Title: Improving the Diagnosis of Recurrent Urinary Tract Infection in Primary Care
Funder: Department of Health and Social Care

Abstract: Recurrent Urinary Tract Infections (RUTIs) affect ~800000 women in the UK annually, causing pain, fever, urinary frequency, and difficulties with work and sexual relationships. Many women are prescribed frequent or even continuous antibiotics for recurrent UTI, which both cause distressing side effects and drive antibiotic resistance. Recurrent UTI may in fact represent different conditions, which could respond best to quite different treatment approaches. Some women may be re-infected from their own bowel flora, others through re-emergence of bacteria from colonies with their bladder wall, while some with ongoing asymptomatic bacteriuria as a normal state may not have true infection at all. GPs find managing this condition challenging because there is insufficient or no evidence on which to base decisions about which women with recurrent UTI will benefit from preventative treatment, and which approach to treatment should be used. I am leading a Randomised controlled trial (RCT) aiming to evaluate the clinical and cost effectiveness of D-Mannose, a food supplement which may help to prevent recurrent UTI. This fully funded trial will efficiently provide both samples and access to patient interviews to support the aims of this fellowship. Aims and Methods Overall Aim 1: To define which women are at greatest risk of subsequent UTIs and therefore which women GPs should consider offering prophylactic treatment (Years one and two) I will use the Clinical Practice Research Datalink to describe the epidemiology of recurrent UTI in UK primary care and the clinical and demographic features associated with increased risk of recurrent UTI. The Infections in Oxford Research Database will additionally provide the unique ability to explore microbiological features associated with recurrent UTI. I will interview patients who suffer from recurrent UTI to understand experiences, self-management, and acceptability of possible treatment approaches. This will provide context for, as well as suggest different approaches to using, my findings from the database analyses. Overall Aim 2: To explore whether microbiological techniques can identify subgroups of women who may have different mechanisms underlying recurrent UTI and therefore may need different treatment approaches (Years three and four) Urine culture techniques will identify women recruited to my RCT of recurrent UTI who have bacteria in their urine when asymptomatic. Whole genome sequencing (WGS) techniques will additionally identify bacteria present at very low levels and bacteria not usually found using standard methods. In women who experience a UTI, WGS will allow us to see if identical species causing a symptomatic UTI are present at low counts when women are asymptomatic, suggesting re-emerging infection from the bladder wall. Impact Findings will help GPs understand which women are higher risk of subsequent UTI, to target investigations and treatments. Better understanding of the mechanisms underlying recurrent UTI could support personalisation of management approaches, resulting in a reduction in unnecessary antibiotic use. Findings will support novel point of care UTI diagnostic development to be fit for purpose. Bladder Health UK and the Royal College of General Practitioners support this fellowship and will partner in dissemination activities.

Lay abstract: Around half of all women will suffer from at least one urinary tract infection (UTI) in their lifetime, and it is the most common bacterial infection treated by General Practitioners (GPs). Up to 800000 women in the UK suffer from frequent UTIs each year. Such 'recurrent UTI' causes painful and distressing symptoms, difficulty in managing daily activities, and problems with sexual relationships. Multiple antibiotic courses or even continuous antibiotics are often prescribed, which can result in bacteria becoming resistant to some antibiotics, making infections harder to treat. GPs, myself included, find recurrent UTI challenging to treat, because we don't yet know which women will benefit from preventative treatment, and which type of treatment might do the most good for which patient. Recurrent UTI probably has a number of distinct causes, each of which could benefit from a different approach to treatment. Some women may get re-infected by bacteria from their own bowel each time, while in others, bacteria may live inside the cells that line their bladder all the time and re-emerge to cause infections. A third group may always have infectious bacteria in their urine, but for them, these bacteria do not usually cause symptoms. Each situation will require a different response, so the current 'one size fits all' approach will not suit everyone: a far more personalised approach is likely to relieve suffering much better, while also reducing unnecessary antibiotics. This fellowship has 2 main aims To help GPs predict which women are likely to suffer from recurrent UTI in the future and so might need preventative treatment To discover whether women can be divided into different groups according to the likely mechanism of their recurrent UTI, which could respond best to different treatmentsTo help GPs to decide which women are likely to suffer from recurrent UTI in the future, I will analyse two large databases. One will include GP consultations and the other will include results of laboratory tests on urine. These datasets will allow me to see if women's medical history, pattern of previous infections and the type of bacteria causing infections relate to their risk of further UTIs. I will also interview up to 35 women who have recurrent UTI to understand how they manage their condition with and without their GP's help. This will help me interpret the findings from the database analyses. I am about to start recruiting 506 women to a large, already fully-funded trial that will find out if a type of sugar prevents recurrent UTI. Trial patients will provide urine samples both when they have symptoms and also when they don't. I will use these samples to describe how many women have bacteria in their urine when they don't have symptoms, and the amount and types of these bacteria. I will then use newly developed genetic testing methods to detect small amounts of bacteria and precisely identify the exact species. We will compare samples from the same woman when she is symptom-free and during an infection to see if identical bacteria are present. This would suggest the bacteria comes from their bladder wall to cause infection, rather than coming from their bowel. A group of women who experience recurrent UTI will guide this research, ensure it is relevant to patients, and help interpret findings. Bladder Health UK will describe my findings on their website and I will work with GPs to develop a webcast. I am collaborating with companies developing new rapid tests for UTI who will benefit from this research. The results will be published in scientific journals and presented at conferences.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION