Clinical effectiveness and bacteriological eradication of three different Short-COurse antibiotic regimens and single-dose fosfomycin for uncomplicated lower Urinary Tract infections in adult women (SCOUT study): study protocol for a randomised clinical trial.

INTRODUCTION: Uncomplicated lower urinary tract infections (uLUTI) are a common problem in primary care. Current local guidelines recommend the use of a single 3 g dose of fosfomycin. However, most general practitioners (GP) prefer short-course therapies to single-dose therapy. No study has compared head-to-head short-course antimicrobial agents for uLUTIs. Therefore, the aim of this randomised clinical trial is to compare three different short-course antibiotic therapies with a single-dose of fosfomycin for these infections. METHODS AND ANALYSIS: This will be a pragmatic, multicentre, parallel group, open trial. Women aged 18 or older and with symptoms of uLUTI and a positive urine dipstick analysis will be randomised to one of the following four groups: a single dose of 3 g of fosfomycin, 2 days of 3 g of fosfomycin o.d., 3 days of pivmecillinam 400 mg three times per day (t.i.d) or 5 days of nitrofurantoin 100 mg t.i.d. A total sample of 1120 patients was calculated. The primary endpoint is clinical effectiveness at day 7, defined as cure of symptoms reported by the patients in a diary including four symptoms: dysuria, urgency, frequency and suprapubic pain, which will be scored on a 4-point severity scale (not present/mild/moderate/severe). Follow-up visits are scheduled at days 7 (phone call), 14 and 28 for assessing evolution. Urine samples will be collected in the three on-site visits and urine cultures performed. If positive, antibiograms for the three antibiotics studied will be performed. Bacterial eradication will be measured at days 14 and 28. ETHICS AND DISSEMINATION: The study was approved by the Ethical Board of IDIAP Jordi Gol (reference number: 21/173-AC) and Spanish Agency of Medicines and Medical Devices. The findings of this trial will be disseminated through research conferences and peer-review journals. TRIAL REGISTRATION NUMBER: NCT04959331; EudraCT Number: 2021-001332-26. TIME SCHEDULE: January 2022 to April 2023.

Multicentre, randomised, open-label, phase IV-III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptible Staphylococcus aureus bacteraemia: study protocol for the SAFO trial.

INTRODUCTION: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia. METHODS: We will perform a superiority, randomised, open-label, phase IV-III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician.Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation).We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant). ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders. TRIAL REGISTRATION NUMBER: The protocol has been approved by AEMPS with the Trial Registration Number EudraCT 2018-001207-37. ClinicalTrials.gov Identifier: NCT03959345; Pre-results.