Open access Protocol 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 Ana Garcia-­Sangenís ‍ ‍,1,2,3 Rosa Morros ‍ ‍,3,4 Mercedes Aguilar-­Sánchez,5 Laura Medina-­Perucha ‍ ‍,1 Alfonso Leiva ‍ ‍,6 Joana Ripoll ‍ ‍,6 Mar Martínez-­Pecharromán,7 Cruz B Bartolomé-Moreno,8,9 Rosa Magallon Botaya ‍ ‍,8,10 Jaime Marín-­Cañada,11 José M Molero ‍ ‍,12 Ana Moragas ‍ ‍,13,14 Amelia Troncoso,15 Ramon Monfà ‍ ‍,1,2,3 Carl Llor ‍ ‍,16,17 SCOUT Study Group To cite: Garcia-­Sangenís A, Morros R, Aguilar-­Sánchez M, et al. Clinical effectiveness and ABSTRACT bacteriological eradication of Strengths and limitations of this study Introduction Uncomplicated lower urinary tract infections three different Short-­COurse (uLUTI) are a common problem in primary care. Current antibiotic regimens and ►► This will be the first randomised controlled trial to local guidelines recommend the use of a single 3 g dose single-­dose fosfomycin for investigate the clinical effectiveness and bacterial of fosfomycin. However, most general practitioners (GP) uncomplicated lower Urinary eradication of four antibiotic regimens administered Tract infections in adult prefer short-­course therapies to single-­dose therapy. to women with symptoms of uncomplicated lower women (SCOUT study): study No study has compared head-­to-­head short-­course urinary tract infection. protocol for a randomised antimicrobial agents for uLUTIs. Therefore, the aim of ►► Although masking techniques are not used, observer clinical trial. BMJ Open this randomised clinical trial is to compare three different bias will be reduced to a minimum as the prima- 2021;11:e055898. doi:10.1136/ short-­course antibiotic therapies with a single-­dose of ry objective and some of the secondary objectives bmjopen-2021-055898 fosfomycin for these infections. will be based on symptoms recorded by the patients ►► Prepublication history for Methods and analysis This will be a pragmatic, themselves and on urine cultures. this paper is available online. multicentre, parallel group, open trial. Women aged 18 or ►► Symptom diaries only contain four domains and To view these files, please visit older and with symptoms of uLUTI and a positive urine are used for only 7 days, and therefore completion the journal online (http://​dx.​doi.​ dipstick analysis will be randomised to one of the following is simple. Nonetheless, if symptom diaries are not org/​10.​1136/​bmjopen-​2021-​ four groups: a single dose of 3 g of fosfomycin, 2 days of returned, a phone call will be made at day 7. 055898). 3 g of fosfomycin o.d., 3 days of pivmecillinam 400 mg ►► In the unlikely event that the COVID-­19 pandemic is three times per day (t.i.d) or 5 days of nitrofurantoin Received 28 July 2021 still present throughout the period that the clinical 100 mg t.i.d. A total sample of 1120 patients was Accepted 01 November 2021 trial is conducted, and this hampers the inclusion of calculated. The primary endpoint is clinical effectiveness patients, the number of clinicians participating will at day 7, defined as cure of symptoms reported by the be increased. patients in a diary including four symptoms: dysuria, © Author(s) (or their urgency, frequency and suprapubic pain, which will be employer(s)) 2021. Re-­use scored on a 4-­point severity scale (not present/mild/ permitted under CC BY-­NC. No moderate/severe). Follow-­up visits are scheduled at days number: 21/173-­AC) and Spanish Agency of Medicines commercial re-­use. See rights 7 (phone call), 14 and 28 for assessing evolution. Urine and Medical Devices. The findings of this trial will be and permissions. Published by BMJ. samples will be collected in the three on-­site visits and disseminated through research conferences and peer-­ urine cultures performed. If positive, antibiograms for review journals. For numbered affiliations see end of article. the three antibiotics studied will be performed. Bacterial Trial registration number NCT04959331; EudraCT eradication will be measured at days 14 and 28. Number: 2021-­001332-­26. Correspondence to Ethics and dissemination The study was approved Time schedule January 2022 to April 2023. Carl Llor; ​carles.​llor@​gmail.​com by the Ethical Board of IDIAP Jordi Gol (reference Garcia-­Sangenís A, et al. BMJ Open 2021;11:e055898. doi:10.1136/bmjopen-2021-055898 1 Open access INTRODUCTION single 3 g dose does not appear to be optimal.19 Fosfo- Lower urinary tract infections (LUTI) are a common mycin resistance is rare in areas with limited use but is problem in primary care consultations. More than 50% on the rise in countries with higher usage, although the of all women experience at least one episode during their susceptibility rates are variable and do not exceed 10% lifetime.1 In more than 80% of cases, LUTI is caused by of the isolates.20–22 However, the use of a single dose is Escherichia coli.1 2 In many clinical settings, urine cultures associated with a higher percentage of relapses, mainly are not routinely performed, and women with symptoms in patients with recurrent LUTIs.23 A single dose of fosfo- of acute cystitis are treated empirically. Thus, empirical mycin–tromethamine and short-­courses of nitrofurantoin treatment in LUTIs should cover E. coli. Resistance of and pivmecillinam are now recommended by the latest uropathogens to the classical antibiotics has significantly guideline of the European Association of Urology for increased in the last years in Spain, mainly because of empirical therapy of uncomplicated LUTI,24 but no study the high use of antibiotics.3 The resistance of enterobac- has compared more than two short-­course antimicrobial teria to third generation cephalosporins, mediated by the agents for uncomplicated LUTIs.25 production of extended spectrum β lactamases (ESBL), is a growing problem in E. coli and Klebsiella pneumoniae strains. Indeed, in 2019, more than half of the E. coli OBJECTIVES isolates reported to the European Antimicrobial Resis- The main aim of the trial is to compare the clinical effec- tance Surveillance Network and more than a third of the tiveness of three short-­course antibiotic regimens (3 g of K. pneumoniae isolates were resistant to at least one anti- fosfomycin one time per day for 2 days; 3 days of pivme- microbial group under surveillance.4 According to recent cillinam 400 mg. t.i.d.; 5 days of nitrofurantoin 100 mg data, the percentage of E. coli resistance to quinolones, t.i.d.) with a single 3 g dose of fosfomycin in uncompli- cotrimoxazole and amoxicillin and clavulanate, although cated LUTIs in adult women at day 7. The clinical effec- variable, ranges from 20% to 40% in Spain and approxi- tiveness of the short-­course antibiotics will be evaluated as mately 10% of the isolates of E. coli are ESBL-­producers.5–7 a secondary objective of the trial: 3 g of fosfomycin 2 days LUTIs caused by resistant microorganisms are associated versus 3 days of pivmecillinam 400 mg. t.i.d, 3 g of fosfo- with longer symptom duration and treatment failure is mycin 2 days versus 5 days of nitrofurantoin 100 mg t.i.d. more likely compared with infections caused by suscep- and 3 days of pivmecillinam 400 mg. t.i.d. versus 5 days of tible strains.8–10 According to the recommendations of the nitrofurantoin 100 mg t.i.d. Infectious Diseases Society of America, empiric antibiotic The other secondary objectives are aimed at evaluating therapy should be substituted when the rates of resistance the following parameters in the four medication arms: surpass 20%.11 This means that the use of amoxicillin and (1) duration of symptoms; (2) bacteriological eradication clavulanate as well as quinolones are no longer recom- measured at day 14; (3) bacteriological eradication at day mended for the empirical treatment of LUTIs in our 28; (4) proportion of patients presenting a relapse of symp- country. toms within the first 4 weeks after inclusion in the study Current guidelines recommend prescribing a single and timing of relapse of symptoms and/or bacteriuria; 3 g dose of fosfomycin or nitrofurantoin 100 mg three (5) proportion of patients developing complications (ie, times per day (t.i.d.) for 5 days.12 13 The rationale for this pyelonephritis and/or urosepsis) within the first 4 weeks; strategy is based on the narrow spectrum of aetiologic (6) proportion of patients presenting adverse and serious agents causing acute cystitis and knowledge of their local adverse events; (7) predictive value of the different clin- antimicrobial resistance patterns.14 Over the last years, ical criteria collected with microbiologically-­ confirmed the use of fosfomycin as the preferred therapy for these LUTI; (8) bacteriological findings, (ie ESBL-­producing infections has significantly increased in Spain. However, bacteria, resistance rates to the study medications); (9) more than half of the Spanish doctors prefer the use of cost-­effectiveness of each of the treatment arms and (10) short-­course therapies over single-­dose therapy.15 Pivme- change in quality of life in the first week. cillinam, an antibiotic widely used in Scandinavian coun- tries for the treatment of LUTIs, has been authorised by the Spanish Agency of Drugs and Medicine Products METHODS AND ANALYSIS (2017), although it is still not marketed. Its effectiveness Trial design has been demonstrated in different randomised clinical This study is a phase IV, multicentre, pragmatic, parallel trials (RCT) and is also recommended for the treatment group, open randomised trial. of uncomplicated LUTI.16 17 The dose that will be used in our RCT has been shown to be the more effective in Study arms a recent systematic review.18 A recent RCT including a Once the patients are included in the trial, they will be total of 513 women with uncomplicated LUTIs found randomised into one of the four treatment groups: (1) that clinical resolution at day 28 occurred in 70% of single 3 g dose of fosfomycin–tromethamine; (2) 3 g of patients taking 100 mg of nitrofurantoin three times per fosfomycin–tromethamine one time per day for 2 days; day for 5 days and in 58% of patients assigned to a single (3) 3 days of pivmecillinam 400 mg t.i.d. and (4) 5 days 3 g dose of fosfomycin. The authors hypothesised that a of nitrofurantoin 100 mg t.i.d. All the drugs and products 2 Garcia-­Sangenís A, et al. BMJ Open 2021;11:e055898. doi:10.1136/bmjopen-2021-055898 Open access used in this study are already marketed, and therefore, with differential diagnosis (ie, vaginal discharge or pain); the manufacturers are responsible for the elaboration (9) hypersensitivity or allergy to β lactams, nitrofurantoin and control of samples. The study drugs will be provided and/or fosfomycin; (10) moderate to severe chronic renal free to the participants by the sponsor. The provision, insufficiency; (11) pre-­ existing polyneuropathy; (12) secondary conditioning and distribution of the study history of lung or liver reaction or peripheral neurop- drugs will be performed by the Barcelona Primary Care athy after previous use of nitrofurantoin; (13) glucose-­ Pharmacy Service. Study drugs will be distributed to the 6-­phosphate dehydrogenase deficiency; (14) porphyria Primary Care Pharmacy Services of the four regions taking or systemic primary carnitine deficiency or of the type part in the study, which will be in charge of providing organic aciduria (ie, methylmalonic aciduria and propio- their primary care sites with the medication. All the study nacidanaemia); (15) oesophageal stricture; (16) current drugs will be kept at room temperature. intake of allopurinol (increases the risk of allergic skin reaction to mecillinam), probenecid (decreases the renal Sample size excretion of mecillinam) or valproate; (17) currently part A minimal clinically important difference of 10% was of another RCT; (18) previous enrolment in the proposed chosen in line with guidance provided by both the Euro- study; (19) patients living in long-­term institutions and/ pean Medicine Agency and the Infectious Disease Society or (20) difficulty in conducting scheduled follow-­up visits. of America.26 27 Assuming a clinical efficacy of 75% for a single-­ dose fosfomycin as demonstrated in a recent Randomisation systematic review,28 a two-­sided type I error of 5%, and Patients will be sequentially assigned as they enter the a statistical power of 80%, we need 253 patients in each study. Randomisation of patients will be performed by group for the intention-­to-­treat analysis. Considering an registering the patient in an electronic case report form estimated drop-­out rate of 10% in each study arm, we aim (CRF) during the index visit. Since this study is open-­label to recruit 280 in each group (total number 1120 LUTIs). to patients and investigators, randomisation will be based on investigator-­blinded blocks of randomly varying size Settings to protect against potential predictability of treatment This RCT will be conducted in 15–20 primary care centres assignments. Blocks will be small in order to decrease the in four regions in Spain: Aragon, Balearic Islands, Catal- potential for mid-­block inequality. Since this is a multi- onia and Madrid. In each area, a total of 280 patients will centre study, a block procedure will be performed to be recruited, with three to eight primary care centres and assign patients to each of the health centres at a 1:1:1:1 one or two microbiology departments being involved. treatment ratio. Participants Blinding Inclusion criteria This is an open study. Neither physicians nor patients will Potential participants are women of 18 years of age or be blind to the patient’s assignment to the drug study older, with clinical features of uncomplicated community-­ group. The open nature of the RCT ensures that the acquired LUTI including: (1) at least one of four key results obtained in this study are very close to the reality symptoms of LUTI: dysuria, urgency including nocturia, of primary care, considering that both the participating frequency and suprapubic tenderness that could be general practitioners (GPs) and the patients with uncom- attributed to an uncomplicated LUTI, and no alterna- plicated LUTI will be aware of the treatment given. tive explanation (ie, symptoms suggestive of sexually-­ transmitted infection or vulvovaginitis), and (2) a urine Outcome measures dipstick analysis positive for either nitrites or leucocyte Primary outcome esterase. Clinical effectiveness is defined as the proportion of patients who report being cured by day 7, defined as the Exclusion criteria resolution of all symptoms (scoring 0 in the symptom Patients with any of the following criteria will be excluded diary) and those who report an improvement of the from this trial: (1), male sex; (2) high suspicion of pyelo- symptoms related to the LUTI (persistence of symptoms nephritis (ie, fever ≥37.5°C or flank pain/tenderness); without objective evidence of infection). We will consider (3) any condition that may lead or predispose to compli- failure in case of need for additional or a change in anti- cated urinary infection, such as indwelling urinary cath- biotic treatment due to UTI or discontinuation due to eter, pregnancy, immunosuppressive therapy, abnormal lack of efficacy. urinary tract, severe neurological disease affecting the bladder or recurrent UTIs, defined as the presence of Secondary outcomes more than 3 UTIs in the previous year or more than two (1) Duration of symptoms (number of days until the last in the previous 6 months; (4) pregnancy or planned preg- day the patient scores 0 in any of the four symptoms); nancy; (5) symptoms consistent with UTI in the preceding (2) bacteriological eradication at day 14, defined as 4 weeks; (6) patients taking long-­term antibiotic prophy- eradication of the infecting strain with no recurrence laxis; (7) ongoing antibiotic therapy or use of any systemic of bacteriuria—less than 1000 colony-­ forming units antibiotic in the previous 7 days; (8) symptoms correlated per millilitre (CFU/mL). Failure will be defined as Garcia-­Sangenís A, et al. BMJ Open 2021;11:e055898. doi:10.1136/bmjopen-2021-055898 3 Open access bacteriuria ≥1000 CFU/mL with the infecting strain; permission can access the data. The CRFs and other (3) bacteriological eradication at day 28 (ie, propor- documents will be stored at a separate and secure loca- tion of patients bacteriologically cured at the final urine tion for 25 years after trial completion. A risk approach sample); (4) proportion of patients presenting a relapse monitoring plan will be developed and followed via peri- of symptoms within the first 4 weeks after inclusion in the odic on-­site/online visits. study and timing of relapse of symptoms and/or bacte- riuria; (5) proportion of patients developing complica- Ascertainment of visits tions within the first 4 weeks; (6) proportion of patients The patients will be randomised to one of the four treat- presenting adverse and serious adverse events; (7) predic- ment strategies. Women will receive information on the tive value of the different clinical criteria with microbi- study by the participating GPs, and if they are interested ologically confirmed LUTI; (8) bacteriological findings in participating, they will be provided with an informed (ESBL-­producing bacteria, resistance rates to the study consent form to read and sign. The participating GPs medications); (9) cost-­effectiveness (drug costs, health will explain the study scheme and the visit programme to resources used, days until recovery and days with limita- the patient (table 1). After randomisation, information tion of activity (productive and non-­productive) and (10) on the strategy to which they have been allocated will be quality of life by means of the EQ-­5D-­5L validated ques- given to the participants, and they will be given the study tionnaire (Spanish version). medication and will be informed as to the appropriate Time schedule measures to take in case of worsening or no improvement The recruiting GPs will commence the study in January of their condition. Patients will be asked about the prior 2022 and will attempt to recruit all eligible patients by 30 duration of symptoms. In addition, they will be given a April 2023. If the necessary sample size is met before this paper-­based diary to be completed by themselves daily for date, the recruitment period will end at the time of inclu- a total of 7 days. Patients will be asked to score a simple sion of the last patient. symptom diary, which has been slightly modified from one used in another RCT on uncomplicated LUTI,29 Data management and monitoring with only four symptoms: dysuria, urgency, frequency The investigators will follow the standard operating and suprapubic pain. Each symptom will be scored by procedures of the trial for better quality of assessment the patient on a 4-­point severity scale (not present/mild/ and outcome data collection. All assessment data and moderate/severe). Patients will be given instructions on case reports in the different arms will be collected at the how to fill in the diary, how to take the study medication baseline visit and at the various follow-­up visits. Collected and reminders of the following visits, and they will be documents and data will be managed by electronic asked on which day they felt cured. This diary will be used CRF. Only the principal investigator or those who have in a pilot study in some centres during 2 months prior to Table 1 Timetable of the study period Day 7 Visit Baseline visit (phone visit) Day 14 Day 28 History taking and clinical examination X   Eligibility X   Explanation of the study and informed consent X   Initial case report form X   Urine dipstick X       Urine culture, including antibiogram if positive X   X X Randomisation X       Dispensing the study medication X       Giving out of the symptom diary X   Assessment of the change in the quality of life X X     Assessment of the clinical outcome   X X X Adherence to the study drug   X     Collection of the symptom diary   X   Monitoring concomitant treatment and use of other antibiotics   X X X Evaluation of adverse events   X X X Evaluation of reattendance to healthcare services and complications   X X X with relation to the infection 4 Garcia-­Sangenís A, et al. BMJ Open 2021;11:e055898. doi:10.1136/bmjopen-2021-055898 Open access the initiation of the trial to ensure that its use is feasible Statistical analysis and reliable. A maximum length of 15 min is expected All treatment strategy comparisons among the for the baseline visit including interview, randomisation, randomised groups will be performed according to the collection of the urine sample and the introduction of principle of intention-­to-­treat; that is, all initially enrolled the data. patients will be included in the analysis according to the GPs will call patients 7 days after their inclusion in the treatment strategy to which the subjects are randomised study to monitor their progress and obtain information regardless of non-­adherence to treatment or treatment about their symptoms. Patients will be scheduled for a failure. The primary statistical comparison of the primary second visit on day 14 (2 weeks after patient inclusion) outcome will be a two-­sided χ2 test of the three short-­ to evaluate their clinical evolution, collect the diaries and course antibiotic regimens with the single dose of fosfo- collect a new urine sample. The last visit will be on day 28, mycin. Time-­to-­event analysis will be used to analyse the and patients will also be asked to collect another urine clinical effectiveness of the four treatment strategies. sample. An evaluation of adverse events, reattendance to Relative risks will be expressed as HRs with associated healthcare services and complications with relation to the 95% CIs derived using the Cox proportional hazards LUTI will be carried out. model. The overall level of significance for the assessment The face-­to-­face visits will coincide with the delivery of of primary and secondary endpoints will be α=0.05. A per-­ the urine sample, thus facilitating the patient to deliver protocol analysis of those who complete the entire trial the sample. The procedure of urine sample collection will without violating the protocol, will also be performed as be decided according to the results of a systematic review a sensitivity analysis of the primary results. A subgroup and meta-­analysis on what the most adequate non-­invasive analyses of the main variables will be carried out by method to collect a urine specimen for diagnosing UTI age groups (premenopausal, postmenopausal) and by in symptomatic non-­pregnant women is, currently being region. Missing outcomes will be accounted for using performed by some of the same study authors (PROS- multiple imputation with chained equation.33 Twenty PERO CRD42021241758). The three urine samples will imputed samples will be generated, and estimates will be be sent to the Departments of Microbiology in each of combined using Rubin rules.34 Direct healthcare costs the four regions for examination of the presence and will be calculated by adding the costs derived from medi- counting of uropathogenic bacteria. cation consumption, medical tests, use of health-­related In the presence of significant bacteriuria (ie, ≥1000 services, cost of relapses and cost of the staff running the bacteria/mL of a single pathogen according to current intervention, for each arm. Indirect costs will be calcu- European guidelines for women with symptoms of lated considering the proportion part of quality adjusted LUTI),30 the isolates will also be examined for resistance life year indicator, the number of days with symptoms and mechanisms and patterns and minimal inhibitory concen- sick days taken.35 All the analyses will be carried out with tration to common antibiotics, including fosfomycin, the statistical software R V.4.0 or higher, and the level of nitrofurantoin and pivmecillinam. All urine samples significance will be 0.05. will be processed according to routine laboratory proce- dures and susceptibility tested according to the European Patient and public involvement Committee on Antimicrobial Susceptibility Testing.31 Women with previous LUTI experience have been invited A urine culture with less than 1000 CFU/mL, multiple to be part of our study team. Participants were selected pathogens or normal flora will be considered contamina- using purposive sampling to cover a wide range of opin- tion and will not be defined as LUTI. We consider that ions and discourses. Age, region, UTI recurrence and about 25% of the suspected LUTIs will not be microbio- socioeconomic characteristics were taken into consider- logically confirmed based on two recent RCTs using the ation. Our patient and public involvement framework same inclusion criteria as in our trial.19 32 is defined as study-­ focused36 following a collaborative 37 Patients will be free to withdraw from the study at any strategy. Participants have been and will be asked to time for any reason without prejudice to future care, and assess all patient-­related materials, as well as well key with no obligation to provide the reason for withdrawal. procedures and documents such as the study protocol In addition, patients presenting signs of upper UTI (ie, and patient information sheets, case report files, recruit- pyelonephritis), treatment failure, serious adverse effects ment strategy and results reports. They will be present or allergic reactions to the medicine will be withdrawn throughout the whole project. All the RCT participants from the study. Patients presenting treatment failure (ie, and all the patients who are interested in the study results ongoing or worsening symptoms) will receive a different will receive a layman study newsletter with a summary of antibiotic according to the pretreatment (day 0) urine the results obtained at the end of the trial. culture results. During the trial, patients will be asked to inform about any signs of worsening symptoms, and inves- tigators will evaluate appropriate measures if they need ETHICS AND DISSEMINATION additional therapy. Since this is a pragmatic trial, patients Ethical issues who decide interrupting the study drug treatment will be The trial will be conducted in accordance with the Decla- withdrawn from the study. ration of Helsinki and Good Clinical Practice guidelines, Garcia-­Sangenís A, et al. BMJ Open 2021;11:e055898. doi:10.1136/bmjopen-2021-055898 5 Open access national and European legislation on clinical trials and will explore the experiences, needs and preferences of data protection and with the study protocol. Consolidated patients and professionals regarding LUTIs and their Standards of Reporting Trials guidelines will be followed treatment, giving information on patients’ values and to inform of the study results. preferences to consider in decision-­making. Approval from the Spanish Agency of Medicines and Medical Devices (6 September 2021) as well as from a national medicines Research Ethics Committee DISCUSSION (IDIAPJGol) have been obtained (reference code Antimicrobial resistance is a growing problem threat- 21/173-­AC, authorised on 23 September 2021. Investiga- ening societal development and human health. LUTIs tors will be required to provide all information related to caused by antibiotic resistant bacteria are associated with the clinical trial to every patient, including the possible increased morbidity and mortality, as well as with higher benefits and harms, other therapeutic choices, right treatment costs due to an increased risk of complications to withdraw and use of their data, via a written patient (urosepsis and pyelonephritis) and admission to hospital information sheet and oral interview. After the patient and productive losses.9 10 The use of broad-­spectrum anti- has been provided with enough time and opportunity to biotics for women with uncomplicated LUTIs has been ask questions and decide whether to participate, written shown to increase and spread the antimicrobial resistance informed consent will be obtained from all participants of uropathogens. After two decades of increased antibi- before study inclusion. otic resistance, the urgency of the problem is now widely understood and inappropriate use of antibiotics is the Adverse events and serious adverse events main driver for the growing development and spread of According to European legislation on clinical trials, this antimicrobial resistance. The SCOUT study will mark a is a low intervention clinical trial: the drugs administered significant move forward from theory to practice in rela- are used in accordance with the terms of the marketing tion to promoting responsible stewardship regarding authorisation with a well-­known safety profile, and the treatment of uncomplicated LUTIs in women. In our clinical trial procedures in the patient pose no additional country, the increase in resistance to antibiotics used risk to the subject compared with usual clinical practice. empirically in LUTIs, such as amoxicillin and clavulanic The study medications used in this clinical trial have been acid and quinolones, is very worrisome, and even more widely prescribed and consumed for a long time, and the so at this time in which quinolones have restrictions due safety profile of these drugs is well documented. Pivme- to safety problems. This problem, along with the fact that cillinam has been widely used in Nordic countries and is most GPs are reluctant to follow the national guidelines now approved in Spain, although it is not yet marketed. and avoid the prescribing of a single 3 g-­dose of fosfo- Considering the low intervention characteristics of the mycin, makes this study very important in an area such trial, only adverse events related to the trial medication as Spain with high resistance rates. Therefore, having and all serious adverse events (regardless of the relation- comparative data in real-­life can constitute the basis for ship with the study drugs) will be recorded, followed implementing the most efficient option with less expo- and analysed. The remaining events will be treated as in sure to antibiotic treatment and contribute to reducing normal clinical practice. the increase in resistance. Very importantly, we are conducting an independent Dissemination clinical trial with medicines without commercial interest. A range of dissemination activities at national and interna- Our aim is to compare different short-­course regimens tional conferences is planned. At the end of the trial, we of most antibiotics used in the empiric treatment of will publish the final report in an open access peer-­review LUTIs and will provide valuable information about the journal even in the case of negative results, and the study most effective treatment for a common infection seen results will also be disseminated via conference presenta- in primary care. We hypothesise that short-­course treat- tions. National stakeholders will be informed about clin- ments will be more effective than the recommended 3 g ical trial results. A summary of the findings will be sent single dose of fosfomycin, resembling what clinicians to the participating practices on completion of the RCT, usually do in routine practice. Since no RCT comparing and the participants will also be informed of the results. the four available regimens has been carried out to date, We will design a booklet to be used in LUTI consultations we still do not know which of the three short courses is with the results of our clinical trial and qualitative studies, more effective in terms of clinical effectiveness and bacte- and a layman version of the trial results will be developed riological eradication. for public dissemination. Author affiliations 1 Complementary studies 2 Institut de Recerca en Atencio Primaria Jordi Gol, Barcelona, Catalonia, Spain After the RCT, two qualitative studies are planned, one UICEC de IDIAP Jordi Gol-­Plataforma ScREN, Barcelona, Catalonia, Spain 3 Medicines Research Unit, Institut de Recerca en Atencio Primaria Jordi Gol, with former patients of our clinical trial and one with Barcelona, Catalonia, Spain healthcare professionals who have also participated 4 Departament de Farmacologia i Terapèutica, Universitat Autònoma de Barcelona, in the clinical trial as investigators. Qualitative studies Bellaterra, Cerdanyola del Vallès, Catalonia, Spain 6 Garcia-­Sangenís A, et al. BMJ Open 2021;11:e055898. doi:10.1136/bmjopen-2021-055898 Open access 5 Microbiology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Open access This is an open access article distributed in accordance with the Llobregat, Catalonia, Spain Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which 6 Primary Care Research Unit of Mallorca, Balearic Islands Health Services; Health permits others to distribute, remix, adapt, build upon this work non-­commercially, Research Institute of the Balearic Islands (IdISBa), Palma De Mallorca, Balearic and license their derivative works on different terms, provided the original work is Islands, Spain properly cited, appropriate credit is given, any changes made indicated, and the use 7 Health Research Institute of Aragón, Zaragoza, Aragon, Spain is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. 8 Health Research Institute of Aragón; Primary Care Prevention and Health Promotion ORCID iDs Research Network (RedIAPP), Zaragoza, Aragon, Spain Ana Garcia-­Sangenís http://​orcid.​org/​0000-​0002-​6689-​6466 9 Parque Goya Health Centre, Family and Community Care Teaching Unit of Zaragoza Rosa Morros http://​orcid.​org/​0000-​0001-​6752-​8748 Sector I, Zaragoza, Aragon, Spain Laura Medina-­Perucha http://​orcid.​org/​0000-​0002-​2981-​2614 10 Arrabal Health Centre, University of Zaragoza, Zaragoza, Aragon, Spain Alfonso Leiva http://​orcid.​org/​0000-​0001-​5306-​8533 11 Villarejo de Salvanés Health Centre, Villarejo de Salvané, Madrid, Spain Joana Ripoll http://​orcid.​org/​0000-​0002-​5251-​7234 12 Rosa Magallon Botaya http://​orcid.​org/​0000-​0002-​5494-​6550 Primary Healthcare Centre San Andrés, Comunidad de Madrid Servicio Madrileno de Salud, Madrid, Spain José M Molero http://​orcid.​org/​0000-​0002-​4426-​2593 13 Universitat Rovira i Virgili, Tarragona, Catalonia, Spain Ana Moragas http://​orcid.​org/​0000-​0002-​1307-​0943 14 Primary Healthcare Centre Jaume I, Tarragona, Spain Ramon Monfà http://​orcid.​org/​0000-​0002-​1324-​3971 15 Primary Care Pharmacy Unit, Institut Català de la Salut, Barcelona, Catalonia, Carl Llor http://​orcid.​org/​0000-​0001-​6644-​717X Spain 16 Via Roma Health Centre, Institut de Recerca en Atencio Primaria Jordi Gol, CIBER de Enfermedades Infecciosas, Barcelona, Catalonia, Spain 17 Department of Public Health, General Practice, University of Southern Denmark, REFERENCES Odense, Funen, Denmark 1 Palou J, Pigrau C, Molina I. 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AG-­S, infections: epidemiology, mechanisms of infection and treatment RMor, RMon and CL are involved in trial supervision. AT is involved in study drug options. Nat Rev Microbiol 2015;13:269–84. management. MA-­S is involved in microbiology coordination. AL and JR contributed 9 van Hecke O, Wang K, Lee JJ, et al. Implications of antibiotic to the statistical design and analysis. All authors have contributed to the conception resistance for patients' recovery from common infections in the of this clinical trial. community: a systematic review and meta-­analysis. Clin Infect Dis 2017;65:371–82. Funding The SCOUT Study received a research grant from the Carlos III Institute 10 Vallano A, Rodríguez D, Barceló ME. Grupo de Estudio de las of Health (ISCIII), Ministry of Science and Innovation (Spain), awarded in the 2020 Infecciones del Tracto Urinario en Atención Primaria. antimicrobial call under the Academic Clinical Trials Call, with reference ICI20/00100, by Primary susceptibility of uropathogens and outcome following antibiotic treatment for urinary tract infections in primary health care. Enferm Care Prevention and Heath Promotion Network GRenSSAP (code RD16/0007/0001), Infecc Microbiol Clin 2006;24:418–25. Balearic Islands (code RD16/0007/0008), Aragón (code RD16/0007/0005), Madrid 11 Guay DRP. Contemporary management of uncomplicated urinary (code RD16/0007/0013) and by European Union ERDF funds (European Regional tract infections. Drugs 2008;68:1169–205. Development Fund). 12 Patología infecciosa. En: Grupo de Trabajo de Enfermedades Infecciosas de la semFYC. Manual de Enfermedades Infecciosas Competing interests CL reports receiving research grants from Abbott en Atención Primaria, 4.a ed. Sociedad Española de Medicina de Diagnostics. The other authors have nothing to declare. Familia y Comunitaria, 2017: 815–47. Patient and public involvement Patients and/or the public were involved in the 13 Guía de terapéutica antimicrobiana del área Aljarafe. Distrito Sanitario Aljarafe Y Hospital San Juan de Dios del Aljarafe, 3a. design, or conduct, or reporting or dissemination plans of this research. Refer to the Edición, 2018. Available: http://www.​juntadeandalucia.​es/​serv​icio​ Methods section for further details. anda​luzd​esalud/​guia​tera​peut​icaa​ljarafe/​guia​Tera​peut​icaA​ljarafe/ Patient consent for publication Consent obtained directly from patient(s). [Accessed 25 Oct 2021]. 14 Cai T, Tamanini I, Tascini C, et al. 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