Research

We share a range of research articles that are useful in helping you understand the development of chronic UTI and the limitations of UTI testing and treatment. We also share important research papers explaining the discovery of the urobiome,  bacterial biofilm in the urinary tract, the emerging role of hormones and research into potential non-antibiotic treatments in the future.

Research Papers on Chronic UTI Development

Cystitis Unmasked, chapter 6:  What Cystitis Does to You

Malone Lee, J (2021) Cystitis Unmasked, pp. 119-150, tfm Publishing Ltd, Shrewsbury. UK.

James Malone-Lee is an Emeritus Professor of Medicine at University College London (UCL) and the author of Cystitis Unmasked. “For 37 years as a clinical scientist at UCL he studied lower urinary tract symptoms. His research group made discoveries that challenged numerous strongly held beliefs about lower urinary tract disease, particularly infection. For many years this new knowledge was rejected by many, but in the wake of corroborative evidence from others around the world, this new thinking is becoming more widely accepted.”

 

 

Unusual Immune Response Bladder Appears to Drive Repeat UTIs

May 2020

Research is now shedding light on why an initial UTI may be a precursor for recurrent UTIs.  “Most women will experience at least one UTI in their lifetime,” said senior author Soman Abraham, Ph.D., a professor in the departments of Pathology, Immunology and Molecular Genetics and Microbiology at Duke University School of Medicine. “In a substantial proportion of these women, UTIs become recurrent with painful frequency.”

https://medschool.duke.edu/news/unusual-immune-response-bladder-appears-drive-repeat-utis

 

 

Early Severe Inflammatory responses to Uropathogenic E.Coli Predispose to Chronic and Recurrent urinary tract infection

August 2010

When uropathogenic Escherichia coli (UPEC) were introduced to the bladders of mice, the acute infection either resolved or evolved into chronic cystits. The development of chronic cystitis was found to be ‘preceded by biomarkers of local and systemic acute inflammation’, including bladder inflammation with injury to the mucosa. Researchers concluded that it is this severe acute inflammatory response which subsequently predisposes individuals to recurrent cystitis.

https://pubmed.ncbi.nlm.nih.gov/20811584/

 

 

Enterococcus faecalis subverts and invades the host urothelium in patients with chronic urinary tract infection

December 2013

Using advanced imaging techniques, urothelial cells shed in response to bladder inflammation were inspected for bacterial invasion and pathology. Researchers found strong evidence of intracellular E. faecalis in the cells harvested from LUTS patients, thereby implicating this bacteria in the development of chronic LUTS.

https://pubmed.ncbi.nlm.nih.gov/24363814/

 

 

Intracellular Bacterial Communities: A Potential Etiology for Chronic Lower Urinary Tract Symptoms

Sept 2015

This review examines emerging evidence for a role of intracellular bacterial communities (IBC) in human infection. Occult and recurrent urinary tract infection is thought be due to the invasion of the bladder wall by uropathogenic Escherichia coli (UPEC) and the formation of biofilm-like IBCs. Infection is frequently undetected due to the concentrations of bacteria in the urine falling short of the threshold used in standard urine culture techniques.

https://pubmed.ncbi.nlm.nih.gov/26189137/

 

 

Bad bugs and beleaguered bladders: Interplay between uropathogenic Escherichia coli and innate host defences

August 2000
This early study describes how strains of uropathogenic Escherichia coli (UPEC) can counter host defences upon entering the urinary tract by attaching to the bladder epithelial cells, where they can replicate or persist in a quiescent state. The invasion of the cells can trigger immune responses such as cytokine production, inflammation and the exfoliation of infected bladder wall cells. Despite host defences and antibiotic treatment, they can persist within the bladder tissue and possibly serve as a reservoir for recurrent infections.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC34019/

 

 

Filamentation by Escherichia coli subverts innate defences during urinary tract infection

December 2006
This paper demonstrates how during acute stages of infection, uropathogenic Escherichia coli (UPEC) can invade cells in the bladder wall to avoid innate defences (immune or antibiotic attack), where they form biofilm-like intracellular bacterial communities (IBC). They go on to colonise the surrounding epithelium and generate further IBC and quiescent intracellular reservoirs (QIRs)
https://pubmed.ncbi.nlm.nih.gov/17172451/

 

A mucosal imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease

October 2017
It is known that the most significant risk factor for developing a UTI is a prior history of urinary infection. This study shows that, in mice, an initial e coli UTI leaves a long-lasting molecular imprint on the tissue of the bladder wall which alters the pathophysiology and allows for subsequent infection. This new knowledge could lead to the development for new treatments for recurrent urinary infections.
https://pubmed.ncbi.nlm.nih.gov/27798558/

Research Exposing Testing Limitations

Cystitis Unmasked, chapter 5:  UTI and the testing mayhem

Malone Lee, J (2021) Cystitis Unmasked, pp. 97-118, tfm Publishing Ltd, Shrewsbury. UK.

 

 

Tarnished Gold – the ‘Standard’ Urine Culture: Reassessing the Characteristics of a Criterion Standard for Detecting Urinary Microbes

July 2023

This article discusses the problems with current UTI testing and diagnosis and the importance of improving on techniques that have not changed in many decades. This outdated and simplistic approach to diagnosis is no longer appropriate, despite many continuing to argue that current UTI care is adequate.

https://www.frontiersin.org/articles/10.3389/fruro.2023.1206046/full

 

 

Spectrum of Bacterial Colonisation Associated with Urothelial Cells from Patients with Chronic Lower Urinary Tract Symptoms

July 2013

Studies of acute urinary tract infection have indicated that it is likely that urothelial cells are invaded by bacteria such as Escherichia coli, with persistence of long-term bacterial reservoirs (persisters), but the role of infection in chronic lower urinary tract symptoms (LUTS) is unknown. This large prospective study with eligible patients with LUTS and controls over a three year period compared routine urine cultures of planktonic bacteria with cultures of shed urothelial cells concentrated in centrifuged urinary sediments, revealing that large numbers of bacteria are undetected by standard urine cultures.

https://pubmed.ncbi.nlm.nih.gov/23596238/

 

 

Reassessment of Routine Midstream Culture in Diagnosis of Urinary Tract Infection

March 2019
Midstream urine (MSU) culture remains the gold standard diagnostic test for confirming urinary tract infection (UTI).  This study was conducted on urine specimens from 33 patients with lower urinary tract symptoms (LUTS) attending their first clinical appointment, 30 LUTS patients on treatment whose symptoms had relapsed and 29 asymptomatic controls.  The outcome shows that the routine MSU culture, adopting the UK interpretation criteria tailored to acute UTI, failed to detect a variety of bacterial species, including recognised uropathogens. Moreover, the diagnostic MSU culture was unable to discriminate between patients and controls and may be unsuitable for excluding UTI in patients with LUTS.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425166/

 

 

The multiple antibacterial activities of the bladder epithelium

January 2017

This study describes the important role of bladder epithelial cells in fighting infection and regulating bladder volume. When other mechanisms have failed to clear the intracellular bacteria, the last resort action is activated.  There will be deliberate exfoliation of epithelial cells in order to rapidly decrease bacterial load, and many of these cells are shed carrying a load of adherent bacteria.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300852/

 

 

The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms

May 2016
In this Schreckenberger et al article, the enhanced urine culture (EQUC) technique is evaluated for detecting microorganisms found in urine specimens usually reported as ‘no growth’ by standard culture methods. The EQUC protocol achieved 84 percent uropathogen detection relative to 33 percent detection by standard urine culture. The streamlined EQUC protocol improves detection of uropathogens that are likely relevant for symptomatic women, giving clinicians the opportunity to receive additional information not currently reported using standard urine culture techniques.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844725/

 

 

USANZ 2017 Conference, Dr Curtis Nickel’s keynote address – Is the MSU test really a Gold Standard test?

Dr Curtis Nickel, Professor of Urology, Queen’s University, Canada … “We make our clinical decisions in infectious disease in urology based on technology that’s over 100-years-old. We’re still taking urine samples, plating it on an AGAR, and putting it in 24 hours in an incubator and then making a decision. We now know that we grow less than one percent of potential uropathogens by this technique; we don’t culture biofilm bacteria; and we miss 99.9 precent of possible microorganisms that are in the environment that might be related to infectious disease.”

https://soundcloud.com/talking-urology/usanz-2017-interviews-dr-curtis-nickel

 

 

American Society for Microbiology 2014 Conference – Interview with Dr Evann Hilt, Dr Paul Schreckenberger and Dr Alan Wolfe

Dr Paul Schreckenberger, Loyola Urinary Education and Research Collaborative (LUEREC), Loyola University, USA … “That’s another myth, the fact that infections are present only when the bacteria are present at 10^5 or greater. And that was never the intent of Kass’ original report. The amount of bacteria in people that have UTI varies. When you get up the urine has been concentrated during the night, sure it can be 10^5. But when you’ve had coffee and urinated it can be 10^2 and that’s also significant. But labs aren’t culturing at 10^2. We miss a lot of true UTIs by setting cut-off limits based on dogma that we think needs to be trashed.”

https://youtu.be/Vlt37Go04oM

 

 

Comment by Professor Helen O’Connell

Helen O’Connell (President USANZ, Australia’s first female urologist and medical researcher) (2023) comments that “Epithelial shedding as a marker of #cUTI is an important paradigm shift @prasadika @anitahclarke @urologyworks. Before it was recognised these are urothelial cells, we were taught they were evidence of contamination ie worthless sample which is not true”

https://twitter.com/oconnellprof/status/1644102867333292033?s=61

Recurrent and Chronic UTI Treatment Research

Cystitis Unmasked, chapter 7:  Treating the patient

Malone Lee, J (2021) Cystitis Unmasked, pp. 151-198, tfm Publishing Ltd, Shrewsbury. UK.

James Malone-Lee is an Emeritus Professor of Medicine at University College London (UCL) and the author of Cystitis Unmasked. “For 37 years as a clinical scientist at UCL he studied lower urinary tract symptoms. His research group made discoveries that challenged numerous strongly held beliefs about lower urinary tract disease, particularly infection. For many years this new knowledge was rejected by many, but in the wake of corroborative evidence from others around the world, this new thinking is becoming more widely accepted.”

 

 

Recalcitrant chronic bladder pain and recurrent cystitis but negative urinalysis: What should we do?

January 2018
Published online on 20 March 2018, this paper instantly became the most popular paper in the history of the International Urogynecology Journal & Pelvic Floor Dysfunction and in the top five percent of nearly one million research outputs ever tracked by Altmetric.  This paper covers a large case series of 624 women, spanning data collected over 10 years, demonstrating that patients with chronic lower urinary tract symtpoms (LUTS) and pyuria experience symptom regression [improvement] and a reduction in urinary tract inflammation [pyuria] associated with antimicrobial therapy. Disease regression was achieved with a low frequency of Adverse Effects (AE).
https://link.springer.com/article/10.1007/s00192-018-3569-7

 

 

Cross-over data supporting long-term antibiotic treatment in patients with painful lower urinary tract symptoms, pyuria and negative urinalysis

December 2018
This research measures the effect of an unplanned treatment cessation with 210 female and 11 male patients from a UK specialist clinic who were undergoing long-term antibiotic treatment chronic painful lower urinary tract symptoms (LUTS) coupled with pyuria and negative standard UTI tests.  The paper shows that after the sudden withdrawal of treatment, 199 patients (90%; female = 188; male = 9) reported deterioration. Symptom scores and signs of inflammation recovered on reinitiating treatment.
https://pubmed.ncbi.nlm.nih.gov/30564872/

 

 

Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial

March 2022

This multicentre, randomised trial tested and compared the efficacy of methenamine hippurate (Hiprex) for prevention of recurrent urinary tract infections with the current standard prophylaxis of a daily low dose antibiotic. It was found that prophylactic treatment with methenamine hippurate could be appropriate for women with a history of recurrent episodes of urinary tract infections, given the demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905684/

 

 

Methenamine: a forgotten drug for preventing recurrent urinary tract infection in multi drug resistant era

April 2014

This article discusses the place of methenamine (Hiprex) in the management of recurrent urinary tract infection and suggests it should be used when recurrent UTIs are not suppressed by more commonly used antibiotics.

https://www.tandfonline.com/doi/full/10.1586/14787210.2014.904202

 

 

Preventive effect of methenamine in women with recurrent urinary tract infections – a case–control study

November 2022

This Norwegian study found that methenamine (Hiprex) had a significant preventive effect in women aged 40 and older with a history of recurrent UTIs for longer than two years.

https://www.tandfonline.com/doi/full/10.1080/02813432.2022.2139363?src=recsys

Research into the Emerging Role of Hormones

Update in Female Hormonal Therapy: What the Urologist Should Know

December 2020

“Estrogen depletion at any age has direct implications on genitourinary health and lower urinary tract function. It is often in the perimenopausal age group that GSM and recurrent UTIs become prevalent, driving women to the urologist for evaluation and treatment. Urinary tract evaluation with imaging and cystoscopy is often of low yield and can be frustrating for both the patient and the clinician. Vaginal estrogen therapy is safe and extremely efficacious in treating these symptoms and lowering the risk of UTIs. It can be used safely in most women, even in those already on systemic HRT.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058921/

 

 

How Estrogen Fights Urinary Tract Infections

June 2013

“The female hormone estrogen may protect against urinary tract infections in postmenopausal women by improving two of the body’s defense mechanisms, a new study found.” The researchers found that the body’s natural antimicrobial proteins were triggered by the hormone, as well as the creating a tightening effect on the surface layer of the bladder epithelium.

https://www.livescience.com/37563-uti-estrogen-menopause.html

 

 

Importance of vaginal hormone treatments for women

May 2023

US urologist Dr. Rachel Rubin discusses the importance of vaginal hormone treatments for women over 45. “The take-home message is that as a practicing urologist, you should be treating genitourinary syndrome of menopause and giving any woman over 45 vaginal hormones, whether in the form of vaginal estrogen or vaginal DHEA,” says Rachel S. Rubin, MD.

https://www.urologytimes.com/view/dr-rubin-on-the-importance-of-vaginal-hormone-treatments-for-women-over-45

 

 

Unpicking UTIs and the role of hormones with Dr Rajvinder Khasriya

May 2022

Experts discuss the role of hormones in UTI and the benefits of vaginal hormone treatments in preventing and managing UTI.

https://www.balance-menopause.com/menopause-library/unpicking-utis-and-the-role-of-hormones-with-dr-rajvinder-khasriya/

The Urinary Microbiome – (Urobiome)

The New World of the Urinary Microbiota in Women

November 2015

This article is one of the first to highlight that the commonly held belief that the bladder is a sterile organ can no longer be accepted. Modern testing (expanded quantitative urine culture and 16S ribosomal RNA gene sequencing) can detect previously unrecognised organisms, making it possible to answer previously intractable scientific and clinical questions. Available data indicates that the urinary bacterial population is strongly linked with urinary symptoms.

htps://pubmed.ncbi.nlm.nih.gov/26003055/ 3

 

 

Urine is Not Sterile: Use of Enhanced Urine Culture Techniques to Detect Resident Bacterial Flora in the Adult Female Bladder

March 2014

In this ground breaking study, researchers 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 can be cultured using an expanded protocol. The most prevalent genera isolated were Lactobacillus (15%), followed by Corynebacterium (14.2%), Streptococcus (11.9%), Actinomyces (6.9%) and Staphylococcus (6.9%). Other genera commonly isolated include AerococcusGardnerellaBifidobacterium, and Actinobaculum. The study demonstrates that urine contains colonies of living bacteria that comprise a resident female urine microbiota.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957746/

 

 

American Society for Microbiology 2014 Conference – Interview with Dr Evann Hilt, Dr Paul Schreckenberger and Dr Alan Wolfe

An interview with the Loyola University research team at the American Society for Microbiology’s 114th Annual Meeting, Boston, USA, May 2014. Representatives from the Loyola Urinary Education and Research Collaborative (LUEREC) team, Alan Wolfe, Evann Hilt and Paul Schreckenberger discuss their discovery of the female urinary microbiome (FUM) and what this could mean for the future of UTI testing and treatment.

Bacterial Biofilm

Bacterial Biofilm and its Role in the Pathogenesis of Disease

February 2020

The presence of chronic disease and infections are commonly linked to the role of biofilms, as biofilm-residing bacteria can be resistant to both the immune system, antibiotics, and other treatments. Biofilm diseases occur in many bodily systems, including the urinary system. The current knowledge on how biofilm may contribute to the pathogenesis of disease indicates a number of different mechanisms. These include the biofilm acting as a reservoir of pathogenic bacteria or creating an inflammatory response. Observations also indicate that biofilm can be formed within the living cells as well as outside the cell. Understanding the role of biofilm is essential to the development of effective treatments for such infections.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167820/

 

 

International Continence Society (ICS) 2015 Conference

An interview with Scott Hultgren and Alan Wolfe at the International Continence Society (ICS) 2015 Conference. Professor Scott Hultgren answers questions and discusses with Professor Alan Wolfe his research team’s work with immunity, biofilms and clinical prevention of recurrent urinary tract infections.

Research into Future Non-Antibiotic Treatments

Importance of Biofilms in Urinary Tract Infections: New Therapeutic Approaches

March 2014

This study looks at the significant role of bacterial biofilms in UTIs, causing persistent infections, relapses and prostatitis. Treating such conditions is challenging and the study looks at a number of therapeutic approaches, as well as highlighting the need for new antimicrobial drugs that inhibit biofilm formation and the associated bacterial virulence.

https://www.hindawi.com/journals/ab/2014/543974/

 

 

Novel particles conferring eradication of deep tissue bacterial reservoirs for the treatment of chronic urinary tract infection

September 2020

This work investigates the use of nitrofurantoin loaded poly (lactic-co-glycolic acid) (PLGA) particles to improve delivery to intracellular targets for the treatment of chronic UTI. The particles were able to deliver the drug to cells through multiple layers of a 3D human bladder organoid model causing minimal cell toxicity, displaying superior killing of bacterial reservoirs harboured within bladder cells compared with unencapsulated drug and were able to kill bacterial biofilms more effectively than the free drug.

https://www.sciencedirect.com/science/article/abs/pii/S0168365920304892?

 

 

 

An encapsulated drug delivery system for recalcitrant urinary tract infection

December 2013
This paper looks into a prototype of a new encapsulated drug delivery system to treat chronic UTI by delivering high-dose antibiotics direct into the bladder where they can permeate cells and eradicate intracellular bacterial reservoirs. The study encapsulated Gentamicin in a polmeric carrier and these capsules killed Enterococcus faecalis in vitro in a dose-responsive, slow-release manner, which suggested this treatment could prove to be successful for recalcitrant UTI.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808553/

 

 

A Dutch Case Report of Successful Treatment of Chronic Relapsing Urinary Tract Infection with Bacteriophages

December 2019

This article reports the treatment of a renal transplant patient who developed a recurrent urinary tract infection with an extended-spectrum β-lactamase (ESBL)-positive Klebsiella pneumoniae strain in the first month post transplant. The infection recurred despite repeated meropenem treatment. The patient developed epididymitis and was then successfully treated with meropenem and bacteriophages.

https://pubmed.ncbi.nlm.nih.gov/31611357/

 

 

Microencapsulation technology

Developed within University College London (UCL) Encapsulation Research Group and based on a novel implementation of electro-hydrodynamic processing. AtoCap Technology enables the encapsulation of patient-specific combinations of generic drugs such as antibiotics and chemotherapeutics into a multi-layered capsule. CapFuran®, enables time-release killing of a variety of patient-derived uropathogenic bacterial species, including E. coli, by a well-known and frequently-used generic antibiotic encapsulated using innovative methodology. In pre-clinical experiments, CapFuran® eradicated bacteria buried deep within a multi-layered human bladder organoid model and also killed bacterial biofilms.

https://atocap.co.uk/executive-and-scientific/capfuran-published-journal-controlled-release-preclinical/

 

 

N-acetylcysteine protects bladder epithelial cells from bacterial invasion and displays antibiofilm activity against urinary tract bacterial pathogens 

July 2021

This Australian study tested the action of NAC against biofilm producing bacteria. It was found to inhibit bladder endothelial cell invasion and biofilm formation by E. coli and E. faecalis, thereby showing potential for enhancing the therapeutic effects of antibiotics in treating UTI.

https://www.mdpi.com/2079-6382/10/8/900

 

Role of Vaccines for Recurrent Urinary Tract Infections: A Systematic Review

May 2020

This study systematically reviewed available research to determine the role of vaccines in the treatment of recurrent UTI. Researchers concluded that the vaccines available currently do appear to have a role in the prevention of recurrent UTI while producing tolerable side effects. They determined that more work is required with regard to longer term benefits for this patient group, and also the role of vaccines in other high-risk patient groups, with the potential for an increasing role in the future.

https://pubmed.ncbi.nlm.nih.gov/31806578/

 

 

An Effective Sublingual Vaccine, MV140, Safely Reduces Risk of Recurrent Urinary Tract Infection in Women

March 2023

This study found that the sublingual vaccine MV140 appeared to safely prevent or reduce the risk of UTI. Resulting benefits are a reduction in antibiotic use and overall disease burden for patients suffering from recurrent UTI.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052183/

 

 

 

Local induction of bladder Th1 responses to combat urinary tract infections

March 2021

This study tested intravesical vaccination with one or more uropathegenic E.coli antigens in mice, compared with subcutaneous administration. It was found to be effective and represented a superior strategy to treat UTI, particularly in subjects with aberrant bladder immune responses.

https://pubmed.ncbi.nlm.nih.gov/33653961/

 

 

Dr. Abraham and Dr. Staats Receive R21 Grant for Novel UTI Vaccine Strategy

April 2023

The National Institute of Allergy, Immunology, and Infectious Diseases has awarded Soman Abraham, PhD, and Herman Staats, PhD, a two-year R21 grant titled “A Novel Vaccination Strategy to Curb Recurrent UTIs”

https://pathology.duke.edu/news/abraham-staats-r21-grant-uti-vaccine

https://abc11.com/uti-symptoms-treatment-what-is-a/10650291/

Video: Dr Soman Abraham The Immune System Response to UTI : UTI Vaccines (Part 1)

https://youtu.be/HCwh5KLV3bg

Video: Dr Soman Abraham How UTI Vaccines Work: UTI Vaccines (Part 2)

https://youtu.be/fNUt-8Ma9xw

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