DURATION OF ANTIBIOTIC TREATMENT IN URINARY TRACT INFECTION (DurATIon-UTI Trial) 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.

Research question 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? Background 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. 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. Aims and Objectives 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. Methods 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). 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. Timelines for Delivery 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. Anticipated impact and dissemination 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.