Research

The Marshall Centre for Infectious Diseases Research and Training, Perth, Western Australia

Headed by 2005 Nobel Prize winner, Professor Barry Marshall

www.ic-bps.com and patient forum www.icbpsforum.com

After receiving letters over the years by people diagnosed with Interstitial Cystitis (IC)/Painful Bladder Syndrome (PBS), Professor Barry Marshall decided it was time to take on a much neglected area of research at his Perth research centre. The first stage of research commenced in late 2016. His team’s mission is:

“To evaluate the current knowledge about IC-BPS (Interstitial Cystitis Bladder Pain Syndrome), establish baseline measurements in normal persons and then find abnormalities in patients which might generate hypotheses, suggest causes and ultimately result in a cure.”

Chronic UTI Group, University College London (UCL), UK

Headed by Dr Jennifer Rohn and Emeritus Professor James Malone-Lee

www.ucl.ac.uk/nephrology/research

The Chronic UTI Group focuses on the microbial diversity and host/pathogen interactions of recalcitrant and recurrent urinary tract infection, with a special interest in how chronic/recurrent UTI differs from uncomplicated acute UTI. They are investigating how protected bacterial reservoirs might facilitate recurrence and antibiotic resistance. The team is currently working on a novel therapeutic treatment for Chronic UTI which is soon to enter clinical trials. It involves encapsulated antibiotics in multi-layered microcapsules, designed to be targeted into the bladder to deliver a high, penetrative dose of therapeutic agent. The Chronic UTI Group research encompasses microbiology, molecular cell biology, immunology, tissue engineering, metagenomics, high-resolution imaging and biofilm biology.

UCL research papers:

• 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 LUTS patients 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.

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• Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection, March 2019
  This study demonstrates new modalities for high-efficiency intracellular drug delivery for diseases such as urinary tract infection (UTI), which is one of the most common infectious diseases globally and which imposes an immense economic and healthcare burden. Common uropathogenic bacteria have been shown to invade the urothelial wall during acute UTI, forming latent intracellular reservoirs that can evade antimicrobials and the immune response. This behaviour likely facilitates the high recurrence rates after oral antibiotic treatments, which are not able to penetrate the bladder wall and accumulate to an effective concentration.  The study data shows that ultrasound-activated microbubbles can safely deliver high concentrations of drugs into urothelial cells, and have the potential to be a more efficacious alternative to traditional oral antibiotic regimes for UTI. This modality of intracellular drug delivery may prove useful in other clinical indications, such as cancer and gene therapy, where such penetration would aid in treatment.
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• Cross-over data supporting long-term antibiotic treatment in patients with painful lower urinary tract symptoms, pyuria and negative urinalysis, December 2018
  This research paper published in the International Urogynecology Journal 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.  Eleven  required hospital due to disease recurrence, including acute urinary tract infection (UTI) and urosepsis. Symptom scores and signs of inflammation recovered on reinitiating treatment.
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• 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 5 percent of nearly 1 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 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).
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• Fallacies and Misconceptions in Diagnosing Urinary Tract Infection, July 2014
  An informative chapter by Professor James Malone-Lee, UCL, from the 2014 online book ‘Novel Insights into Urinary Tract Infections and their Management’. It describes the deficiencies of gold standard UTI diagnostic tools, such as MSU culture and the urinary dipstick and the accepted diagnostic thresholds, which are proven to miss up to 50 percent of infections. The article places emphasis on the importance of low-level microscopic pyuria and reported symptoms when making a diagnosis.
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• Spectrum of Bacterial Colonization Associated with Urothelial Cells from Patients with Chronic Lower Urinary Tract Symptoms, July 2013
  This paper discusses a study into chronic lower urinary tract symptoms (LUTS) and the link to the invasion of e coli into the bladder wall cells during acute UTI, where the invading bacteria set up long term bacterial reservoirs. The large prospective study followed LUTS patients and controls over a three year period and compared routine urine cultures and enhanced cultures of concentrated urinary sediment. The study found the two groups had complex but significantly distinct profiles of bacteria. Data suggested that LUTS-associated bacteria are within or extremely closely associated with shed bladder wall cells, which explains how routine cultures might fail to detect these bacteria and that common diagnoses and treatments of chronic urinary tract symptoms needs re-examination.
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• Enterococcus faecalis subverts and invades the host urothelium in patients with chronic urinary tract infection, December 2013
  This paper looks at the role of intracellular infection in Chronic UTI causing more subtle lower urinary tract symptoms (LUTS).   During the study they harvested bladder wall cells shed in response to inflammation and used advanced imaging techniques to look for signs of bacterial pathology and invasion. The data found strong evidence of enterococcus faecalis harboured within bladder wall cells shed from LUTS patients.
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• 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.
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• The Inadequacy of Urinary Dipstick and Microscopy as Surrogate Markers of Urinary Tract Infection in Urological Outpatients with Lower Urinary Tract Symptoms without Acute Frequency and Dysuria, May 2010
  This study discredits the reliability of using urinary dipsticks and microscopic pyuria as diagnostic tools to rule out UTI in patients with chronic lower urinary tract symptoms (LUTS). The study concludes by calling for the abandonment of these as gold standard diagnostic tools.
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Loyola Urinary Education and Research Collaborative (LUEREC), Chicago, USA

Headed by Professor Alan Wolfe

http://ssom.luc.edu/luerec/

The Loyola research team was the first to publish the discovery of the female urinary microbiota (FUM) in 2012 and continues to make in-roads in developing an understanding of the urinary microbiota and how it relates to health and disease. Once they have a clear understanding of the urinary microbiota, they hope to develop innovative treatments for various LUTS conditions and syndromes that are, at present, misunderstood.

LUEREC research papers:

• The female urinary microbiota, urinary health and common urinary disorders, January 2017
  In this review Linda Brubaker and Alan Wolfe provide clinical context and updated information regarding the female urinary microbiota (FUM). They provide information about distinct characteristic of these microbial communities in health and dysbiosis. They explain that gaining knowledge about FUM may be useful to help advance prevention, diagnosis and treatment of common lower urinary tract disorders in women. They suggest by adopting enhanced culturing techniques in clinical labs that better describe the microbes in the FUM, this could one day provide clinicians and patients with knowledge to appropriately modify and improve treatment for lower urinary tract disorders without antibiotic use.
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• The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms, May 2016
  In this Shreckenberger 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.
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• The New World of the Urinary Microbiota in Women, May 2015
  In this paper Linda Brubaker and Alan Wolfe from the Loyola University, Chicago, reveal emerging evidence proving the healthy bladder is not sterile. It shows the limitations of traditional tools used in the clinical setting to diagnose UTI, including dipsticks and urine cultures. It discusses the need to adopt new testing methods to detect previously unrecognised organisms that are likely responsible for patients’ symptoms.
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• An interview with the Loyola research team at the American Society for Microbiology’s 114^th Annual Meeting, Boston, USA, May 2014
  Representatives from the 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.

The Center for Women’s Infectious Disease Research (cWIDR), Washington University School of Medicine, USA

www.cwidr.wustl.edu

Hultgren Lab headed by Professor Scott Hultgren
Lewis Lab headed by Professor Amanda Lewis

The Center for Women’s Infectious Disease Research (cWIDR) is investigating common and often overlooked infections affecting women, such as acute and chronic urinary tract infections, interstitial cystitis and sexually transmitted diseases. The research combines women’s health, microbiology, immunology and infectious diseases, and has made significant progress with acute, recurrent and chronic UTI with the discoveries and understanding of uropathogenic E. coli (UPEC), intracellular bacterial communities (IBC) and biofilm infection.

cWIDR research papers:

• A mucosal imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease, full release 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.
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• Gram-Positive Uropathogens, Polymicrobial Urinary Tract Infection, and the Emerging Microbiota of the Urinary Tract, April 2016
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• Filamentation by Escherichia coli subverts innate defenses during urinary tract infection
  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).
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• 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.
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• 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.

Other research papers

• Population Dynamics of an Escherichia coli ST131 lineage during recurrent urinary tract infection, August 2019
  “Abstract:  Recurrent urinary tract infections (rUTIs) are extremely common, with ~ 25% of all women experiencing a recurrence within 1 year of their original infection. Escherichia coli ST131 is a globally dominant multidrug resistant clone associated with high rates of rUTI. Here, we show the dynamics of an ST131 population over a 5-year period from one elderly woman with rUTI since the 1970s. Using whole genome sequencing, we identify an indigenous clonal lineage (P1A) linked to rUTI and persistence in the fecal flora, providing compelling evidence of an intestinal reservoir of rUTI. We also show that the P1A lineage possesses substantial plasmid diversity, resulting in the coexistence of antibiotic resistant and sensitive intestinal isolates despite frequent treatment. Our longitudinal study provides a unique comprehensive genomic analysis of a clonal lineage within a single individual and suggests a population-wide resistance mechanism enabling rapid adaptation to fluctuating antibiotic exposure.”
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• Intracellular Bacterial Communities: A Potential Etiology for Chronic Lower Urinary Tract Symptoms, July 2015
  This review examines the emerging evidence of intracellular bacterial communities (IBC) in occult and recurrent UTI (due to invasion of the cells in the bladder wall and the formation of biofilm-like IBC) in patients with chronic LUTS and negative cultures.
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• Importance of Biofilms in Urinary Tract Infections: New Therapeutic Approaches, March 2014
  This review examines the role biofilm plays in persistent UTI and prostatitis. It discusses the difficulties in eradicating biofilm infections and looks at new therapeutic approaches, including nanoparticles, biofilm enzyme inhibitors, bacteriophages and low-energy surface acoustic waves and the urgent need for new antimicrobial drugs to inhibit bacterial virulence and biofilm formation.
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