Clinical and bacteriological effectiveness of three different short-course antibiotic regimens and single-dose fosfomycin for uncomplicated lower urinary tract infections in women (SCOUT): a pragmatic, multicentre, open-label, randomised clinical trial.

# Clinical and bacteriological effectiveness of three different short-course antibiotic regimens and single-dose fosfomycin for uncomplicated lower urinary tract infections in women (SCOUT): a pragmatic, multicentre, open-label, randomised clinical trial *The Lancet 2026* Articles Clinical and bacteriological effectiveness of three different short-course antibiotic regimens and single-dose fosfomycin for uncomplicated lower urinary tract infections in women (SCOUT): a pragmatic, multicentre, open-label, randomised clinical trial Carl Llor, Ramon Monfà, Ana Garcia-Sangenís, Alfonso Leiva, Jaime Marín-Cañada, María Antonia Sánchez-Calavera, Ana Moragas, Mercedes Aguilar-Sánchez, Amelia Troncoso-Mariño, Ricardo Rodríguez-Barrientos, José M Molero, Dan Ouchi, Cristina Miranda-Jiménez, Silvia Fernández-García, Rosa Morros Summary Background Most guidelines recommend nitrofurantoin, fosfomycin, and sometimes pivmecillinam for Lancet 2026; 407: 1603–13 uncomplicated urinary tract infections (UTIs), but direct comparisons between these antibiotics are needed. This Published Online study evaluated the eectiveness and safety of a single dose of fosfomycin compared with two doses of fosfomycin April 20, 2026 and short-course regimens of nitrofurantoin and pivmecillinam in women with UTI symptoms. https://doi.org/10.1016/ S0140-6736(25)02171-3 See Comment page 1574 Methods This phase 4, pragmatic, multicentre, parallel-group, open-label, randomised clinical trial was conducted in Institute for Primary Health Spanish primary care centres from 2022 to 2024. Women aged 18 years or older with at least one UTI-specific Care Research Jordi Gol i Gurina, symptom (dysuria, urinary urgency, urinary frequency, or suprapubic tenderness) and a positive urine dipstick test Barcelona, Spain (C Llor PhD, for either nitrites or leukocyte esterase were randomly assigned (1:1:1:1) to one of four treatments: a single 3 g dose of R Monfà MSc, fosfomycin, two 3 g doses of fosfomycin, nitrofurantoin (100 mg three times per day for 5 days), or pivmecillinam A Garcia-Sangenís MSc, A Moragas PhD, D Ouchi PhD, (400 mg three times per day for 3 days). Doctors and patients were not masked to group assignment. The primary C Miranda-Jiménez MSc, outcome was the proportion of patients with clinical resolution (defined as the disappearance of all infection S Fernández-García MD, symptoms) at day 7. This trial is registered with ClinicalTrials.gov (NCT04959331) and EudraCT (2021-001332-26) and R Morros PhD); CIBER de is completed. Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain (C Llor PhD, Findings Of the 804 patients assessed for eligibility between April 4, 2022 and Nov 14, 2024, 768 patients were R Monfà MSc, randomly allocated (191 to the single-dose fosfomycin group, 194 to the two-dose fosfomycin group, 190 to the A Garcia-Sangenís MSc, nitrofurantoin group, and 193 to the pivmecillinam group). Patients had a median age of 48 years (IQR 34–63). Race A Moragas PhD, R Morros PhD); Unidad de Investigación Clínica and ethnicity data were not collected. Among the 720 women with available data included in the primary analysis, y Ensayos Clínicos, Institute for single-dose fosfomycin had the lowest proportion of clinical resolution (109 [59%] of 185 patients), while nitrofurantoin Primary Health Care Research had the highest (128 [74%] of 172 patients; dierence 15·5 percentage points [95% CI 5·9 to 25·1] vs single-dose Jordi Gol—Plataforma SCReN, fosfomycin; p=0·0168), followed by pivmecillinam (127 [70%] of 182; dierence 10·9 percentage points Barcelona, Spain (C Llor PhD, R Monfà MSc, [1·1 to 20·6]; p=0·2352) and the two-dose fosfomycin group (122 [67%] of 181; dierence 8·5 percentage points A Garcia-Sangenís MSc, [–1·4 to 18·3]; p=0·6935). Adverse events occurred in 38 (19·9% [95% CI 14·9 to 26·1) of 191 patients who received C Miranda-Jiménez MSc, single-dose fosfomycin, 51 (26·3% [20·6 to 32·9]) of 194 who received two-dose fosfomycin, 51 (26·8% [21·0 to 33·6]) R Morros PhD); Via Roma Health of 190 who received nitrofurantoin, and 41 (21·2% [16·1 to 27·5]) of 193 who received pivmecillinam. Most adverse Centre, Catalonian Health Institute, Barcelona, Spain events were mild and self-limiting, primarily gastrointestinal. Four serious adverse events occurred, of which one was (C Llor PhD); Research Unit for related to the study treatment (one case of pyelonephritis in the pivmecillinam group). General Practice, Department of Public Health, University of Interpretation Nitrofurantoin was the most eective treatment and single-dose fosfomycin the least eective treatment Southern Denmark, Odense, Denmark (C Llor PhD); Study for UTIs. Adverse events were mild. The role of fosfomycin as a first-line antibiotic for uncomplicated UTI should be Group for Urinary Tract re-evaluated. Infections, European Society of Clinical Microbiology and Funding Carlos III Institute of Health, Spanish Ministry of Science and Innovation, and European Regional Infectious Diseases, Basel, Switzerland (C Llor PhD); Development Fund. Universitat Autònoma de Barcelona, Bellaterra, Copyright © 2026 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar Cerdanyola del Vallès, Spain (R Monfà MSc, technologies. S Fernández-García MD, R Morros PhD); Research Introduction infections (UTIs) being one of the leading indications.1 Network on Chronicity Primary Antibiotics are among the most frequently prescribed The high volume of antibiotic use in this setting Care, and Health Promotion, Balearic Islands Health medications in primary care, with lower urinary tract contributes to the growing challenge of antimicrobial Articles Research Institute, Palma de Mallorca, Spain Research in context (A Leiva PhD); Villarejo de Salvanés Health Centre, Evidence before this study fosfomycin with a single-dose regimen in patients diagnosed Villarejo de Salvanés, Madrid, We searched PubMed using the terms (randomized OR trial with uncomplicated UTIs. A Spanish randomised clinical trial Spain (J Marín-Cañada MD); OR systematic review) AND (fosfomycin OR nitrofurantoin published in 2013 found that two doses of 3 g fosfomycin, Network for Research on OR pivmecillinam) AND (urinary tract infection OR UTI administered 3 days apart, were as effective as a 3-day course of Chronicity, Primary Care, and Health Promotion—Research OR cystitis), without language restrictions, for studies published low-dose ciprofloxacin. The search identified nine studies Unit, Primary Care up to Oct 10, 2025. Six systematic reviews were identified that comparing pivmecillinam at various doses and durations with Management, Madrid Health compared the efficacy of single-dose oral fosfomycin with other other antibiotics (two with amoxicillin, three with norfloxacin, Service, Madrid, Spain antibiotic regimens for the treatment of uncomplicated lower and one each with cephalexin, sulfadiazine–trimethoprim, and (J Marín-Cañada MD, R Rodríguez-Barrientos MD); urinary tract infections (UTIs) in women. The most recent an aminoglycoside), showing similar efficacy across therapies. Aragonese Health Service, meta-analysis included ten studies, two of which used No studies were found comparing pivmecillinam with Universidad de Zaragoza, two different comparators and two of which compared single fosfomycin or nitrofurantoin. Zaragoza, Spain doses of other antibiotics. The comparator antibiotics (M A Sánchez-Calavera MD); Added value of this study Jaume I Health Centre, comprised quinolones (five studies), β-lactams or In an open-label, pragmatic, randomised controlled trial Catalonian Health Institute, cephalosporins (three studies), nitrofurantoin (three studies), involving 768 women presenting to primary care with Tarragona, Spain and sulphonamides (one study). This meta-analysis showed (A Moragas PhD); University symptoms of uncomplicated lower UTI, clinical effectiveness at comparable proportions of clinical resolution between single- Rovira i Virgili, Reus, Spain day 7 was lower in those treated with a single 3 g dose of (A Moragas PhD); Microbiology dose fosfomycin and the comparators. One systematic review fosfomycin than in those who received other short-course Department, Hospital and meta-analysis, which included three randomised controlled antibiotic regimens (two 3 g doses of fosfomycin, Universitari de Bellvitge, trials, specifically compared fosfomycin and nitrofurantoin and L’Hospitalet de Llobregat, nitrofurantoin at 100 mg three times daily for 5 days, or found them to be equivalent in terms of clinical efficacy and Spain (M Aguilar-Sánchez PhD); pivmecillinam at 400 mg three times daily for 3 days). Primary Care Pharmacy Unit, safety. Clinical cure rates at both short-term (<4 weeks) and Catalonian Health Institute, longer-term (>4 weeks) follow-up were similar between groups, Implications of all the available evidence Barcelona, Spain and no significant differences were observed in microbiological Current guidelines recommend a single 3 g dose of fosfomycin (A Troncoso-Mariño PhD); San cure rates within 4 weeks of treatment. However, one open- tromethamine or short courses of pivmecillinam or Andrés Health Centre, Servicio Madrileño de Salud, Madrid, label randomised clinical trial showed that a 5-day course of nitrofurantoin as the first-line treatment for uncomplicated Spain (J M Molero MD); nitrofurantoin (100 mg three times per day) was associated UTIs. The results of the current study support findings from a Universitat de Girona, Girona, with a higher probability of clinical resolution (difference 12% previous randomised clinical trial indicating the lower efficacy Spain (S Fernández-García MD) [95% CI 4–21]) and microbiological resolution (difference 11% of single-dose fosfomycin compared with nitrofurantoin. In Correspondence to: [95% CI 1–20]) at 28 days post-treatment compared with a light of this new evidence, the use of short-course antibiotic Dr Carl Llor, Institute for Primary Health Care Research Jordi Gol i single 3 g dose of fosfomycin. The search did not identify any regimens should be encouraged over single-dose fosfomycin. Gurina, 08007 Barcelona, Spain studies comparing the efficacy of different dosing regimens of cllor@health.sdu.dk resistance, emphasising the need for evidence-based one found fosfomycin to be non-inferior to various prescribing practices that balance ecacy with comparators, while the other showed no significant stewardship.2 Up to 10% of women have an acute dierences between fosfomycin and nitrofurantoin.9,10 uncomplicated UTI annually, and over half of women are However, a previous randomised trial of 513 women aected in their lifetime.3 Rising global antibiotic found higher clinical resolution at day 28 with resistance, especially in Escherichia coli, is limiting oral nitrofurantoin (70%) than with a single 3 g dose of treatment options, even for uncomplicated cases.4 fosfomycin (58%).11 Current European and US guidelines on the treatment Pivmecillinam, a prodrug of mecillinam, has been of UTIs recommend the use of either a single 3 g dose of used for over 40 years in several European countries and fosfomycin or 100 mg of nitrofurantoin three times per in Canada for uncomplicated UTI,12,13 and was recently day for 5 days.5,6 These recommendations are based on approved by the US Food and Drug Administration for fosfomycin’s broad activity against β-lactamase- the treatment of uncomplicated UTIs in adult women. producing uropathogens and on the low resistance rates Nitrofurantoin, pivmecillinam, and fosfomycin are to both antibiotics reported in Europe and considered first-line antibiotics for uncomplicated lower North America.7 Over the past few years, the use of UTIs by most guidelines;14 however, there are no head- fosfomycin as the preferred therapy for these infections to-head trials comparing these three antibiotics.2 We has considerably increased in many European countries, aimed to evaluate the clinical eectiveness and safety of including Spain. However, more than half of Spanish a single dose of fosfomycin compared with a two-dose doctors prefer to prescribe two doses of fosfomycin regimen of fosfomycin and short-course regimens of trometamol rather than a single dose, claiming that the nitrofurantoin and pivmecillinam in women presenting single dose is less eective.8 Of two systematic reviews to primary care facilities with symptoms of uncom- comparing single-dose fosfomycin with other antibiotics, plicated UTI. 1604 Articles Methods probenecid (which reduces renal excretion of mecillinam), Study design or valproate; active malignancy or terminal illness; current This was a phase 4, pragmatic, multicentre, parallel- participation in another randomised clinical trial; previous group, open-label, randomised clinical trial conducted in enrolment in the present study; residency in long-term 34 primary care centres in Spain between April 4, 2022, care institutions; or anticipated diculties in attending and Dec 12, 2024. The trial design has been published,15 scheduled follow-up visits. and both the trial protocol and statistical analysis plan are included in the appendix (pp 16–72). The study was Randomisation and masking See Online for appendix conducted in four Spanish Autonomous Communities, This was an open-label trial; neither physicians nor across which seven dierent microbiology departments patients were masked to the assignment of the patient to participated. The study was reviewed and approved by the study group. Participants were randomly assigned to the Primary Care Research and Ethics Committee of the one of four treatment groups (1:1:1:1): a single-dose Institute for Primary Health Care Research Jordi Gol fosfomycin group, a two-dose fosfomycin group, a (IDIAPJGol; Barcelona, Spain; reference number nitrofurantoin group, and a pivmecillinam group. Block 21/173-AC), and by the Spanish Agency of Medicines and randomisation was used (block size eight), with Medical Devices. All patients provided written informed stratification by study centre. Randomisation was consent. Patients with a history of UTIs were actively independently executed at each participating site, and involved before the start of the study and contributed to investigators were masked to the randomisation process. its design. We adhere to the updated 2025 CONSORT Randomisation was done before receipt of baseline guidelines to ensure transparent reporting of our urine culture results. Patient allocation was implemented randomised controlled trial, revising all relevant sections through Research Electronic Data Capture (REDCap), a accordingly.16 The trial is registered with ClinicalTrials.gov secure, web-based application designed for data (NCT04959331) and EudraCT (2021-001332-26). collection and randomisation management.17 The system automatically assigned the next available treatment from Participants the preloaded randomisation list once participant Eligible patients were women aged 18 years or older eligibility was confirmed. Access to the randomisation attending primary care consultations with clinical module within REDCap was strictly limited to the site features of uncomplicated community-acquired lower investigator teams. The independent statistician who UTIs, including at least one of the four specific symptoms generated the randomisation list had no access to any (dysuria, urinary urgency, urinary frequency, or patient-level data throughout the study. suprapubic tenderness), and no alternative explanation (ie, symptoms suggestive of sexually transmitted Procedures infection or vulvovaginitis), and a urine dipstick analysis After randomisation, participants were informed of their positive for nitrites or leukocyte esterase. assigned treatment strategy and instructed on appropriate Exclusion criteria comprised the following: male sex; actions in case of symptom worsening or lack of high suspicion of pyelonephritis, defined as fever of at improvement. They were provided with the study least 38·5°C or flank pain or tenderness; any condition medication and given guidance on its predisposing the patient to complicated UTI, including proper administration: for the single-dose fosfomycin indwelling urinary catheter, immunosuppressive therapy, group, a single oral 3 g dose of fosfomycin trometamol; abnormal urinary tract anatomy, severe neurological for the two-dose fosfomycin group, two oral 3 g doses of disease aecting bladder function, or recurrent UTIs fosfomycin trometamol, with the second dose taken 24 h (defined as at least three UTIs in the past year or at after the first dose; for the nitrofurantoin group, oral least two in the past 6 months); pregnancy or breastfeeding; nitrofurantoin at a dosage of 100 mg three times per day UTI symptoms within the preceding 4 weeks; use of for 5 days; and for the pivmecillinam group, oral long-term antibiotic prophylaxis; ongoing antibiotic pivmecillinam at a dosage of 400 mg three times per day therapy or use of systemic antibiotics within the previous for 3 days. Participants allocated to the fosfomycin groups 7 days; symptoms indicative of alternative diagnoses, such were instructed to take the medication on an empty as vaginal discharge or pain; known hypersensitivity or stomach or at least 2 h after meals. Participants in the allergy to β-lactams, nitrofurantoin, or fosfomycin; nitrofurantoin and pivmecillinam groups were moderate to severe chronic renal insuciency; pre-existing recommended to take the doses with meals. Each patient polyneuropathy; history of pulmonary or hepatic reactions, was provided with a symptom diary to document the or peripheral neuropathy following nitrofurantoin use; progression of their symptoms from days 0 to 7, along glucose-6-phosphate dehydrogenase deficiency; porphyria, with instructions for its completion and a request to systemic primary carnitine deficiency, or organic acidurias return it on day 14. Follow-up visits were scheduled on such as methylmalonic aciduria or propionic acidaemia; days 7, 14, and 28, and could be performed within 2 days oesophageal stricture; concurrent use of allopurinol (due following each of these timepoints (eg, days 7–9 for the to increased risk of allergic skin reactions with mecillinam), day 7 visit). Articles Urine cultures were obtained at baseline and during Adverse events were specifically assessed at contact day 14 and day 28 visits. A midstream clean-catch urine points on days 7, 14, and 28, with patients also able to collection was recommended. In each of the primary care report any harms at any time during the 28-day follow-up centres, urine specimens were delivered to the period, with a focus on pyelonephritis as a special event of microbiology laboratory within 24 h of collection. All tubes interest. Adverse events were evaluated by a clinician contained boric acid. If processing (from collection to from the recruitment team, who was therefore aware of plating) was not possible within 2 h, the sample was stored the treatment group to which the patient had been at 4°C until the following morning, at which point it was assigned. Events were categorised by severity, seriousness, sent to the microbiology department. All urine samples and relatedness to the study drug. The investi gator was were processed according to routine laboratory procedures, responsible for reporting all events deemed serious, and and susceptibility to common antibiotics (fosfomycin and the causal relationship with the investigational product nitrofurantoin) was evaluated by analysing the breakpoints was determined based on clinical judgement. In the case based on minimum inhibitory concentrations (MICs) or of a serious adverse event, the pharmacovigilance depart- zone diameter breakpoints. All study antibiotics were ment was notified, and a serious adverse event notification assessed for susceptibility using zone diameter breakpoints form from the Spanish Agency of Medicines and Medical in accordance with the European Committee on Anti- Devices was completed. microbial Susceptibility Testing guidelines.18 Susceptibility Two additional secondary outcomes will be reported to pivmecillinam was assessed by the disk diusion separately: the predictive value of clinically confirmed method, whereas susceptibility to the other antibiotics was UTI, based on the dierent clinical criteria collected in the assessed by automated broth microdilution. In the study, for the diagnosis of microbiologically confirmed presence of substantial bacteriuria (ie, ≥10³ colony-forming UTI; and the cost-eectiveness of each trial strategy. units [CFU] per mL of a single pathogen, according to current European guidelines for women with symptoms Statistical analysis of lower UTI),5 the isolates were examined for resistance We hypothesised a clinically important minimum mechanisms and patterns and MICs to common dierence of 10 percentage points in the primary antibiotics, including fosfomycin, nitrofurantoin, and outcome of clinical resolution, based on the latest guide- pivmecillinam. line on the evaluation of medicinal products indicated for the treatment of bacterial infections, issued by the Outcomes European Medicines Agency (EMA).19 Assuming a The primary outcome was clinical eectiveness on day 7, clinical ecacy of 75% for single-dose fosfomycin, as measured by clinical resolution, which was defined as the recently found in a systematic review,10 with a two-sided disappearance of all infection symptoms, as reported by type I error rate of 5%, and a statistical power of 80% patients, on day 7, indicating the day the infection was (β=0·2), at least 253 patients per group with an available considered cured. Patient outcomes were classified as primary outcome were required for the study to be either clinical resolution, improvement, or failure. conclusive. Considering an estimated 10% dropout rate Improve ment was defined as symptom relief with some in each study group, we aimed to recruit 280 patients persistence, but without signs of infection and with no per group, for a total planned inclusion of 1120 patients. need for further antibiotics. Failure was defined as a The primary statistical comparison of the primary change or addition of antibiotics due to lack of ecacy or outcome was a two-sided χ² test comparing the ongoing infection. three short-course antibiotic regimens with the single Several secondary outcomes were considered: time (in dose of fosfomycin. 95% CIs were estimated using days) until patient-reported clinical resolution; normal approximation. Pairwise comparisons were bacteriological eradication measured at day 14, defined as adjusted using the Bonferroni method.20 Ecacy analyses eradication of the infecting strain with no recurrence of were primarily based on the intention-to-treat (ITT) bacteriuria (<10³ CFU/mL); bacteriological eradication at population, defined as all patients who were randomly day 28; clinical resolution at day 14; clinical resolution at assigned to a treatment group and received at least day 28; distribution of microorganisms causing UTI and one dose of the assigned treatment. Per-protocol analysis resistance rates of uropathogens to the study antibiotics; of the primary outcome was used as a secondary analysis; number of patients who used antibiotics other than the the per-protocol population was defined as all women in study medication during the trial; recurrences, defined as the ITT population who completed all ecacy assess- the reappearance of infection within the first 4 weeks after ments and had no protocol deviations, and who were clinical resolution of the initial episode; patient satisfaction adherent to the medication (taking at least 80% of the within each treatment strategy; visual analogue scale prescribed doses). Missing data were minimised through scores to assess the general health status (0–100 scale); trial monitoring and cross-checking. For the main and patient adherence to the study medication in each outcome, missingness was assumed to be not at random. strategy, considering patients to be adherent if they Clinical outcomes at days 14 and 28 were imputed using reported taking at least 80% of the prescribed doses. the last observation carried forward from day 7. Secondary 1606 Articles microbiological outcomes were analysed using a the single-dose fosfomycin group and as recovered in the complete-case approach. two-dose fosfomycin, nitrofurantoin, and pivmecillinam We did two sensitivity analyses of the primary outcome. groups), and counterintuitive scenario (missing values In the first, we adjusted the main analysis for the imputed as recovered in the single-dose fosfomycin group stratification variable of baseline urine culture results. In and as treatment failures in the two-dose fosfomycin, the second, missing data for the primary outcome were nitrofurantoin, and pivmecillinam groups). Additionally, imputed using a best-case scenario (all missing values ecacy outcomes were reanalysed for individuals who imputed as recovered), worst-case scenario (all missing tested positive for E coli in baseline urine cultures, as well values imputed as treatment failure), extreme superiority as separately for premenopausal and postmenopausal scenario (missing values imputed as treatment failure in women. 804 patients assessed for eligibility 36 excluded 22 informed consent not obtained 4 recurrent urinary tract infections 3 negative urine dipstick 3 antibiotic intake during the previous 7 days 2 hypersensitivity to study treatment 1 high suspicion of pyelonephritis 1 lactation 768 randomly assigned 191 assigned to single-dose 194 assigned to two-dose 190 assigned to nitrofurantoin 193 assigned to pivmecillinam fosfomycin group and received fosfomycin group and received group and received at least one group and received at least one at least one dose (included in at least one dose (included in dose (included in ITT and dose (included in ITT and ITT and safety analyses) ITT and safety analyses) safety analyses) safety analyses) 6 excluded from primary analysis 13 excluded from primary analysis 18 excluded from primary analysis 11 excluded from primary analysis (missing data) (missing data) (missing data) (missing data) 185 included in primary analysis 181 included in primary analysis 172 included in primary analysis 182 included in primary analysis 52 excluded from per-protocol 77 excluded from per-protocol 84 excluded from per-protocol 64 excluded from per-protocol analysis analysis analysis analysis 21 protocol deviation 28 protocol deviation 28 protocol deviation 19 protocol deviation 10 missed day 7 visit 1 low adherence (<80%) 3 low adherence (<80%) 19 missed day 7 visit 9 missed day 14 visit 18 missed day 7 visit 29 missed day 7 visit 12 missed day 14 visit 12 missed day 28 visit 21 missed day 14 visit 13 missed day 14 visit 14 missed day 28 visit 9 missed day 28 visit 11 missed day 28 visit 139 included in per-protocol analysis 117 included in per-protocol analysis 106 included in per-protocol analysis 129 included in per-protocol analysis 29 discontinued study 45 discontinued study 41 discontinued study 40 discontinued study 21 lost to follow up 36 lost to follow up 31 lost to follow up 29 lost to follow up 4 protocol deviation 5 protocol deviation 1 protocol deviation 4 protocol deviation 2 intercurrent disease 3 intercurrent disease 5 intercurrent disease 4 intercurrent disease 2 withdrew consent 1 withdrew consent 3 withdrew consent 2 withdrew consent 1 adverse reaction 1 adverse reaction 162 completed study 149 completed study 149 completed study 153 completed study Figure: Trial profile ITT=intention-to-treat. Articles Single-dose Two-dose Nitrofurantoin Pivmecillinam fosfomycin group fosfomycin group group group (n=191) (n=194) (n=190) (n=193) Median age, years 50 (35·5–64·5) 47·5 (34–62) 47 (33–62) 49 (34–64) Previous UTI At any time 164 (86%) 161 (83%) 152 (80%) 154 (80%) In the year preceding inclusion in the trial 83/164 (51%) 75/161 (47%) 71/152 (47%) 76/154 (49%) General health condition, median visual analogue scale* 70 (50–90) 70 (50–90) 70 (50–90) 70 (57·5–80) Median days since onset of symptoms 2 (1–3) 2 (1–4) 2 (1–4) 2 (1–3) UTI-specific symptoms Dysuria 163 (85%) 174 (90%) 154 (81%) 162 (84%) Urinary urgency 161 (84%) 167 (86%) 153 (81%) 166 (86%) Urinary frequency 165 (86%) 172 (89%) 166 (87%) 178 (92%) Suprapubic pain 141 (74%) 137 (71%) 127 (67%) 146 (76%) Median number of UTI-specific symptoms† 4 (3–4) 4 (3–4) 3 (3–4) 4 (3–4) Other symptoms Feverish sensation 27 (14%) 19 (10%) 21 (11%) 27 (14%) General discomfort 91 (48%) 95 (49%) 85 (45%) 89 (46%) Restriction of daily activities 57 (30%) 44 (23%) 44 (23%) 48 (25%) Haematuria 67 (35%) 77 (40%) 69 (36%) 79 (41%) Cloudy urine 89 (47%) 99 (51%) 91 (48%) 103 (53%) Foul-smelling urine 55 (29%) 60 (31%) 45 (24%) 41 (21%) Urinalysis Urine dipstick positive for leukocytes 189/191 (99%) 189/193 (98%) 184/190 (97%) 186/193 (96%) Urine dipstick positive for nitrites 57/191 (30%) 48/193 (25%) 49/190 (26%) 46/192 (24%) Baseline urine culture obtained 187 (98%) 185 (95%) 183 (96%) 183 (95%) Confirmed UTI‡ 109/187 (58%) 102/185 (55%) 91/183 (50%) 119/183 (65%) Contaminated 24/187 (13%) 20/185 (11%) 22/183 (12%) 19/183 (10%) Negative 54/187 (29%) 63/185 (34%) 70/183 (38%) 45/183 (25%) Number of uropathogens isolated‡ 107 104 95 120 Escherichia coli 74/107 (69%) 78/104 (75%) 67/95 (71%) 88/120 (73%) Staphylococcus saprophyticus 9/107 (8%) 5/104 (5%) 6/95 (6%) 10/120 (8%) Proteus mirabilis 9/107 (8%) 5/104 (5%) 6/95 (6%) 4/120 (3%) Klebsiella pneumoniae 7/107 (7%) 4/104 (4%) 4/95 (4%) 8/120 (7%) Others§ 8/107 (7%) 12/104 (12%) 12/95 (13%) 10/120 (8%) Proportion of strains resistant to the allocated antibiotic¶ 10/100 (10%) 10/96 (10%) 9/87 (10%) 12/76 (16%) Proportion of E coli strains resistant to the allocated antibiotic|| 1/74 (1%) 2/78 (3%) 0/65 5/60 (8%) Additional information regarding patient characteristics is provided in the appendix (p 2). UTI=urinary tract infection. *Visual analogue scale ranged from 0 (worst health status) to 100 (best health status). †UTI-specific symptoms included are dysuria, urinary urgency, urinary frequency, and suprapubic pain. ‡Positive culture was defined as the growth of at least 10 colony-forming units per mL of at least one uropathogen; some cultures had polymicrobial growth; there were two patients with missing details on the uropathogen identified in the single-dose fosfomycin group. §Citrobacter koseri, Enterococcus faecalis, Streptococcus agalactie, Klebsiella aerogenes, Morganella morganii, Lactobacillus crispatus, Staphylococcus saccharolyticus, Citrobacter freundii, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhimurium, Enterobacter cloacae, or Klebsiella variicola. ¶Antibiograms for study treatments were done in cultures positives for any uropathogen; a pivmecillinam antibiogram was an additional determination compared with usual practice (this extra determination was not done on 43 occasions); a nitrofurantoin antibiogram was not done on four occasions; a fosfomycin antibiogram was not done on nine occasions in the single-dose fosfomycin group and on six occasions in the two-dose fosfomycin group; all these cases were treated as missing values. ||Antibiograms for study treatments were done in cultures positive for E coli; a pivmecillinam antibiogram was not done on 28 occasions; a nitrofurantoin antibiogram was not done on two occasions; all these cases were treated as missing values. Table 1: Baseline characteristics in the intention-to-treat population (n=768) The safety population included all patients who received Two-sided Bonferroni-adjusted p values <0·05 were any trial drug. Safety data were summarised using considered statistically significant. Analyses were done descriptive statistics. Adverse events were compared with R software (version 4.3.1). across three short-course antibiotic regimens and single- dose fosfomycin using 95% CIs (Wilson method). Risk Role of the funding source dierences and relative risks (with 95% CIs) were The funders of the study had no role in study design, calculated for each short course versus single-dose data collection, data analysis, data interpretation, or fosfomycin. writing of the report. 1608 Articles Clinical resolution on Clinical resolution on Clinical resolution on Clinical resolution on Bacterial eradication Bacterial eradication day 7 day 7 in patients with day 14 day 28 on day 14 on day 28 a positive baseline urine culture Two-dose fosfomycin vs single-dose 8·5 (–1·4 to 18·3) 13·7 (0·3 to 27·2) 5·4 (–3·9 to 18·3) 5·3 (–4·1 to 14·8) 4·0 (–10·5 to 18·4) 4·6 (–10·7 to 19·8) fosfomycin Nitrofurantoin vs single-dose fosfomycin 15·5 (5·9 to 25·1)* 34·9 (22·9 to 46·8)* 12·7 (3·8 to 21·6)* 12·6 (3·5 to 21·7)* –3·0 (–18·4 to 12·4) 8·3 (–6·7 to 23·3) Pivmecillinam vs single-dose fosfomycin 10·9 (1·1 to 20·6) 22·0 (9·6 to 34·5)* 8·8 (–0·3 to 17·9) 8·8 (–0·5 to 18·0) –0·1 (–14·5 to 14·3) –0·2 (–15·5 to 15·1) Values are percentage points difference (95% CI). Numbers and percentages of participants with each outcome per group are provided in the appendix (p 5). *Significant difference at the 5% level after adjustment using the Bonferroni method. Table 2: Pairwise comparisons of efficacy outcomes Results All patients in ITT Population with a Between April 4, 2022, and Nov 14, 2024, 804 patients population positive baseline urine were assessed for eligibility, of whom 36 were excluded. culture The remaining 768 patients were randomly allocated to Best-case scenario* one of the four study groups (191 to the single-dose Two-dose fosfomycin vs single-dose fosfomycin 9·4 (–0·1 to 18·9) 14·4 (1·4 to 27·5) fosfomycin group, 194 to the two-dose fosfomycin group, Nitrofurantoin vs single-dose fosfomycin 16·6 (7·5 to 25·8)† 34·7 (23·2 to 46·2)† 190 to the nitrofurantoin group and 193 to the Pivmecillinam vs single-dose fosfomycin 11·3 (1·9 to 20·7) 21·6 (9·4 to 33·8)† pivmecillinam group) and received at least one dose of Worst-case scenario‡ study treatment and constituted the ITT population Two-dose fosfomycin vs single-dose fosfomycin 5·8 (–4·0 to 15·6) 11·3 (–2·0 to 24·6) (figure). The target sample size was not reached, as the Nitrofurantoin vs single-dose fosfomycin 10·3 (0·6 to 20·0) 28·7 (16·1 to 41·2)† study was terminated due to the exhaustion of available Pivmecillinam vs single-dose fosfomycin 8·7 (–1·0 to 18·4) 21·0 (8·6 to 33·4)† funding. Within the ITT population, 491 (64%) completed Extreme superiority§ the study according to the protocol and comprised the Two-dose fosfomycin vs single-dose fosfomycin 12·5 (3·0 to 22·1)† 17·2 (4·1 to 30·2) per-protocol population. Nitrofurantoin vs single-dose fosfomycin 19·8 (10·5 to 29·0)† 37·5 (25·9 to 49·0)† The median age in the ITT population was 48 years Pivmecillinam vs single-dose fosfomycin 14·4 (5·0 to 23·9)† 24·3 (12·1 to 36·5)† (IQR 34–63). Baseline characteristics were balanced Counterintuitive outcomes¶ among the groups (table 1; appendix p 2). The baseline Two-dose fosfomycin vs single-dose fosfomycin 2·7 (–7·0 to 12·4) 8·6 (–4·7 to 21·8) characteristics of patients who completed the study Nitrofurantoin vs single-dose fosfomycin 7·2 (–2·5 to 16·8) 25·9 (13·4 to 38·5)† versus those who discontinued are described in the Pivmecillinam vs single-dose fosfomycin 5·6 (–4·0 to 15·2) 18·2 (5·8 to 30·6)† appendix (p 3). 631 (82%) of the population had previously had a UTI at any time, with 305 (48%) having had a UTI Data are percentage points difference (95% CI) in proportion of patients with clinical resolution at day 7. ITT=intention- in the previous year. Urinary frequency was the most to-treat. *All missing values for the primary outcome are imputed as recovered. †Significant difference at the 5% level after adjustment using the Bonferroni method. ‡All missing values for the primary outcome are imputed as treatment predominant symptom (681 [89%] patients), followed by failures. §For the primary outcome, missing values in the single-dose fosfomycin group are imputed as treatment failures, dysuria (653 [85%]) and urinary urgency (647 [84%]). whereas in the two-dose fosfomycin, nitrofurantoin, and pivmecillinam groups, they are imputed as recovered. ¶For the Baseline urine culture results were available for most primary outcome, missing values in the single-dose fosfomycin group are imputed as recovered, whereas in the two-dose fosfomycin, nitrofurantoin, and pivmecillinam groups, they are imputed as treatment failures. patients (738 [96%]), among whom 421 (57%) tested positive for at least one uropathogen. The proportion was Table 3: Pairwise main outcome comparisons with missing data imputation higher among women presenting with three or four UTI- specific symptoms (appendix p 4). The most frequently isolated microorganism was E coli (307 [72%] of 426 isolates; dierence greater than 10 percentage points in the table 1). 41 patients presented with a uropathogen nitrofurantoin group versus the single-dose fosfomycin resistant to the allocated study treatment, most often due group (15·5 percentage points [95% CI 5·9–25·1]; to microorganisms other than E coli. The distribution of p=0·0168) and in the pivmecillinam group versus the these patients was similar across study groups, with a single-dose fosfomycin group (10·9 percentage points slightly higher incidence in the pivmecillinam group. [1·1–20·6]; p=0·2352; table 2). The dierence in the Among 720 patients with available primary outcome proportion of patients with clinical resolution between the data, nitrofurantoin was the most eective treatment at two-dose fosfomycin group and the single-dose fosfomycin day 7, with clinical resolution occurring in 128 (74%) group was 8·5 percentage points (–1·4 to 18·3; p=0·6935). of 172 patients, followed by pivmecillinam (127 [70%] Similar results were obtained in the per-protocol analysis of 182) and the two-dose fosfomycin group (122 [67%] of 181; (appendix p 6). In a sensitivity analysis of patients with a appendix p 5). The single-dose fosfomycin regimen was microbiologically confirmed UTI at baseline, compared the least eective (109 [59%] of 185). Pairwise comparisons with the single-dose fosfomycin group, clinical resolution of the proportion of patients with clinical resolution at at day 7 was statistically significantly higher in the day 7 between study groups showed a clinically meaningful nitrofurantoin group (34·9 percentage points Articles [22·9–46·8]; p<0·0001) and pivmecillinam group bacteriological eradication were similar between groups (22·0 percentage points [9·6–34·5]; p=0·0068), and a at days 14 and 28 (table 2; appendix p 5). A subanalysis of clinically relevant dierence of 13·7 percentage points patients with E coli-positive cultures at baseline showed (0·3–27·2; p=0·3986) was found in the two-dose nitrofurantoin had the highest clinical ecacy, with fosfomycin group (table 2; appendix p 7). No dierences significantly higher proportions of patients with clinical between groups were detected for patients who did not resolution than other treatments. Microbiological test positive for baseline urine cultures (appendix p 7). responses at day 14 were similar; however, nitrofurantoin Additional sensitivity analyses of the primary outcome showed relatively better outcomes at day 28 (appendix based on imputation of missing data (worst-case, best- p 10). case, extreme superiority, and counterintuitive scenarios) The resistance rates of uropathogens to the allocated showed consistent results across all scenarios, with study group antibiotics were similar, ranging from ranking from highest to lowest clinical resolution around 10% for the single-dose fosfomycin, two-dose maintaining the order nitrofurantoin, pivmecillinam, fosfomycin, and nitrofurantoin regimens, to 16% for two-dose fosfomycin, and single-dose fosfomycin (table 3). pivmecillinam (table 1). For E coli in particular, the Patients in the single-dose fosfomycin group showed the dierences in the percentage of resistance among groups lowest rate of clinical resolution and required more time ranged from 0% for nitrofurantoin to 8% for pivmecillinam to reach clinical resolution (appendix pp 8–9). (table 1). No dierences were observed in the ecacy Nitrofurantoin also had the highest clinical resolution outcomes between postmenopausal and premenopausal at days 14 and 28, occurring in 139 (81%) and 136 (79%) of women (appendix p 11). An additional antibiotic course 172 patients, respectively, whereas the single-dose was required in 57 (30%) of 191 patients in the single-dose fosfomycin regimen was the least eective, with rates fosfomycin group, 37 (19%) of 194 in the two-dose of 126 (68%) and 123 (66%) of 185 patients, respectively fosfomycin group, 30 (16%) of 190 in the nitrofurantoin (appendix p 5). Both microbiological response and group, and 31 (16%) of 193 in the pivmecillinam group. Single-dose fosfomycin group Two-dose fosfomycin group Nitrofurantoin group Pivmecillinam group (n=191) (n=194) (n=190) (n=193) Patients with one or more adverse events 38/191 (19·9% [14·9–26·1]) 51/194 (26·3% [20·6–32·9]) 51/190 (26·8% [21·0–33·6]) 41/193 (21·2% [16·1–27·5]) Discontinuation due to adverse event 0/191 (0·0% [0·0–2·0]) 1/194 (0·5% [0·1–2·9]) 5/190 (2·6% [1·1–6·0]) 3/193 (1·6% [0·5–4·5]) Patients with at least one serious adverse event* 0/191 (0·0% [0·0–2·0]) 1/194 (0·5% [0·1–2·9]) 1/190 (0·5% [0·1–2·9]) 2/193 (1·0% [0·3–3·7]) Related to trial drug† 0/191 (0·0% [0·0–2·0]) 0/194 (0·0% [0·0–1·9]) 0/190 (0·0% [0·0–2·0]) 1/193 (0·5% [0·1–2·9]) Total number of adverse events reported 41 73 77 57 Expected adverse events‡ 33/41 (80·5% [66·0–89·8]) 55/73 (75·3% [64·4–83·8]) 54/77 (70·1% [59·2–79·2]) 38/57 (66·7% [53·7–77·5]) Adverse event of special interest: pyelonephritis 0/191 (0·0% [0·0–2·0]) 0/194 (0·0% [0·0–1·9]) 2/190 (1·1% [0·3–3·8]) 1/193 (0·5% [0·1–2·9]) Adverse event severity§ Mild 30/40 (75·0% [59·8–85·8]) 60/72 (83·3% [73·1–90·2]) 55/77 (71·4% [60·5–80·3]) 40/54 (74·1% [61·1–83·9]) Moderate 9/40 (22·5% [12·3–37·5]) 11/72 (15·3% [8·8–25·3]) 21/77 (27·3% [18·6–38·1]) 10/54 (18·5% [10·4–30·8]) Severe 1/40 (2·5% [0·4–12·9]) 1/72 (1·4% [0·2–7·5]) 1/77 (1·3% [0·2–7·0]) 4/54 (7·4% [2·9–17·6]) Most common adverse events¶ Diarrhoea 17/191 (8·9% [5·6–13·8]) 27/194 (13·9% [9·7–19·5]) 7/190 (3·7% [1·8–7·4]) 7/193 (3·6% [1·8–7·3]) Abdominal pain 3/191 (1·6% [0·5–4·5]) 6/194 (3·1% [1·4–6·6]) 7/190 (3·7% [1·8–7·4]) 5/193 (2·6% [1·1–5·9]) Vulvovaginal candidiasis 6/191 (3·1% [1·4–6·7]) 3/194 (1·5% [0·5–4·4]) 3/190 (1·6% [0·5–4·5]) 5/193 (2·6% [1·1–5·9]) Nausea 2/191 (1·0% [0·3–3·7]) 1/194 (0·5% [0·1–2·9]) 6/190 (3·2% [1·5–6·7]) 6/193 (3·1% [1·4–6·6]) Headache 0/191 (0·0% [0·0–2·0]) 2/194 (1·0% [0·3–3·7]) 5/190 (2·6% [1·1–6·0]) 7/193 (3·6% [1·8–7·3]) Fatigue 0/191 (0·0% [0·0–2·0]) 2/194 (1·0% [0·3–3·7]) 9/190 (4·7% [2·5–8·8]) 2/193 (1·0% [0·3–3·7]) Vaginitis 2/191 (1·0% [0·3–3·7]) 3/194 (1·5% [0·5–4·4]) 2/190 (1·1% [0·3–3·8]) 1/193 (0·5% [0·1–2·9]) Pruritus 0/191 (0·0% [0·0–2·0]) 3/194 (1·5% [0·5–4·4]) 2/190 (1·1% [0·3–3·8]) 2/193 (1·0% [0·3–3·7]) Dizziness 1/191 (0·5% [0·1–2·9]) 0/194 (0·0% [0·0–1·9]) 4/190 (2·1% [0·8–5·3]) 1/193 (0·5% [0·1–2·9]) Somnolence 0/191 (0·0% [0·0–2·0]) 0/194 (0·0% [0·0–1·9]) 5/190 (2·6% [1·1–6·0]) 0/193 (0·0% [0·0–2·0]) Data are n/N (% [95% CI]); values represent the number of affected patients, except where otherwise noted. The safety population included all the patients who had received any dose of a trial drug. Events were coded according to the terms used in the Medical Dictionary for Regulatory Activities (version 27.1). *Serious adverse events recorded were acute myocardial infarction (pivmecillinam group), mesenteric panniculitis (two-dose fosfomycin group), and pyelonephritis (nitrofurantoin and pivmecillinam groups), all of which resolved with recovery. †The relationship of the severe adverse event to a trial drug was assessed by the pharmacovigilance department; one case of pyelonephritis in the pivmecillinam group was judged to be related to the study drug. ‡Expected adverse events were those described in the technical data sheet for each study treatment; values represent the number of expected adverse events out of all adverse events reported. §Values represent the number of adverse events of each severity level out of all adverse events reported for which severity data were available; severity data were missing for five adverse events. ¶Adverse events reported during treatment are listed in the order of descending overall frequency; events that occurred in fewer than five cases are not included in the table; the maximum number of adverse events reported per patient was four (occurring in four patients). Table 4: Summary of adverse events (safety population) 1610 Articles When this exposure was adjusted based on the baseline Discussion urine culture result, the dierences increased in patients In women with uncomplicated UTIs, single-dose with a positive result, with pivmecillinam being the fosfomycin was less eective by day 7 than other short- treatment that required the fewest additional courses course regimens, with clinical resolution occurring in a (appendix p 12). The proportions of patients with significantly lower proportion of patients with recurrence were similar across study groups, although microbiologically confirmed UTIs at baseline— slightly higher in the fosfomycin groups. 88% of all 34·9 percentage points lower versus the nitrofurantoin reconsultation visits (ranging from 83% in the group and 22·0 percentage points lower versus the nitrofurantoin group to 96% in the two-dose fosfomycin pivmecillinam group. Our results support findings from a group) were in primary care settings (appendix p 13). Of previous trial that showed nitrofurantoin to be the 681 patients with available adherence information, substantially more eective than single-dose fosfomycin.11 good adherence was observed in all 179 (100%) patients Our study is novel in that it compares four antibiotic taking single-dose fosfomycin, 168 (98%) of 171 taking regimens head to head, and it is the first to compare two-dose fosfomycin, 150 (94%) of 160 taking two dierent formulations of fosfomycin. Furthermore, nitrofurantoin, and 171 (99%) of 173 taking pivmecillinam. no studies have previously compared pivmecillinam with Satisfaction was similar across groups (appendix p 13). either of the other two antibiotics. Adverse events occurred in 38 participants We conducted a pragmatic clinical trial, with clinical (19·9% [95% CI 14·9–26·1]) in the single-dose fosfomycin resolution on day 7 selected as the primary outcome, group, 51 (26·3% [20·6–32·9]) in the two-dose fosfomycin reflecting standard practice in primary care. In women group, 51 (26·8% [21·0–33·6]) in the nitrofurantoin group, with uncomplicated UTIs, clinical resolution typically and 41 (21·2% [16·1–27·5]) in the pivmecillinam group occurs within 1 week.21 A Swedish study reported median (table 4). Compared with single-dose fosfomycin, the risk recovery times of 4 days (IQR 2–5) for women treated with dierence for the occurrence of any adverse event was antibiotics and 6·5 days (3–10) for those not treated.22 6·4 percentage points (95% CI –5·5 to 18·0) for two-dose Clinical outcomes are most relevant to patients and guide fosfomycin, 6·9 (–5·1 to 18·7) for nitrofurantoin, and follow-up decisions, such as additional visits or treatments. 1·3 (–10·1 to 12·7) for pivmecillinam. The corresponding In primary care, uncomplicated UTIs are typically relative risks were 1·3 (95% CI 0·9–1·9), 1·4 (0·9–2·0), managed without microbiological analysis. Including and 1·1 (0·7–1·6), respectively (appendix p 14). Most microbiological response in a composite primary outcome, adverse events were mild (75%, 83%, 71%, and 74% of the as recommended by the EMA19 and considered in recent adverse events in each group, respectively), and were trials evaluating new drugs for uncomplicated UTI,23 consistent with the drugs’ known safety profiles (table 4). would have excluded patients without a positive baseline Moderate and severe events occurred in less than 21% and culture (317 [43%] of 738 in our study, including those with less than 3% of patients, respectively. Treatment negative or contaminated cultures). In a study by Huttner discontinuations due to adverse events were infrequent, and colleagues,11 which compared nitrofurantoin with a ranging from 0·0% (0·0–2·0) in the single-dose single dose of fosfomycin using the same inclusion criteria fosfomycin group to 2·6% (1·1–6·0) in the nitrofurantoin as in our study (one or more of the localising urinary tract group. symptoms, as proposed by Nicolle),3 72% of urine cultures A total of four serious adverse events occurred during were positive, although the study population was younger the trial, only one of which was considered related to the (median age 44 years [31–64]).11 Age is associated with UTI study drug. Two serious adverse events occurred in the misdiagnosis, suggesting that some of our participants pivmecillinam group (one acute myocardial infarction might have had non-infectious urethral symptoms at and one pyelonephritis [related to study drug]), one in the enrolment. Other primary care studies report even lower nitrofurantoin group (pyelonephritis), and one in the rates of microbiologically confirmed UTIs. For instance, a two-dose fosfomycin group (mesenteric panniculitis). All multicentre trial conducted across four European serious adverse events resolved completely, with full countries, which also used the same inclusion criteria, patient recovery. found that only 36% of nearly 800 women with suspected The most common adverse events were diarrhoea, UTIs had culture-confirmed infections.24 occurring particularly among patients allocated to Accurately diagnosing UTIs in primary care remains fosfomycin, followed by abdominal pain and vulvovaginal challenging. Current methods—based on symptoms, candidiasis. Pyelonephritis, a prespecified event of signs, and dipstick tests—lack precision, leading to both special interest, occurred in two patients treated with overtreatment and undertreatment. Improved point-of- nitrofurantoin (1·1% [95% CI 0·3–3·8]) and one treated care diagnostics are urgently needed, as existing tools with pivmecillinam (0·5% [0·1–2·9]), but not among such as urine dipsticks have low sensitivity and specificity.25 those receiving fosfomycin. Overall, no unexpected safety Additionally, these tools cannot provide information on signals were identified, and the incidence and nature of the antibiotic susceptibility of pathogens. Bacterial culture adverse events were similar across treatments and tests on solid media take 18–24 h, delaying clinical consistent with known drug safety profiles. decisions, and a previous trial showed minimal eects on Articles improving antibiotic use.26 The gold standard— backgrounds of participants; however, there was no microscopy, culture, and susceptibility testing—takes exclusion of patients on the basis of racial or ethnic group, 2–3 days and can be limited by contamination by host and some patients from minoritised groups contributed flora. Although our trial’s contamination rate was to the study design. Laboratory analyses were not under 13%, other studies report rates up to 30%.27 Delays centralised, which could have introduced variability in and sample issues can lead to inconclusive results, microbiological methods across dierent sites. However, highlighting the urgent need for faster, more accurate this study was designed to be pragmatic, reflecting the point-of-care tests to guide antibiotic prescribing in real-world conditions of both health centres and primary care. microbiological departments. This also explains the high The resistance of E coli to fosfomycin is primarily number of losses in the per-protocol population, as attributed to plasmid-mediated genes encoding patients with persistent symptoms are more likely to fosfomycin-modifying enzymes, which raises concerns contact a health-care provider than those who are clinically about the potential for broader resistance development. cured. The lack of microbiological data, particularly for Although there has been a notable increase in fosfomycin patients with treatment failure who received an additional consumption over the past decade in Spain, resistance antibiotic course and were excluded from analysis, might rates remain below 10%, as also observed in this study. have led to underestimation of dierences between Data from more than 70 000 community urine cultures in treatment groups. Consequently, microbiological cure Catalonia in 2024 showed that 3·8% of E coli isolates were rates appeared similar across all the treatment groups in resistant to fosfomycin, with resistance to nitrofurantoin our trial. remaining under 1%.28 The discrepancy between the When selecting an antibiotic regimen, ecacy is reduced in vivo fosfomycin ecacy and what would be paramount, but other factors, such as adherence and expected based on in-vitro resistance rates suggests tolerability, should also be considered. Shorter regimens, microbiological and pharmacological factors.29 A single such as one or two doses of fosfomycin, might improve 3 g dose might not sustain urine concentrations above the adherence due to their simplicity, as shown in our study. MIC for a sucient duration, particularly given However, overall adherence across all four antibiotic interindividual variability in pharmacokinetics. The regimens was high, and patient satisfaction did not dier improved outcomes observed with two-dose regimens substantially between treatments. Adverse event rates suggest that single dosing might be insucient to were similar, although side-eect profiles varied: maintain eective exposure, consistent with fosfomycin’s gastrointestinal symptoms were more common with predominantly time-dependent antibacterial activity.30 fosfomycin; fatigue and somnolence with nitrofurantoin; The reduced activity of fosfomycin in low urine pH and and headache and nausea with pivmecillinam. E coli persistence in the bladder could explain its lower In conclusion, this pragmatic randomised clinical trial ecacy, as a single dose might not sustain a MIC in the comparing first-line antibiotics for uncomplicated UTIs urine for long enough to clear the infection.31 Future in women found that a single dose of fosfomycin had the studies will be required to investigate these hypotheses. lowest clinical eectiveness among the regimens tested, The planned sample size was not reached in our study, whereas nitrofurantoin had the highest eectiveness, representing a key limitation. For the primary outcome, followed by pivmecillinam, particularly in patients with the final sample size yielded an estimated power positive baseline urine cultures. These findings suggest of 66·7%, below the originally intended 80%. Although that the role of fosfomycin as a first-line treatment for statistically significant results were observed for the uncomplicated UTIs should be re-evaluated. primary and some secondary outcomes, the reduced Contributors sample size might have limited the detection of clinically CL, RMon, AG-S, and RMor conceptualised and designed the study. relevant dierences (ie, those ≥10 percentage points) due The conduct of the trial and recruitment were performed by JM-C, RR-B, to the loss of statistical power. Additionally, the trial was JMM, MAS-C, AL and AM. The microbiological analysis was coordinated by MA-S. The study drug management was performed by AT-M, and the open label, which might have introduced the potential for pharmacovigilance was conducted by SF-G, CMJ, and RMor. CL, RMon, ascertainment bias. Given that the trial involved AG-S and RMor led the application for funding. The data analysis was four groups with dierent treatment principles, daily performed by RMon and DO, with RMor directly accessing and verifying the underlying data reported in the manuscript. CL and RMon prepared doses, and durations, the fabrication of a placebo would the initial draft manuscript. All authors had full access to the data in the not have been feasible. In addition, there was consistency study and reviewed, edited, and approved the submission of the between the main outcome and the clinical ecacy muscript for publication. among positive urine cultures, which helps mitigate Declaration of interests concerns over bias. Women were followed up for only JM-C has received payments from the Health Department of the Madrid 1 month, which might have limited the detection of late- Community and a research grant from the Carlos III Institute of Health, Ministry of Science and Innovation (Spain), under grant number occurring events. However, this follow-up duration is ICI20/00148. SF-G has received grants from the Strategic Research and consistent with that used in other studies of uncomplicated Innovation Plan for Health (Pla Estratègic de Recerca i Innovació en UTI that excluded patients with recurrent infections. We Salut) 2022–2024, funded by the Department of Health of the did not collect data on the specific racial or ethnic Government of Catalonia. RMor has participated in a Data Safety 1612 Articles Monitoring Board or Advisory Board for Archivel Farma and CONNECTA 15 Garcia-Sangenís A, Morros R, Aguilar-Sánchez M, et al, and the Therapeutics. All other authors declare no competing interests. SCOUT Study Group. Clinical eectiveness and bacteriological eradication of three dierent short-course antibiotic regimens and Data sharing single-dose fosfomycin for uncomplicated lower urinary tract Individual, de-identified participant data used in these analyses can be infections in adult women (SCOUT study): study protocol for a made available, upon request to the corresponding author, to any randomised clinical trial. BMJ Open 2021; 11: e055898. qualified investigator following approval of a protocol and signed forms. 16 Hopewell S, Chan AW, Collins GS, et al. CONSORT 2025 The trial protocol, statistical analysis plan, and participant documents statement: updated guideline for reporting randomised trials. BMJ are available online at https://www.idiapjgol.org. 2025; 389: e081123. 17 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Acknowledgments Research electronic data capture (REDCap)—a metadata-driven We thank the general practitioners, nurses, patients, and the pharmacy methodology and workflow process for providing translational and microbiology services sta who participated in the trial and research informatics support. J Biomed Inform 2009; 42: 377–81. contributed to advancing knowledge of antibiotic treatment for urinary 18 European Committee on Antimicrobial Susceptibility Testing tract infections. The study was funded by grants from the Carlos III (EUCAST). Breakpoint tables for interpretation of MICs and zone Institute of Health, Ministry of Science and Innovation (Spain), awarded diameters, version 11.0, 2021. https://www.eucast.org/fileadmin/ in the 2020 call under the Academic Clinical Trials Call, with eucast/pdf/Document_Archive/bacteria/breakpoint_tables/v_11.0_ reference ICI20/00100, and by EU European Regional Development Breakpoint_Tables.pdf (accessed April 3, 2026). Fund. 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