract infection in children hinges around the determination of an appropriate threshold of bacterial growth that correlates with clinical disease. They propose lowering the diagnostic threshold to ≥104 CFU/ml andaccompanying this analysis with a rapid, simple, and reliable detector of significant pyuria such as a hemocytometer WBC count or LE test, in particular which can be done in a point of care setting and would remove the need for microscopy in the microbiology or core laboratory.

Clinical decision rule to identify febrile young girls at risk for urinary tract infection
The Archive of Paediatric Adolescent Medicine 2000
Gorelick MH and Shaw KN

This study was a cohort study of female children under 2 years of age seen at the Emergency Department of an urban US hospital in a one year period. The study results noted that the presence of 2 or more of the following 5 variables—less than 12 months old, white race, temperature of 39.0°C or higher, fever for 2 days or more, and absence of another source of fever on examination led to identification of 95% of children with UTI and elimination of 30% of unnecessary urine cultures.

Low bacterial counts in infants with urinary tract infection
The Journal of Paediatrics 1998
Hansson S, Brandström P, Jodal U, Larsson P

This study analysed the number of colony-forming units in urine cultures obtained by suprapubic aspiration in a group of 366 unselected infants with symptomatic urinary tract infection. Seventy-three (20%) of 366 infants had fewer than 100,000 colony-forming units per milliliter. Such low counts were significantly related to low numbers of leukocytes in the urine. The authors conclude that the findings emphasise the importance of sampling technique; in infants, the method of choice is suprapubic aspiration, or catheterization, which eliminates the risk that urinary tract infection is overlooked because of low bacterial counts.

Pyuria and bacteriuria in urine specimens obtained by catheter from young children with fever
The Journal of Paediatrics 1994
Hoberman A, Wald ER, Reynolds EA, Penchansky L, Charron M

This study analysed the results of urinalysis and culture of 2181 urine specimens obtained by catheter from febrile children aged less than 24 months to determine the following: (1) an optimal cutoff point in considering a bacterial colony count clinically “significant,” (2) the accuracy of leukocyte esterase and nitrite tests in identification of pyuria and bacteriuria, and (3) the utility of pyuria (defined as≥10 leukocytes/mm3) in the discrimination of urinary tract infection from asymptomatic bacteriuria. They concluded that for urine specimens obtained by catheter, urinary tract infection is best defined by both a leukocyte count ≥10/mm3 and a CFU count ≥50,000/ml.

Low bacterial count urinary tract infections in infants and young children
The European Journal of Paediatrics 2005
Theodoros A. Kanellopoulos Paul J. Vassilakos Marinos Kantzis Aikaterini Ellina Fevronia Kolonitsiou Dimitris A. Papanastasiou

The purpose of the study was to compare bacterial species, clinical, laboratory and imaging findings in infants and children with high (≥105 colony forming units (CFU)/ml, group A patients) and low (≤5×104 CFU/ml, group C patients) bacterial count in urine cultures during first episode of urinary tract infection. Group B included patients with intermediate CFU/ml. They concluded that low bacterial count urinary tract infections mainly affect infants and young children and are often due to gram-negative bacteria other thanE. coli. Clinical and laboratory findings, prevalence of pyelonephritis, reflux and urological malformations are similar in high and low bacterial count urinary tract infections.

Diagnostic accuracy of urinary biomarkers in infants younger than 3 months with urinary tract infection
The Korean Journal of Paediatrics 2018
Nani Jung, Hye Jin Byun, MD, Jae Hyun Park, MD, Joon Sik Kim, MD, Hae Won Kim, MD, and Ji Yong Ha

This study evaluated the diagnostic accuracy of urinary biomarkers, such as neutrophil gelatinase-associated lipocalin (uNGAL) and β-2 microglobulin (uB2MG), in early detection of urinary tract infection (UTI) in 422 infants aged under 3 months with fever whether UTI was suspected or not. They concluded that the accuracy of uNGAL in the diagnosis of UTI is high in febrile infants aged under 3 months. uNGAL can help in the early diagnosis and treatment of UTI in infants.

Urinary tract infection in infants: the significance of low bacterial count
The Journal of Nephrology 2016
Swerkersson S, Jodal U, Åhrén C, Sixt R, Stokland E, Hansson S

This study retrospectively analysed 430 infants age <1 year with symptomatic UTI diagnosed by suprapubic aspiration. They concluded that UTI with low bacterial count is common and of importance since it may be associated with VUR and renal damage. Non-E. coli species and low inflammatory response were more prevalent in UTI with low bacterial count.

Use of rapid dipstick tests to exclude urinary tract infection in children
British Journal of Biomedical Science 1998
Sharief N, Hameed M, Petts D

This study evaluated the use of rapid dipstick tests in the diagnosis of urinary tract infection in children. Urine was collected from 375 children admitted to a general paediatric ward in a UK hospital, in whom UTI was a possibility on clinical grounds. Of these, 124 were less than one year old. Urine was tested with a dipstick for the presence of nitrite and leucocyte esterase. Bacterial culture and examination for white cells, red cells and other formed elements were performed. The results of the dipstick tests, microscopy and culture were correlated with the clinical details. The authors concluded that the dipstick method is most likely to be useful as a screening test to exclude UTI in children, but may be less suitable for infants. It should not be used to diagnose urinary tract infection.

Low urinary bacterial counts: do they count?
Paediatric Nephrology 2016
Tullus K

The authors note in this study that as many as one in every five infants with a UTI will be missed with the commonly used cut-off level of ≥105 colony forming units (CFU)/mL. Children with low bacterial counts during an acute infection have a significant risk of receiving delayed or even no antibiotic treatment. They note that study results are skewed if 20 % of the subjects with a true infection are wrongly included in a control group diagnosed as having no UTI due to low bacterial counts. However they note that this issue cannot be easily solved by lowering the cut-off level and generally accepting that any bacterial count signifies a “true” infection as this approach will drastically reduce the specificity of the culture result.

They propose that if possible, urine samples for culture should be collected from babies, infants and small children with a suprapubic bladder puncture, or a catheterised sample. In such samples bacterial counts as low as 103 CFU/mL are generally regarded as significant. Where this option is not available the treating doctor needs to take all relevant clinical and laboratory parameters into account and if clinically important data support the diagnosis of a UTI not disregard this diagnosis based only on low bacterial counts. They suggest that blood test results showing C-reactive protein or procalcitonin can, in a child with fever, help the physician differentiate between a febrile bacterial UTI and a viral infection. A positive nitrite test provides, albeit with a low sensitivity, strong support for a UTI diagnosis.

Study of urinary tract infection and bacteriuria in neonatal sepsis
The Indian Journal of Paediatrics 2012
Samayam P, Ravi Chander B

This prospective study of 200 neonatal children was established to determine the number of UTIs in neonatal sepsis and to evaluate bacteriuria as indicator of neonatal urinary tract infection for use in resource limited settings. They found UTI in neonatal sepsis of 6%, with urine culture positivity in late onset sepsis being much higher than in early onset sepsis. They concluded that bacteriuria has good sensitivity and specificity in resource limited settings in detecting septic neonates with UTI.

To clean or not to clean: effect on contamination rates in midstream urine collections in toilet-trained children
Paediatrics 2007
Vaillancourt S, McGillivray D, Zhang X, Kramer MS

The authors of this study assessed the effect of perineal/genital cleaning on bacterial contamination rates of midstream urine collections in toilet-trained children. All toilet-trained children who were between the ages of 2 and 18 years and had a midstream urine sample requested were eligible and a total of 350 children were enrolled. They found urine contamination rates are higher in midstream urine that is collected from toilet-trained children when obtained without perineal/genital cleaning.

The Uriscreen test was not better than standard urinalysis and dipstick tests for detecting urinary tract infection in children
The BMJ Evidence-Based Medicine 2000
Robert S Wigton, MD, MS

The authors of this study sampled 121 children (68% girls) who were 1 month to 17 years of age and who presented to the emergency department with symptoms of UTI. A urine sample was obtained from each child by using age appropriate methods. Within 15 minutes of collection, urine samples were tested in 4 ways. A Uriscreen test, a dipstick test, a urinalysis and a quantitative urine culture. They found that 5 of 39 boys (13%) and 30 of 82 girls (37%) had UTIs. The Uriscreen test had perfect sensitivity but low specificity and was no better than the dipstick or urinalysis tests for detecting UTI early.

Urinary microbiome

The New World of the Urinary Microbiome in Women
The American Journal of Obstetrics and Gynaecology 2015
Linda Brubaker and Alan J Wolfe

This paper highlights the inadequacies of the current tools for urinary bacterial testing, outlines new options, details the current interpretation of testing results, and proposes potential clinical uses and relevance. Given the advances in urinary microbial testing, the paper argues this will benefit better understanding of the UM and the bladder, in turn this has significant potential to improve patient treatment.

Culturing of female bladder bacteria
Nature Communications 2018
Krystal Thomas-White, Samuel C. Forster, Nitin Kumar, Michelle Van Kuiken, Catherine Putonti, Mark D. Stares, Evann E. Hilt, Travis K. Price,Alan J. Wolfe & Trevor D. Lawley 2018

Using a detailed genomic and functional analysis of the bladder microbiota to the gastrointestinal and vaginal microbiotas revealed similar vaginal and bladder microbiota, that are distinct from those observed in the gastrointestinal microbiota.B acterial strains isolated from the vagina and bladder in the same women identified highly similar Escherichia coli, Streptococcus anginosus, Lactobacillus iners, and Lactobacillus crispatus. This suggests an interlinked female urogenital microbiota that is not only limited to disease causing bacteria but also characteristic of normal health-associated commensals.

A case control study examining the bladder microbiome
The European Journal of Obstetrics Gynaecology and Reproductive Biology 2017
Natasha Curtiss, Aswini Balachandrana, Louise Krskab, Claire Peppiatt-Wildmanb, Scott Wildmanb, Jonathan Ducketta

This study aimed to characterise the microbiome in women with no bladder symptoms in comparison to the bladder microbiome in patients with overactive bladder syndrome (OAB). They concluded that the female human bladder has a diverse microbiome noting significant differences between bacterial species present in OAB patients and controls.

Does the Urinary Microbiome Play a Role in Urgency Urinary Incontinence and Its Severity
Frontiers in Cellular & Infection Microbiology 2016
Lisa Karstens , Mark Asquith, Sean Davin, Patrick Stauffer, Damien Fair W.Thomas Gregory, JamesT.Rosenbaum, Shannon K.McWeeney and Rahel Nardos

A pilot study aiming to establish how the urinary microbiome is different between women with and without Urinary Urge Incontinence. They also sought to identify if characteristics of the urinary microbiome are associated with UUI severity. The results demonstrated that the urinary microbiome may play an important role in the pathophysiology of UUI and that loss of microbial diversity may be associated with the severity of patient symptoms.

Gram-Positive Uropathogens, Polymicrobial Urinary Tract Infection, and the Emerging Microbiota of the Urinary Tract
American Society for Microbiology 2016
Kimberly A. Kline and Amanda L. Lewis

The paper reviews the most common uropathogens: Staphylococcus, Enterococcus, and Streptococcus, reviews the issues around polymicrobial urinary tract infection and it’s significance for urine culture. It notes the potential under-reporting of fastidious organisms and atypical Gram-positives as causes of urinary tract infection. Finally, the authors summarize the current research literature discussing the urobiome and discuss the potential role of urogenital microbiota in UTI susceptibility.

Microbial metagenome of urinary tract infection
Scientific Reports 2018
Ahmed Moustafa, Harinder Singh, Weizhong Li, Kelvin J. Moncera, Manolito G. Torralba, Yanbao Yu, Oriol Manuel, William Biggs, J. Craig Venter, Karen E. Nelson, Rembert Pieper, Amalio Telenti

This study, using genomic analysis from patients, found cases of infection with potential pathogens often missed during routine urine culture due to bacterial species specific growth requirements. They note that conventional microbiological methods are inadequate to identify a large diversity of microbial species that are present in urine, newer genomic testing seems to more comprehensively and quantitatively describe the urinary microbiome.

The Urinary Microbiome and its Contribution to LUTS
Urology and Urodynamics 2017
Marcus J. Drake, Nicola Morris, Apostolos Apostolidis, Mohammad S. Rahnama and Julian R. Marchesi

The International Consultation on Incontinence Research Society (ICI-RS) established a literature review and expert consensus discussion focusing on the increasing awareness of the urinary microbiome, and potential research priorities. Focus was given to differing bacteria interpretation levels in laboratory and the direction of testing towards known UTI causing pathogens. This selective culture compared to newer metogenomic RNA sequencing highlights the possibility that protective or harmful bacteria may be overlooked where microbiological methods are selective. Also reviewed was the potential relationship between a patient’s microbiome and lower urinary tract dysfunction, whether low-count levels of bacterial infections may be clinically significant and mechanisms which could associate micro-organisms with lower urinary tract symptoms.

Questions and challenges associated with studying the microbiome of the urinary tract
Annals of Translational Medicine 2017
Yige Bao, Kait F. Al, Ryan M. Chanyi, Samantha Whiteside, Malcom Dewar1, Hassan Razvi, Gregor Reid, Jeremy P. Burton

This paper highlights the opportunities for urinary microbiome investigations and the experiences of the researchers in working with these low abundance samples in the urinary tract. They conclude that learning about the microbiome’s role in urology and disease is in its infancy. There are few longitudinal studies and more are required to understand the urinary microbiome’s development and its influence on health and disease from birth to death. A greater understanding of the role the microbiome play will lead to the modulation of the improvement of health outcomes

The Urinary Microbiota: A Paradigm Shift for Bladder Disorders?
Current Opinion in Obstetrics and Gynaecology 2016
Linda Brubaker, MD, MS and Alan Wolfe, PhD

The study reviews and notes that now that Improved techniques for microbial detection are available, study of the FUM may show an impact on common lower urinary tract disorders, such as urinary incontinence and urinary tract infection. By making refinements to it may be possible to describe the FUM of healthy states, as well as the spectrum of vulnerable, dysbiotic microbial communities that may predispose women to lower urinary tract disorders.

UTI testing

Detecting clinically relevant microrganims we can do better
The International Continence Society 2015
Paul C. Schreckenberger, Travis K. Price, Evann E. Hilt, Tanaka Dune, Cynthia Brincat, Linda Brubaker, Elizabeth R. Mueller, Alan J. Wolfe

This paper compared the standard urine culture to an improved urine culture protocol for detection of clinically relevant microorganisms. Urine analysis of 115 patients using expanded quantitative urine culture protocol detected significantly more unique species (82) compared to the standard culture (8). The standard culture missed 75% (93/124) of the uropathogens detected using the enhanced protocols. Standard cultures detected most Escherichia coli (92% – 22/24), but detected only a minority of all other uropathogens (9% – 9/100). Many uropathogens were detected by EQUC at levels (colony forming units per milli-litre – CFU/mL) below the accepted threshold for UTI diagnosis (≥105 CFU/mL) and thus would not be considered to be causing infection despite the patient reporting UTI symptoms.

Detecting uropathogens in a urogynaecologic population: a comparison of UTI diagnostic thresholds
The International Continence Society 2017
Price T, Hilt E, Dune T, Brincat C, Brubaker L, Mueller E, Schreckenberger P, Wolfe A

This paper describes a study enrolling 75 patients. Using catheterized urine samples, comparisons were made between standard urine culture (SC) thresholds and an enhanced quantitative urine culture (EQUC) protocol. Four diagnostic thresholds for uropathogen detection were compared: ≥105 , ≥104 and ≥103 CFU/ml by SC and the presence if any uropathogen detected by EQUC.

The team summarised “EQUC detected 23 known and emerging uropathogens present in nearly all patients 92% (69/75). The proportion of patients with at least one uropathogen detected declined as the diagnostic threshold increased (≥103 = 81%, ≥104 = 71% and ≥105 = 61%). The effect of the diagnostic threshold was related to the characteristics of the uropathogens present. At ≥105 CFU/mL, most (85%) patients with detected uropathogens had Gram-negative bacteria. In contrast, when the “any” detection threshold was used, only 38% had Gram-negative uropathogens; the other 62% had polymicrobial or Gram-positive uropathogens. Many (23/37, 62%) treated patients reported symptom resolution within one week. Conversely, many (60%) untreated patients with at least one uropathogen present below the ≥105 CFU/mL reported that their UTI symptoms persisted (‘same’ or ‘worse’) one week later”. They concluded that current diagnostic methods for UTI are failing patients particularly those with gram positive or polymicrobial infections. Testing is currently directly towards gram negative bacteria such as E-coli.

Discrediting microscopic pyuria and leucocyte esterase as diagnostic surrogates for infection in patients with lower urinary tract symptoms: results from a clinical and laboratory evaluation
BJU International 2013
Kupelian AS, Horsley H, Khasriya R, Amussah RT, Badiani R, Courtney AM, Chandhyoke NS, Riaz U, Savlani K, Moledina M, Montes S, O’Connor D, Visavadia R, Kelsey M, Rohn JL, Malone-Lee J.

This study highlights the poor performance of dipstick urine analysis, and direct microscopy, as surrogate markers of UTI in patients with LUTS. A series of laboratory analyses also examine the effects of urine handling and processing on test integrity, which have important implications for clinical practice.

The Problems affecting the diagnosis of urinary tract infection
Ageing Population 2015
Temenuga Dacheva & James Malone-Lee

This paper discusses the evidence that contradicts many widely accepted standards with respect to the diagnosis of urinary tract infection. The current gold standard reference used to diagnose urinary infection in acute and chronic disease appears to contain very significant errors. The surrogate indicators of urinary tract infection (UTI), dipsticks and urine microscopy, have been calibrated to this dubious standard set by Kass. Urinalysis tests results are conditioned on patients in hospital with pyelonephritis; these methods are not valid for acute cystitis nor chronic lower urinary tract symptoms. Many studies have shown that urine dipstick analysis and midstream urine sample culture are very insensitive and provide flawed data. The authors stress that the symptoms that a patient describes are very good indicators of disease. In particular, hesitancy, reduced stream, intermittency and terminal dribbling are the most sensitive markers of urinary tract infection in patients with non acute lower urinary tract symptoms.

Urine is Not Sterile Use of Enhanced Urine Culture Techniques to Detect Resident Bacterial Flora in the Adult Female Bladder
The Journal of Clinical Microbiology 2014
Evann E. Hilt, Kathleen McKinley, Meghan M. Pearce, Amy B. Rosenfeld, Michael J. Zilliox, Elizabeth R. Mueller, Linda Brubaker, Xiaowu Gai, Alan J. Wolfe, Paul C. Schreckenberger

This paper presented detailed research that urine contains communities of living bacteria that comprise a resident female urine microbiota. The team used a modified culture protocol that included plating larger volumes of urine, incubation under varied atmospheric conditions, and prolonged incubation times to demonstrate that many of the organisms identified in urine by 16S rRNA gene sequencing are, in fact, cultivable using an expanded quantitative urine culture (EQUC) protocol.

Urine trouble: should we think differently about UTI?
The International Urogynaecology Journal 2017
K. Price & Evann E. Hilt & Tanaka J. Dune & Elizabeth R. Mueller & Alan J. Wolfe & Linda Brusker

The authors of this paper identified four major limitations to current clinical descriptions of a UTI: the language of UTI, UTI diagnostic testing, the Escherichia coli-centric view of UTI, and the colony-forming units (CFU) threshold-based diagnosis. They noted that newer methods and technology, combined with continued rigorous clinical research can be used to correct these limitations. They argue that clinicians need to learn new methods of interpretation of UTI testing, such as EQUC. No single study will provide guidance for all clinical situations and clinical judgment will remain a valued tool in patient care but it is long overdue with the body of evidence for patients to deserve better, improved care.

Women with symptoms of UTI but negative Urine test
Journal of Microbiology 2017
S Heytens, A De Sutter, L Coorevits, P Cools, J Buelens, L Van Simaey, T Christiaens, M Vaneechoutte, G Claeys

This paper examined whether the 20-30% of patients with a negative culture actually were positive for infection using PCR testing for E coli and Staphylococcus saprophyticus. Using a patient cohort of 220 they found in the symptomatic group, 80.9% (178/220) of the urine cultures were positive for any uropathogen and 95.9% (211/220) were E. coli qPCR-positive.

The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms
The Journal of Clinical Microbiology 2016
Travis K. Price, Tanaka Dune, Evann E. Hilt, Krystal J. Thomas-White, Stephanie Kliethermes, Cynthia Brincat, Linda Brubaker, Alan J. Wolfe, Elizabeth R. Mueller, Paul C. Schreckenberger

The authors of this study using an EQUC protocol achieved 84% uropathogen detection relative to 33% detection by standard urine culture. This method of detection will aid clinician and patient, providing an opportunity to receive additional information not currently reported using standard urine culture techniques.

Diagnosis of coliform infection in acutely dysuric women
N Engl J Med. 1982 Aug 19;307(8):463-8.
Stamm WE, Counts GW, Running KR, Fihn S, Turck M, Holmes KK.

This paper re-evaluated the current criteria for diagnosing coliform infection of the lower urinary tract in symptomatic women. The traditional diagnostic criterion, greater than or equal to 10(5) bacteria per milliliter of midstream urine, identified only 51 per cent of women whose bladder urine contained coli-forms. The authors advance that the best diagnostic criteria to be greater than or equal to 10(2) bacteria per millilitre. They recommend that clinicians and microbiologists should alter their approach to the diagnosis and treatment of women with acute symptomatic coliform infection of the lower urinary tract.

Common errors in diagnosis and management of urinary tract infection
Nephrology Dialysis Transplantation, Volume 14, Issue 11, 1 November 1999, Pages 2746–2753
Martina Franz & Walter H Horl.

This paper examines the issues around the definition of UTI and problems faced by current testing methods. General practicioners, paediatricians, urologists, and nephrologists are frequently consulted because of symptoms suggestive of UTI, but there are large differences in the management of such patients with respect to definition of UTI, diagnosis, and treatment. In particular, the clinical relevance of low-count bacteriuria and asymptomatic UTI as well as the potential indications for antimicrobial therapy continue to be controversial.

Men only

The Prevalence and Overlap of Interstitial Cystitis/Bladder Pain Syndrome and Chronic Prostatitis/Chronic Pelvic Pain Syndrome in Men
RAND Interstitial Cystitis Epidemiology Male Study. The Journal of Urology, v. 189, no. 1, Jan. 2013, p. 141-145

Published in the Rand Coporation Journal, the authors analysed the Rand Interstitial Cystitis Study to establish the prevalence of chronic prostatitis/chronic pelvic pain syndrome in men in the USA. Using population based screening methods, they applied these case definitions to determine the prevalence of these conditions in men. The authors summarise that symptoms of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome are widespread among men in the United States. This prevalence in men approaches that in women, suggesting that this condition may be underdiagnosed in the male population.

Other

Epidemiology of urinary tract infections: incidence, morbidity, and economic costs – abstract
Full paper (opens as PDF)
The American Journal of Medicine, Volume 113, Issue 1, 5 – 13
Foxman, Betsy

Published in 2003 in Disease a Month, this paper discusses the absence of data regarding the accuracy of UTI incidence in all populations whilst providing current data available globally, the economic costs of UTI management, factors that increase susceptibility to UTI, and the long-term medical consequences of UTI.

The unexplored relationship between urinary tract infections and the autonomic nervous system
Autonomic Neuroscience: Basic and Clinical, Volume 200, 29 – 34 2016
Hibbing ME, Conover MS, Hultgren SJ.

This paper summarizes efforts to understand the molecular mechanisms of the interactions between Uropathogenic E-coli and the host. They review the progress that has been made in: i) generating vaccines and anti-virulence compounds that prevent and/or treat UTI by blocking bacterial adherence to urinary tract tissue and; and ii) clarify the mechanisms by which anti-inflammatories are able to alleviate symptoms and improve disease prognosis. They include potential relationships between the automic nervous system and UTI. While these relationships have not been experimentally explored, the known interactions between numerous UTI characteristics (symptoms, complicating factors, and inflammation) and ANS function suggest that UTIs are directly impacting ANS stimulation and that ANS (dys)function may alter UTI prognosis.

Urinary tract infections: epidemiology, mechanisms of infection and treatment options.
Nature Reviews of Microbiology 2015
Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ

The authors of this paper examine the mechanisms of development during bladder and kidney infection, comparing and contrasting the virulence factors used by Uropathogenic E-coli, K. pneumoniae, P. mirabilis, E. faecalis and P. aeruginosa. They review treatments available, antibiotic resistance mechanisms, new combination therapies and future therapeutic interventions that use vaccines and small molecules to target virulence factors.

From physiology to pharmacy: developments in the pathogenesis and treatment of recurrent urinary tract infections
Current Urology Reports in 2014
Silverman JA, Schreiber HL, Hooton TM & Hultgren SJ

This paper discusses recent findings regarding recurrent UTIs in women, including progress in understanding the mechanisms of recurrence as well as emerging treatments. The authors conclude that continuing understanding of recurrent UTIs will require ongoing investigations into genomics, bacteriology, and the human microbiome in order to develop appropriate and responsible treatment strategies.