Title: DURATION OF ANTIBIOTIC TREATMENT IN URINARY TRACT INFECTION (DurATIon-UTI Trial)_x000D_ _x000D_ Impact of duration of antibiotic therapy on effectiveness, safety and selection of antibiotic resistance in adult women with urinary tract infections (UTI): a randomised controlled trial.
Funder: Department of Health and Social Care

Abstract: Aims of the research_x000D_ This research aims to find the shortest antibiotic treatment duration needed to treat urinary tract infections effectively (UTI). We will focus on women with bladder and kidney infections and the antibiotics commonly used for these infections. We will also look at the impact of each antibiotic and treatment duration on antibiotic resistance in bacteria found in the urine._x000D_ _x000D_ Background to the research_x000D_ UTIs are among the most common infections treated with antibiotics and are far more common in women than men. Over four million prescriptions for UTIs are issued to women in the UK every year. However, there is little evidence to help clinicians decide how many days of antibiotic treatment are necessary. We need to use the shortest treatment duration which ensures that the infection is properly treated. This could avoid bacteria becoming antibiotic resistant, and ensure the antibiotics remain effective for treating UTIs in the future._x000D_ _x000D_ Design and methods used_x000D_ We will recruit 2248 adult women with UTI symptoms who have come to see a doctor in either a hospital or GP surgery, and for whom the doctor judges that antibiotics are needed. We will include women with symptoms of bladder and kidney infections. Following current guidelines we will use different antibiotics depending on the type of infection they have. Women who agree to take part will be randomised to an appropriate antibiotic and length of treatment. Because we don’t know the most effective treatment duration, we will randomise women to take their treatment for one of five or six different treatment durations in days (for example comparing 1, 2, 3, 4 and 5 days of treatment for a bladder infection). Our main focus will be to compare how many women have got fully better 6 weeks after starting antibiotics. We will also measure how long each woman experiences UTI symptoms, whether the bacteria in their urine are killed by the antibiotic, whether the women develop further UTIs, and if so whether the bacteria are resistance to any antibiotics, and the value for money of each treatment duration. We will collect this information from participants’ medical notes, by asking them to complete a symptom diary and from urine samples sent during follow-up. _x000D_ _x000D_ Patient and public involvement (PPI)_x000D_ We involved nine women with repeated bladder and kidney infections in developing the study proposal. They highlighted their uncertainty around the correct length of antibiotic courses and felt that we should focus on the proportion of women getting fully better because they were worried that shorter courses could result in ongoing symptoms or relapse. Our team includes a PPI representative who will join regular meetings as well as jointly leading our PPI work. A group of four women will help us develop trial materials, ensure the study process is acceptable, and optimise recruitment and dissemination._x000D_ _x000D_ Dissemination_x000D_ With our PPI and Engagement team, we will circulate findings to stakeholders and patients. Bladder Health UK will publish information on their website (https://bladderhealthuk.org) and newsletter. Team members who play leading roles in organisations that focus on improving antibiotic use, including NHS England and NHS Improvement, will ensure our findings reach key decision-makers in addition to authoring publications in peer reviewed journals.

Lay abstract: Research question _x000D_ What is the minimum duration of NICE-guideline recommended antibiotic treatment which maintains good clinical outcome while reducing antibiotic use and minimising antimicrobial resistance in adult women treated for UTI?_x000D_ _x000D_ Background_x000D_ Bacterial urinary tract infection (UTI) is common, affecting 10% of women/year and causing substantial morbidity. It is one of the commonest antibiotic prescribing indications. UTI is classified as pyelonephritis if involving the kidneys, and cystitis if involving the bladder only. Effective oral antibiotic options are limited by increasing antibiotic resistance and concerns regarding fluoroquinolone safety. There is a lack of evidence on optimal treatment durations for UTI; international guidance varies widely. _x000D_ _x000D_ Randomised control trials (RCTs) of antibiotic treatment durations typically use non-inferiority designs to compare a limited number of fixed durations. For this study we will use a novel RCT design which instead determines optimal treatment duration over a range of intervals (measured in days) by modelling duration-response curves. This avoids inherent inefficiencies of trials of arbitrary durations, and associated high trial costs._x000D_ _x000D_ Aims and Objectives_x000D_ For adult women with UTI we will establish the minimum duration of antibiotic treatment which maintains good clinical outcomes, and the impact of treatment duration on antimicrobial resistance selection in symptomatic recurrences We will explore the cost effectiveness and patient acceptability of different treatment durations._x000D_ _x000D_ Methods_x000D_ We will conduct an open-label, parallel group, multi-arm RCT in adult women with pyelonephritis or cystitis. As cystitis interventions, we will randomise 1,510 participants (to nitrofurantoin or pivmecillinam, and then to one of five antibiotic durations: 1,2,3,4 or 5 days. As a pyelonephritis intervention, we will randomise 738 participants to one of six antibiotic durations (4,6,8,10,12 or 14 days) of a beta-lactam antibiotic according to local policy (typically cephalexin or co-amoxiclav)._x000D_ _x000D_ The trial is powered on a primary outcome of sustained clinical cure at day 42. Secondary outcomes include: symptom resolution, treatment side-effects, number of symptomatic recurrences, antimicrobial resistance selection in recurrences, hospitalisation, antibiotic use, adherence, participant experience and a health economic evaluation. _x000D_ _x000D_ Timelines for Delivery_x000D_ The study will be conducted over 36 months. 9 months is allowed for study set up. The pilot trial will begin at month 10 and roll into the full trial after month 15 if site set up and recruitment criteria are met. The trial will run at 70-80 primary care practices and up to 15 acute NHS trusts until month 30. Data cleaning, analysis and write-up will occur in the final six months. _x000D_ _x000D_ Anticipated impact and dissemination _x000D_ This study will generate robust data on the optimal antibiotic management (antibiotic type, duration) of pyelonephritis and cystitis in adult women. These data will directly benefit patients, clinicians and care services, and will be used to inform guidelines and appropriate prescribing practice nationally and internationally. We will present this research at high-profile international conferences, and publish our findings in pre-prints and peer-reviewed journals. We will work with patient support charities to disseminate findings to patients. We will engage with the media to facilitate widespread dissemination of findings to the public.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION