Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY)

Paediatrics, infant, urinary tract infection, antibiotics ALL Metrics - Views Downloads How to cite this article Waterfield T, McMullan R, Lyttle MD et al. Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.14103.2) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente Select a format first ▬ ✚ Research Article Revised Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations] Thomas Waterfield https://orcid.org/0000-0001-9452-7716 1,2, Ronan McMullan2, Mark D Lyttle https://orcid.org/0000-0002-8634-7210 3, [...] Stuart Hartshorn4, Kerry Woolfall5, Sanjay Patel6, Wesley Hayes7, Andrew Marshall https://orcid.org/0000-0003-0529-0425 8, Kathryn Ferris https://orcid.org/0000-0001-5220-7466 1, Ashley Agus9, Christina Campbell9, Rachael Rice9, Andrew Jackson9, Lynn Murphy https://orcid.org/0000-0001-9263-6337 9, Mike Clarke https://orcid.org/0000-0002-2926-7257 9Thomas Waterfield https://orcid.org/0000-0001-9452-7716 1,2, Ronan McMullan2, [...] Mark D Lyttle https://orcid.org/0000-0002-8634-7210 3, Stuart Hartshorn4, Kerry Woolfall5, Sanjay Patel6, Wesley Hayes7, Andrew Marshall https://orcid.org/0000-0003-0529-0425 8, Kathryn Ferris https://orcid.org/0000-0001-5220-7466 1, Ashley Agus9, Christina Campbell9, Rachael Rice9, Andrew Jackson9, Lynn Murphy https://orcid.org/0000-0001-9263-6337 9, Mike Clarke https://orcid.org/0000-0002-2926-7257 9 PUBLISHED 12 Feb 2026 Author details Author details 1 Queen's University Belfast, Belfast, Northern Ireland, UK 2 HCS Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK 3 Perth Children's Hospital Foundation, Perth, Western Australia, Australia 4 Children's Emergency Department, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK 5 University of Liverpool Department of Public Health Policy and Systems, Liverpool, England, UK 6 University Hospital Southampton NHS Foundation Trust, Southampton, England, UK 7 Great Ormond Street Hospital Children's Charity, London, England, UK 8 Oxford University Hospitals NHS Foundation Trust, Oxford, England, UK 9 Northern Ireland Clinical Trials Unit, Belfast, UK 2 HCS Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK 3 Perth Children's Hospital Foundation, Perth, Western Australia, Australia 4 Children's Emergency Department, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK 5 University of Liverpool Department of Public Health Policy and Systems, Liverpool, England, UK 6 University Hospital Southampton NHS Foundation Trust, Southampton, England, UK 7 Great Ormond Street Hospital Children's Charity, London, England, UK 8 Oxford University Hospitals NHS Foundation Trust, Oxford, England, UK 9 Northern Ireland Clinical Trials Unit, Belfast, UK Thomas Waterfield Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Ronan McMullan Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Mark D Lyttle Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Stuart Hartshorn Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Kerry Woolfall Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Sanjay Patel Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Wesley Hayes Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Andrew Marshall Roles: Methodology, Writing – Review & Editing Roles: Methodology, Writing – Review & Editing Kathryn Ferris Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Ashley Agus Roles: Data Curation, Formal Analysis, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Data Curation, Formal Analysis, Funding Acquisition, Methodology, Writing – Review & Editing Christina Campbell Roles: Data Curation, Formal Analysis, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Data Curation, Formal Analysis, Funding Acquisition, Methodology, Writing – Review & Editing Rachael Rice Roles: Project Administration, Resources, Supervision Roles: Project Administration, Resources, Supervision Andrew Jackson Roles: Investigation, Project Administration, Resources, Supervision, Writing – Review & Editing Roles: Investigation, Project Administration, Resources, Supervision, Writing – Review & Editing Lynn Murphy Roles: Funding Acquisition, Methodology, Project Administration, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Project Administration, Writing – Review & Editing Mike Clarke Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS Urinary tract infections (UTIs) are the most common serious bacterial infections in febrile infants. Current UK guidelines recommend parenteral antibiotics for infants under three months with suspected UTI, despite evidence supporting oral therapy in low-risk infants. To assess whether oral antibiotics are non-inferior to parenteral antibiotics for treating suspected UTIs based on treatment failure, need for additional therapy, and secondary outcomes. Multicentre, randomised controlled, open-label, non-inferiority trial with embedded internal pilot. Twenty one paediatric emergency departments and assessment units across the UK. Infants aged 29–90 days with suspected UTI, abnormal urinalysis, and low risk of invasive bacterial infection. Exclusion criteria included prematurity, prior hospitalisation, structural renal abnormalities, and clinical signs of sepsis or meningitis. Participants were randomised 1:1 to receive either oral antibiotics or standard care with intravenous (IV) antibiotics for 36–48 hours pending urine culture results. The primary outcome was the requirement for additional parenteral antibiotics within seven days of randomisation. A range of secondary outcomes were also planned, including treatment failure, time to recovery, adverse events, antibiotic adherence, quality of life, family impact, and healthcare resource use. Feasibility outcomes collected during the internal pilot included recruitment rate, site activation, protocol adherence, and retention. Clinical outcomes were collected but not powered for formal comparison. 27 participants were recruited between 20 May 2024 and 13 March 2025 (which included the 6 month internal pilot), representing 27% of the pilot target. Protocol adherence was high, and no cases of meningitis occurred. Two cases of bacteraemia (one per randomised group) had uncomplicated clinical courses. Oral therapy was associated with shorter hospital stays and reduced parental time off work. While trial procedures were successfully implemented, recruitment challenges suggest that a larger randomised trial of this treatment comparison is not feasible in this setting. Northern Ireland Clinical Trials Unit (NICTU) ISRCTN Clinical Trials Registry, ISRCTN10907780, Trial Dates 20 May 2024 to 13 March 2025 Urinary tract infections (UTIs) are the most common serious bacterial infections in babies with a fever. In the UK, current guidelines recommend giving antibiotics through a vein (IV) to babies under three months old with suspected UTIs. However, recent evidence suggests that giving antibiotics by mouth might work just as well for babies who are otherwise healthy. This study aimed to find out whether oral antibiotics are just as effective as IV antibiotics for treating UTIs in young infants. Researchers ran a trial in 10 hospitals across the UK, involving babies aged 29 to 90 days who were at low risk of serious infection. The babies were randomly assigned to receive either oral antibiotics or IV antibiotics for 36–48 hours while waiting for urine test results. The main goal was to see how many babies needed additional IV antibiotics within a week. Researchers also looked at other factors like recovery time, side effects, how well families managed the treatment, and the impact on daily life. During the initial phase of the study, 27 babies were enrolled. No cases of meningitis occurred, and both treatment groups had one case of bloodstream infection, which were mild and resolved without complications. Babies who received oral antibiotics spent less time in hospital, and their parents took less time off work. Although the study procedures worked well, it was difficult to recruit enough participants. Because of this, the researchers concluded that a larger trial comparing oral and IV antibiotics may not be practical in this setting. Paediatrics, infant, urinary tract infection, antibiotics Corresponding Author(s) Thomas Waterfield ([email protected]) Grant information: This project is funded by the National Institute for Health Research (NIHR) under its Health Technology Assessment Programme (Grant Reference Number NIHR152733)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © Crown copyright, 2026 Waterfield T et al.. This open access work is licensed under the Open Government Licence v3.0 How to cite: Waterfield T, McMullan R, Lyttle MD et al. Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.14103.2) First published: 17 Oct 2025, 5:104 (https://doi.org/10.3310/nihropenres.14103.1) Latest published: 12 Feb 2026, 5:104 (https://doi.org/10.3310/nihropenres.14103.2) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We have revised the manuscript to improve clarity and transparency in response to reviewer feedback. Specifically, we have clarified international variation in guideline recommendations regarding the route of antibiotic therapy in young infants with suspected UTI and explicitly highlighted this ongoing debate as a key rationale for the trial. We have provided additional explanation for the inclusion of infants with caregiver-reported fever, noting its clinical relevance while acknowledging that planned sensitivity analyses were not feasible due to early trial termination following the pilot phase. We have clarified the pragmatic approach to urine collection, reflecting UK NICE guidance and real-world practice, and explicitly defined the day-28 secondary outcome as the requirement for additional parenteral antibiotic therapy to avoid ambiguity. We have revised the manuscript to improve clarity and transparency in response to reviewer feedback. Specifically, we have clarified international variation in guideline recommendations regarding the route of antibiotic therapy in young infants with suspected UTI and explicitly highlighted this ongoing debate as a key rationale for the trial. We have provided additional explanation for the inclusion of infants with caregiver-reported fever, noting its clinical relevance while acknowledging that planned sensitivity analyses were not feasible due to early trial termination following the pilot phase. We have clarified the pragmatic approach to urine collection, reflecting UK NICE guidance and real-world practice, and explicitly defined the day-28 secondary outcome as the requirement for additional parenteral antibiotic therapy to avoid ambiguity. See the authors' detailed response to the review by Ghassan Ghssein See the authors' detailed response to the review by Kazuki Iio Urinary tract infections (UTIs) are the most common serious bacterial infection (SBI) in febrile infants, accounting for over 90% of all SBIs in this age group1–7. Diagnosing UTIs in young infants is particularly challenging due to several factors. Clinical features are often non-specific, such as poor feeding, irritability, fever, and vomiting. Urine collection is difficult, as infants are unable to provide a clean-catch midstream sample8–12. These diagnostic challenges necessitate a cautious clinical approach. Current UK national guidelines recommend empirical treatment with broad-spectrum parenteral antibiotics for all febrile infants under three months of age with suspected UTI, pending culture results13,14. In contrast, for infants aged over three months, oral antibiotics are considered appropriate while awaiting culture confirmation15,16. This discrepancy in treatment recommendations stems from concerns regarding the absorption and efficacy of oral antibiotics in younger infants17. However, substantial evidence indicates that, beyond the neonatal period (>28 days), oral antibiotics are well absorbed, well tolerated, and effective in treating UTIs17–21. The prevailing cautious approach contributes to significantly higher healthcare resource use in febrile infants compared to older children22. Reducing the use of “just in case” parenteral antibiotics could lower healthcare costs, alleviate pressure on paediatric inpatient services, and enhance patient and family experience by shortening hospital stays and minimising invasive procedures. Two previous randomised trials have evaluated the use of oral antibiotics in this population. The first, conducted by Hoberman et al. in the United States and published in 1999, included 306 infants with febrile UTI, 144 of whom were under six months of age20. Infants were randomised to receive either oral or parenteral antibiotics. The study found no significant differences between groups in time to defervescence, microbiological cure, or complications such as recurrent UTI and renal scarring. Notably, treatment costs were significantly lower in the oral antibiotic group (US$1,473 vs. US$3,577)20. Similarly, Montini et al. conducted a non-inferiority trial in Italy in 2007, comparing oral and parenteral antibiotics in infants with febrile UTI, including 186 infants under six months of age21. Their findings mirrored those of Hoberman et al., with no significant differences in clinical outcomes, including time to defervescence, microbiological cure, normalisation of inflammatory markers, or incidence of renal scarring. Reflecting this evidence, several international consensus guidelines recommend oral antibiotics as first-line therapy for infants with suspected UTI; however, recommendations are not uniform. For example, the American Academy of Pediatrics supports oral antibiotic treatment in infants older than 28 days, whereas Swiss consensus guidance recommends oral therapy in infants over 60 days of age. These discrepancies highlight ongoing clinical uncertainty regarding the optimal route of antibiotic administration in this population and provide a key rationale for conducting this randomised controlled trial2,10,23. The overall aim of the EASY trial was to assess whether oral antibiotics, given while awaiting urine culture results, are as effective as parenteral antibiotics. Effectiveness was measured by treatment failure, defined as the need for additional parental antibiotics and various secondary outcomes. The trial also aimed to evaluate the impact of oral antibiotics on healthcare resource use, costs, and selected outcomes through a cost-consequence analysis. The EASY internal pilot aimed to assess the feasibility of recruiting a sufficient number of eligible participants to support progression to a definitive trial. The pilot evaluated recruitment rates, screening and consent procedures, and randomisation processes. Patients, carers, and members of the public were involved from the outset of the EASY study. A PPI group of 12 individuals including parents with lived experience of UTIs in infants, met five times to inform study design. Additional input was gathered from children and young people. PPI members helped shape the research focus on antimicrobial stewardship and reducing unnecessary hospital stays, and contributed to defining inclusion criteria, consent timing, and safety measures for early discharge. They supported randomisation and helped refine the non-inferiority margin to 3–5%. Two secondary outcomes; time to defervescence and time to normal feeding were proposed by the group. A parent representative was a co-applicant and part of the Trial Management Group. The PPI group contributed to protocol development, participant materials, recruitment strategies. Multicentre, randomised controlled, open-label, non-inferiority trial with embedded internal pilot, comparing parenteral antibiotics versus oral antibiotics for the management of suspected UTI in low-risk infants. During the pilot phase of the EASY study, two key protocol amendments were implemented to improve recruitment feasibility and better align with clinical practice: 1. Modification of Inclusion & Exclusion Criteria: The original protocol required participants to meet specific laboratory thresholds for C-reactive protein (CRP) and white cell count (WCC). Also, the original protocol excluded infants ‘requiring re-admission to hospital after birth for >24 hours’. The CRP and WCC criteria were removed and the exclusion criteria changed to ‘re-admission to hospital after birth for >24 hours for parenteral antibiotics.’ This was done to broaden eligibility and reduce unnecessary exclusions, based on feedback from recruiting sites and early screening data. 2. Adjustment to Timing of Randomisation: Initially, randomisation was required before the administration of a second dose of parenteral antibiotics. This was revised to allow randomisation within 24 hours of hospital arrival. These changes were made in consultation with trial oversight committees, participating sites and the trial management group, and were intended to enhance recruitment while maintaining the safety and scientific validity of the study. Recruitment for the EASY trial was conducted across 21 paediatric emergency departments (EDs) and assessment units throughout the United Kingdom. Participating sites were drawn from the Paediatric Emergency Research in the UK and Ireland (PERUKI) network and the General and Adolescent Paediatric Research in the United Kingdom and Ireland (GAPRUKI) network. Participants were screened from attendances to paediatric EDs and assessment units at recruiting sites. All individuals meeting the study’s inclusion criteria were entered into a screening log. For those not recruited, the reason for non-enrolment was documented. Eligibility was assessed by a physician listed on the site’s Delegation Log, in accordance with the trial’s inclusion and exclusion criteria. Medical care and clinical decisions for trial participants were provided by appropriately qualified treating physicians. Informed written consent was obtained from the parent or guardian of each participant by a trained member of the clinical team prior to inclusion in the trial. Families were provided with a participant information leaflet, consent form, and verbal explanation of the study. Consent was documented before randomisation and trial procedures. Participants could withdraw at any time without detriment, and data collected up to withdrawal were retained unless otherwise requested. General practitioners were notified of their patients’ participation via letter. Participants were eligible for enrolment if all the following criteria were met: Participants were excluded if any of the following criteria applied: 1. Gestational age at birth <30 weeks. 2. Discharge from hospital more than 7 days after birth. 3. History of re-admission to hospital that required treatment with parenteral antibiotics 4. Known or suspected structural renal abnormality. 5. Clinical evidence of sepsis and/or meningitis, including: 6. Receipt of vaccination within 48 hours before attendance. 7. Serum sodium 6.5 mmol/L (laboratory or blood gas sample). 9. Plasma creatinine >50 µmol/L. 10. Inability to tolerate oral medication. 11. Urine sample not sent for culture. 12. Received additional antibiotics (with the exception of the parenteral antibiotic administered within 24 hours of hospital attendance) 13. Declined consent for participation. 14. Not clinically well on global assessment Initial clinical assessment and management of febrile infants under three months of age were conducted according to standard care protocols. Blood and urine testing were performed, and broad-spectrum parenteral antibiotics were administered as clinically indicated, in line with national guidelines and local policy. Urine can be collected by the method deemed most appropriate by the treating clinician. These initial interventions were not influenced by trial participation, and administration of parenteral antibiotics was not delayed for consent procedures. Screening for trial eligibility was initiated once initial laboratory results were available. Only infants meeting the predefined “low-risk” criteria were invited to participate. Randomisation was required within 24 hours of presentation to hospital. Eligible participants were randomised in a 1:1 ratio to one of two treatment groups: Randomisation was performed using an automated web-based or telephone system employing randomly permuted blocks. Stratification was applied by recruitment site, sex, age group (29–60 days vs. 61–90 days), and prior antibiotic use. Allocation concealment was maintained through secure storage of the randomisation sequence in a restricted section of the Trial Master File, accessible only to the trial statistician. Following informed consent, randomisation was completed by a trained and delegated member of the research team. Each participant was assigned a unique study number, which was used for all trial documentation and data collection. Enrolment into the study was documented in the participant’s medical record. This was an open label, unblinded trial. Parents or guardians, healthcare providers, and outcome assessors were aware of the allocated intervention. This pragmatic design allowed for realistic evaluation of clinical effectiveness, including hospital admission decisions unrelated to antibiotic administration. The trial statistician, who had no role in trial conduct, remained unblinded to facilitate data monitoring and linkage with the Data Monitoring and Ethics Committee (DMEC). The broader trial team was also unblinded to support data management, case review, and pharmacovigilance activities. Both oral and parenteral antibiotics used in the EASY trial were administered in accordance with their licensed indications and standard clinical practice. As the safety profiles of these agents are well established, and their use did not exceed routine care, the trial was classified as a Type A Clinical Trial of an Investigational Medicinal Product (CTIMP). A risk-adapted approach to trial management was adopted. The most prescribed oral antibiotics included cephalexin, co-amoxiclav, and trimethoprim. Parenteral antibiotics included ceftriaxone, cefotaxime, gentamicin, amoxicillin, cefuroxime, and co-amoxiclav. All study drugs were stored, prescribed, and dispensed according to local site procedures and manufacturer recommendations. No additional labelling or accountability measures were required beyond standard practice. Antibiotic administration followed local prescription schedules. Treatment could be modified or discontinued based on clinical assessment or urine culture results. Adherence was monitored through inpatient prescription records and verbal reports from parents/guardians at follow-up. Use of concomitant medications, including antipyretics, was permitted and recorded. The EASY trial was designed to evaluate the clinical effectiveness and cost consequences of oral versus parenteral antibiotics in febrile infants with suspected UTI. The primary clinical outcome of the full trial was the requirement for additional parenteral antibiotics within seven days of randomisation. A range of secondary outcomes were also planned, including requirement for additional parenteral antibiotics at day 28, time to recovery, adverse events, antibiotic adherence, quality of life, family impact, escalation of care at day 7 and day 28, length of stay and healthcare resource use. The primary objective of the internal pilot was to assess feasibility, specifically the ability to recruit eligible participants to support progression to a full-scale trial. Feasibility outcomes included: Number of sites opened during the pilot phase Recruitment rate per site per month Total number of participants recruited Screening and consent process performance Adherence to randomisation procedures These metrics were evaluated against predefined stop-go criteria to determine whether continuation to the main trial was justified. The criteria were as follows: The EASY trial was powered to detect non-inferiority in treatment failure rates between oral and parenteral antibiotics. Assuming a treatment failure rate of 0.5% and a non-inferiority margin of 2%, a total of 524 participants were required to achieve 90% power with a one-sided 97.5% confidence interval. Allowing for up to 10% loss to follow-up, the final sample size was set at 584 participants. The internal pilot phase was designed to recruit 99 participants, representing approximately 17% of the total sample size. This pilot was conducted to assess feasibility, including recruitment rates, site activation, and protocol adherence, rather than to evaluate clinical outcomes. As this manuscript focuses on the internal pilot phase, analyses were limited to descriptive statistics to assess feasibility. Recruitment rates, site activation, and protocol adherence were summarised and compared against predefined stop-go thresholds. No formal hypothesis testing or clinical outcome comparisons were conducted. The full trial included intention-to-treat and per-protocol analyses to evaluate non-inferiority in treatment failure rates, alongside secondary clinical and health economic outcomes. A total of 27 participants were recruited during the internal pilot (20 May 2024 to 13 March 2025) from 10 UK sites, representing 27% of the target sample size for the pilot (n=99). Of these, 14 (52%) were randomised to receive oral antibiotics and 13 (48%) to receive intravenous (IV) antibiotics. Following review of the internal pilot, the trial was terminated on 25 March 2025 due to poor recruitment. A flow diagram of recruitment is shown in Figure 1. Participants in both groups were similar in age (mean ~57 days) the IV group included a higher proportion of females. Most participants were of White ethnicity, with limited representation from Asian, Black, and mixed ethnic backgrounds. Gestational age at birth was predominantly 39–40 weeks. Vital signs and physical examination findings were broadly comparable across randomised groups, with minor differences in heart rate and respiratory rate. Urinalysis showed high positivity for leucocytes in both groups. Table 1 summarises the baseline characteristics. Common presenting symptoms included decreased feeding and abnormal activity, which were more frequently reported in the oral group. Vomiting and diarrhoea were similarly distributed across both randomised groups. Blood results showed comparable inflammatory markers and electrolyte levels, although the IV group had slightly higher haemoglobin and platelet counts. Most participants received parenteral antibiotics prior to randomisation. These data are shown in Table 2. Following randomisation, oral antibiotics were predominantly cefalexin (93%) and co-amoxiclav (7%), while IV antibiotics included amoxicillin, cefotaxime, or ceftriaxone (or combination of). Antibiotic treatment was discontinued before completion of the initially prescribed course in 43% of the oral group and 50% of the IV group, primarily due to negative urine culture results. Despite early discontinuation, adherence to prescribed doses was 100% in both groups. Table 3 summarises antibiotic administration and adherence. Most participants completed the study as per protocol (86% oral, 92% IV). Protocol deviations occurred in both groups, with 11 events in the oral group and 7 in the IV group. The most common deviations were related to follow-up outside the scheduled timeline. No deviations were reported for consent procedures. Treatment failure, defined as the need for additional parenteral antibiotics within seven days of randomisation, occurred in 3/14 (21.4%) participants in the oral group and 1/13 (7.7%) in the IV group. At day 28, no additional treatment failures were observed. No escalation in care; such as hospital admission, ICU transfer, change in antibiotic therapy, or death was reported in either group at day 7 or day 28. Time to defervescence was shorter in the oral group (mean 6.2 hours) compared to the IV group (mean 24.9 hours). Time to normal feeding and activity, as reported by parents, was slightly longer in the oral group, with high variability. Length of hospital stay was notably shorter in the oral group (mean 25.2 hours) compared to the IV group (mean 62.1hours). Clinical outcomes are summarised in Table 4. Adverse events (AEs) were more frequent in the IV group (9 events observed in 5 patients) than in the oral group (3 events in 2 patients). Adverse reactions (ARs) and unexpected adverse reactions (UARs) were reported only in the IV group, 7 and 3 events respectively. Serious adverse events (SAEs) occurred in 1 patient in the oral group and 2 in the IV group. No serious adverse reactions (SARs) or serious unexpected adverse reactions (SUSARs) were reported. Gastrointestinal disorders, renal and urinary tract infections, and skin disorders were the most reported AEs, with higher incidence in the IV group. ARs and UARs were exclusive to the IV group, primarily involving gastrointestinal and skin-related symptoms. Table 5 summarises the safety outcomes. From initial presentation at the ED to hospital discharge, participants in the oral intervention group experienced shorter overall hospital stays, with a mean duration of 25.2 hours (SD 19.7) compared to a 62.1 hours (SD 46.1) in the IV group (mean 62.1) (Table 4). Inpatient admission rates were lower in the oral group (78.6%) versus IV (100%), with shorter inpatient durations (26.6 vs. 58.2 hours). Parents in the oral group reported less time missed from work (mean per participant 1.7 hours; 95% CI: -2.6–6.0) compared to the IV group (25.5 hours; 95% CI: -11.2–62.2). Time missed from usual activities was also lower in the oral group (30.0 hours; 95% CI -14.9 - 74.9) vs. 49.0 hours; 95% CI -71.8, 169.8). The EASY trial was designed to assess the clinical and cost-effectiveness of oral versus IV antibiotics for febrile UTI amongst low-risk febrile infants. However, the trial was terminated following the internal pilot phase due to poor recruitment. While the internal pilot successfully demonstrated protocol adherence and safety across both treatment arms, several feasibility challenges emerged. Recruitment during the EASY trial was significantly slower than anticipated, with only 27 participants enrolled across 10 sites during the internal pilot phase, well below the target of 99. This shortfall may reflect a lower-than-expected incidence of UTIs in the eligible population or a reluctance among paediatricians to randomise infants to oral therapy. Anecdotal feedback from sites suggests that clinicians often favoured IV antibiotics due to concerns about missing cases of bacteraemia, despite the study’s stringent low-risk inclusion criteria. Indeed, two cases of bacteraemia were identified, one in each treatment group. Both these infants had an uncomplicated clinical course, with no escalation in care, supporting the safety of the trial protocol. Notably, no cases of meningitis were observed, further validating the risk stratification approach used to identify suitable candidates for oral therapy. These challenges are common to many randomised trials that are terminated early due to poor recruitment24. A systematic review of 172 randomised trials found that the most common reasons for trial closure included an over estimation of disease prevalence and ‘prejudiced views of recruiters’ both of which affected the EASY pilot25. Although recruitment was limited, preliminary findings suggest oral antibiotics may offer some benefits. Infants in the oral group tended to have shorter hospital stays and fewer inpatient admissions, with parents reporting less disruption to work and daily activities, although statistical significance testing was not undertaken on the data. These trends warrant further investigation in adequately powered studies. These findings align with previous trials demonstrating comparable clinical outcomes between oral and IV antibiotics in this population20,21. However, recruitment data from the internal pilot phase indicate that continuing the trial would have been futile under the current design. The combination of slow recruitment, high exclusion rates, and clinician hesitancy indicates that substantial modifications would be required to achieve adequate sample sizes. Proposed adjustments such as increasing the non-inferiority margin and reducing the recruitment target may improve feasibility but risk undermining the trial’s statistical robustness and generalisability. The internal pilot phase of the EASY trial has several limitations that should be acknowledged. First, the absence of an embedded qualitative or perspectives study limited our ability to fully explore and understand the barriers to recruitment. While anecdotal feedback from sites suggested clinician hesitancy and a preference for intravenous treatment, a formal evaluation of stakeholder views including those of parents and healthcare professionals would have provided valuable insights to inform future trial design and implementation strategies. Second, the internal pilot study is underpowered to detect differences in clinical outcomes between the treatment groups. With only 27 participants recruited, the sample size was insufficient to draw definitive conclusions regarding treatment failure, safety, or efficacy. As such, any observed differences should be interpreted with caution. This internal pilot phase of the EASY study demonstrated that while protocol adherence and safety were achievable, significant recruitment challenges driven by low disease prevalence and clinician reluctance made continuing the trial futile. These barriers, commonly reported in trials terminated early, underscore the importance of understanding recruiter perceptions and trial context. Future research should consider alternative designs or implementation strategies to evaluate oral antibiotic therapy in this population. This study received ethical approval from the South Central – Hampshire A Research Ethics Committee on December 22, 2023 (Reference: 23/SC/0426). Due to the small sample size, the dataset cannot be effectively deidentified. As required by the research ethics committee, data, with personal identifiers removed can only be made available upon receipt of a reasonable request to the corresponding author ([email protected]). Additional files related to this study are available at: https://doi.org/10.1186/ISRCTN10907780 Zenodo: The CONSORT checklist for ‘Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY)’. https://doi.org/10.5281/zenodo.1727987926. Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Faculty Opinions recommendedReferences - 1. Waterfield T, Lyttle MD, Munday C, et al.: Validating Clinical Practice Guidelines for the management of febrile infants presenting to the emergency department in the UK and Ireland. Arch Dis Child. 2022; 107(4): 329–334. PubMed Abstract | Publisher Full Text - 2. Pantell RH, Roberts KB, Adams WG, et al.: Evaluation and management of well-appearing febrile infants 8 to 60 days old. Pediatrics. 2021; 148(2): e2021052228. PubMed Abstract | Publisher Full Text - 3. 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Tosif S, Baker A, Oakley E, et al.: Contamination rates of different urine collection methods for the diagnosis of Urinary Tract Infections in young children: an observational cohort study. J Paediatr Child Health. 2012; 48(8): 659–64. PubMed Abstract | Publisher Full Text - 12. Tzimenatos L, Mahajan P, Dayan PS, et al.: Accuracy of the urinalysis for Urinary Tract Infections in febrile infants 60 days and younger. Pediatrics. 2018; 141(2): e20173068. PubMed Abstract | Publisher Full Text | Free Full Text - 13. Fever in under 5s: assessment and initial management. NICE clinical guideline [NG143]. Published: 07 November 2019; Last updated: 26 November 2021. Reference Source - 14. Infant < 90 days of age with fever and no source pathway for children presenting to hospital from the community. British Society for Antimicrobial Chemotherapy (BSAC). Published 2021. Reference Source - 15. Urinary Tract Infection in under 16s: diagnosis and management. NICE clinical guideline [CG54]. Published: 22 August 2007; Last updated: 31 October 2018. Reference Source - 16. Pyelonephritis (acute): antimicrobial prescribing. NICE guideline [NG111]. Published: 31 October 2018. Reference Source - 17. Cave D: Can oral antibiotics be used to treat Urinary Tract Infections in infants aged 2–3 months? Arch Dis Child. 2021; 106(11): 1135–1138. PubMed Abstract | Publisher Full Text - 18. Strohmeier Y, Hodson EM, Willis NS, et al.: Antibiotics for acute pyelonephritis in children. Cochrane Database Syst Rev. 2014; 2014(7): CD003772. PubMed Abstract | Publisher Full Text | Free Full Text - 19. Bocquet N, Sergent Alaoui A, Jais JP, et al.: Randomized trial of oral versus sequential IV/oral antibiotic for acute pyelonephritis in children. Pediatrics. 2012; 129(2): e269–75. PubMed Abstract | Publisher Full Text - 20. Hoberman A, Wald ER, Hickey RW, et al.: Oral versus initial intravenous therapy for Urinary Tract Infections in young febrile children. Pediatrics. 1999; 104(1 Pt 1): 79–86. PubMed Abstract | Publisher Full Text - 21. Montini G, Toffolo A, Zucchetta P, et al.: Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial. BMJ. 2007; 335(7616): 386. PubMed Abstract | Publisher Full Text | Free Full Text - 22. Leigh S, Grant A, Murray N, et al.: The cost of diagnostic uncertainty: a prospective economic analysis of febrile children attending an NHS Emergency Department. BMC Med. 2019; 17(1): 48. PubMed Abstract | Publisher Full Text | Free Full Text - 23. Buettcher M, Trueck J, Niederer-Loher A, et al.: Swiss consensus recommendations on Urinary Tract Infections in children. Eur J Pediatr. 2021; 180(3): 663–674. PubMed Abstract | Publisher Full Text | Free Full Text - 24. Briel M, von Elm E, Elger B, et al.: Understanding the mechanisms of trial discontinuation due to poor recruitment: interviews with stakeholders in clinical trials. Cochrane Global Evidence Summit; Cape Town, South Africa, September, 2017. Reference Source - 25. Rooshenas L, Paramasivan S, Jepson M, et al.: Perceived barriers and facilitators of staff recruiting participants to clinical trials: a qualitative evidence synthesis. Trials. 2024; 25: 86. - 26. EASY Trial Team: EASY Trail - consort checklist. Zenodo. 2025. https://zenodo.org/records/17279880 Author details Author details 1 Queen's University Belfast, Belfast, Northern Ireland, UK 2 HCS Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK 3 Perth Children's Hospital Foundation, Perth, Western Australia, Australia 4 Children's Emergency Department, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK 5 University of Liverpool Department of Public Health Policy and Systems, Liverpool, England, UK 6 University Hospital Southampton NHS Foundation Trust, Southampton, England, UK 7 Great Ormond Street Hospital Children's Charity, London, England, UK 8 Oxford University Hospitals NHS Foundation Trust, Oxford, England, UK 9 Northern Ireland Clinical Trials Unit, Belfast, UK 2 HCS Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK 3 Perth Children's Hospital Foundation, Perth, Western Australia, Australia 4 Children's Emergency Department, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK 5 University of Liverpool Department of Public Health Policy and Systems, Liverpool, England, UK 6 University Hospital Southampton NHS Foundation Trust, Southampton, England, UK 7 Great Ormond Street Hospital Children's Charity, London, England, UK 8 Oxford University Hospitals NHS Foundation Trust, Oxford, England, UK 9 Northern Ireland Clinical Trials Unit, Belfast, UK Thomas Waterfield Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Ronan McMullan Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Mark D Lyttle Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Stuart Hartshorn Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Kerry Woolfall Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Sanjay Patel Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Wesley Hayes Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Andrew Marshall Roles: Methodology, Writing – Review & Editing Roles: Methodology, Writing – Review & Editing Kathryn Ferris Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Ashley Agus Roles: Data Curation, Formal Analysis, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Data Curation, Formal Analysis, Funding Acquisition, Methodology, Writing – Review & Editing Christina Campbell Roles: Data Curation, Formal Analysis, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Data Curation, Formal Analysis, Funding Acquisition, Methodology, Writing – Review & Editing Rachael Rice Roles: Project Administration, Resources, Supervision Roles: Project Administration, Resources, Supervision Andrew Jackson Roles: Investigation, Project Administration, Resources, Supervision, Writing – Review & Editing Roles: Investigation, Project Administration, Resources, Supervision, Writing – Review & Editing Lynn Murphy Roles: Funding Acquisition, Methodology, Project Administration, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Project Administration, Writing – Review & Editing Mike Clarke Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This project is funded by the National Institute for Health Research (NIHR) under its Health Technology Assessment Programme (Grant Reference Number NIHR152733)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) Copyright © Crown copyright, 2026 Waterfield T et al.. This open access work is licensed under the Open Government Licence v3.0 metrics VIEWS $counts.viewCount downloads Citations CITE how to cite this article Waterfield T, McMullan R, Lyttle MD et al. Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.14103.2) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. track receive updates on this article Track an article to receive email alerts on any updates to this article. Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 12 Feb 2026 Revised Views 0 How to cite this report: Tse Y. Reviewer Report For: Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.15492.r39603) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-104/v2#referee-response-39603 https://openresearch.nihr.ac.uk/articles/5-104/v2#referee-response-39603 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 10 Mar 2026 Approved with Reservations VIEWS 0 Thank you for asking me to review this randomised control study testing non-inferiority between standard treatment (IV antibiotics) with the intervention arm being oral antibiotics in a population which is traditionally felt to be more vulnerable for non-response and developing ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close Thank you for asking me to review this randomised control study testing non-inferiority between standard treatment (IV antibiotics) with the intervention arm being oral antibiotics in a population which is traditionally felt to be more vulnerable for non-response and developing sepsis, or not being able to reliably take oral antibiotics hence the dogma has always been IV antibiotics. The study reflected a real-life dilemma of a baby who does not look too ill with a possible urine infection. It was well designed and well written up having been through two peer reviewers and one revision already. Unfortunately, due to insufficient recruitment the trial could not proceed through the internal pilot so was terminated – this should be reflected in the title. Main points for revision are to make it clearer to the reader what was done to the infants in each arm – for example until one reads the paper in detail it is unclear that one dose of IV antibiotics has already been given before randomisation. Also, as trial was terminated before the pilot was completed, the positive findings need to be made much more cautious as readers may read them as definitive. For example, shorter hospital stays and admission rates. They need to reinforce throughout that no clinical inferences should be drawn. Other specific comments Title

Background

Discussion In summary, the authors made a noble attempt at answering this important real life dilemma. It is important to report negative trials, and they present important transparent data to help future trials succeed. It is well written with excellent description of methods. There is a need to reinforce throughout that no clinical inferences should be drawn to any results positive or otherwise. The study reflected a real-life dilemma of a baby who does not look too ill with a possible urine infection. It was well designed and well written up having been through two peer reviewers and one revision already. Unfortunately, due to insufficient recruitment the trial could not proceed through the internal pilot so was terminated – this should be reflected in the title. Main points for revision are to make it clearer to the reader what was done to the infants in each arm – for example until one reads the paper in detail it is unclear that one dose of IV antibiotics has already been given before randomisation. Also, as trial was terminated before the pilot was completed, the positive findings need to be made much more cautious as readers may read them as definitive. For example, shorter hospital stays and admission rates. They need to reinforce throughout that no clinical inferences should be drawn. Other specific comments Title - Should reflect that this was a pilot

- Participants should be ‘known structural renal abnormalities’ - First line of result should state early termination due to insufficient recruitment. When I first read the abstract, I was confused why only 27 patients recruited and the light bulb moment only pinged when I read the conclusion twice. - Intervention should state infants were started on IV antibiotics then randomised within 24 hours to either arm

- Rationale well described

- PPI need to be put into abbreviations at first mention. Would exclude children and young people as PPI as they are not the patient group (infants) - parents rightly are. - Summary of key protocol amendments should go at the end of methods for better flow – readers have not read this paper before.

- Although pilot data, the much higher adverse events and adverse reaction in the IV arm should be bought to attention to the readers, and make a compelling case to try a similar study again but with an easier recruitment design. In summary, the authors made a noble attempt at answering this important real life dilemma. It is important to report negative trials, and they present important transparent data to help future trials succeed. It is well written with excellent description of methods. There is a need to reinforce throughout that no clinical inferences should be drawn to any results positive or otherwise. - Is the work clearly and accurately presented and does it cite the current literature? Partly - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Partly - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Paediatric nephrology, Childhood urinary tract infection, Medication safety in children CITE HOW TO CITE THIS REPORT Tse Y. Reviewer Report For: Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.15492.r39603) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-104/v2#referee-response-39603 https://openresearch.nihr.ac.uk/articles/5-104/v2#referee-response-39603 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Ghssein G. Reviewer Report For: Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.15492.r39506) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-104/v2#referee-response-39506 https://openresearch.nihr.ac.uk/articles/5-104/v2#referee-response-39506 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 20 Feb 2026 Ghassan Ghssein, Lebanese University, Beirut, Lebanon Approved VIEWS 0 Dear Authors, The revised version of your paper entitled "Empirical oral Antibiotics for possible UTI in well appearing Young febrile infants (EASY)" has been carefully reviewed. I would like to thank you for your responses. I think ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close The revised version of your paper entitled "Empirical oral Antibiotics for possible UTI in well appearing Young febrile infants (EASY)" has been carefully reviewed. I would like to thank you for your responses. I think ... Continue reading Dear Authors, The revised version of your paper entitled "Empirical oral Antibiotics for possible UTI in well appearing Young febrile infants (EASY)" has been carefully reviewed. I would like to thank you for your responses. I think that this paper is suitable for indexing in its present form. Best Regards, The revised version of your paper entitled "Empirical oral Antibiotics for possible UTI in well appearing Young febrile infants (EASY)" has been carefully reviewed. I would like to thank you for your responses. I think that this paper is suitable for indexing in its present form. Best Regards, Competing Interests: No competing interests were disclosed. Reviewer Expertise: Clinical Epidemiology, Infectious Diseases, Microbiology, Bacteriology, Bacterial Metallophores, Antimicrobial Resistance CITE HOW TO CITE THIS REPORT Ghssein G. Reviewer Report For: Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.15492.r39506) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-104/v2#referee-response-39506 https://openresearch.nihr.ac.uk/articles/5-104/v2#referee-response-39506 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Version 1 VERSION 1 PUBLISHED 17 Oct 2025 Views 0 How to cite this report: Iio K. Reviewer Report For: Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.15336.r38903) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-104/v1#referee-response-38903 https://openresearch.nihr.ac.uk/articles/5-104/v1#referee-response-38903 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 20 Jan 2026 Approved VIEWS 0 The EASY trial was a randomized controlled trial aimed at evaluating the non-inferiority of oral antibiotics compared with parenteral antibiotics for urinary tract infections (UTIs) in infants aged 29–90 days. The present manuscript focuses on the internal pilot phase of ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close The EASY trial was a randomized controlled trial aimed at evaluating the non-inferiority of oral antibiotics compared with parenteral antibiotics for urinary tract infections (UTIs) in infants aged 29–90 days. The present manuscript focuses on the internal pilot phase of the study, which ultimately led to termination of the RCT due to difficulties in participant recruitment. Overall, the trial methodology was well structured and robust, without any critical flaws that would compromise the validity of the results. I would like to offer several minor comments and suggestions for each section.

I recommend revising the final paragraph of this section, as there are discrepancies among existing recommendations regarding the use of oral antibiotics in the population studied in this trial. For example, the Swiss consensus recommendations (reference 23) suggest parenteral rather than oral antibiotics in children under 60 days of age, whereas the AAP guideline (reference 2) recommends oral antibiotics in children older than 28 days. I assume that these controversies are a key motivation for conducting this RCT; therefore, it would be helpful to explicitly state that there is ongoing debate on this topic.

Among the inclusion criteria, I am slightly concerned about the inclusion of patients with “subjective” fever, as previous literature suggests that parent-perceived body temperature elevation has low specificity for predicting actual fever. I recommend that the authors report the proportion of patients included based solely on subjective fever reported by parents.

1: (Teng C. et al., 2008) In addition, the method of urine collection should be clearly described; I assume urethral catheterization was used in this age group. Finally, treatment failure at day 28 is listed as a secondary outcome. Could the authors clarify how this outcome was defined? For example, does this refer to recurrence of fever or UTI within 28 days after completion of antibiotic therapy? Overall, the trial methodology was well structured and robust, without any critical flaws that would compromise the validity of the results. I would like to offer several minor comments and suggestions for each section.

I recommend revising the final paragraph of this section, as there are discrepancies among existing recommendations regarding the use of oral antibiotics in the population studied in this trial. For example, the Swiss consensus recommendations (reference 23) suggest parenteral rather than oral antibiotics in children under 60 days of age, whereas the AAP guideline (reference 2) recommends oral antibiotics in children older than 28 days. I assume that these controversies are a key motivation for conducting this RCT; therefore, it would be helpful to explicitly state that there is ongoing debate on this topic.

Among the inclusion criteria, I am slightly concerned about the inclusion of patients with “subjective” fever, as previous literature suggests that parent-perceived body temperature elevation has low specificity for predicting actual fever. I recommend that the authors report the proportion of patients included based solely on subjective fever reported by parents.

1: (Teng C. et al., 2008) In addition, the method of urine collection should be clearly described; I assume urethral catheterization was used in this age group. Finally, treatment failure at day 28 is listed as a secondary outcome. Could the authors clarify how this outcome was defined? For example, does this refer to recurrence of fever or UTI within 28 days after completion of antibiotic therapy? - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Yes - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes

1. Teng C, Ng C, Nik-Sherina H, Zailinawati A, et al.: The Accuracy of Mother's Touch to Detect Fever in Children: A Systematic Review. Journal of Tropical Pediatrics. 2007; 54 (1): 70-73 Publisher Full TextCompeting Interests: No competing interests were disclosed. Reviewer Expertise: I have experience in several observational studies of febrile illnesses in childhood, including Kawasaki disease and urinary tract infections. CITE HOW TO CITE THIS REPORT Iio K. Reviewer Report For: Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.15336.r38903) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-104/v1#referee-response-38903 https://openresearch.nihr.ac.uk/articles/5-104/v1#referee-response-38903 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 12 Feb 2026Thomas Waterfield, Queen's University Belfast, Belfast, UK12 Feb 2026Author ResponseResponse to Reviewer We thank the reviewer for their thoughtful and constructive comments, which have helped improve the clarity and interpretation of the manuscript. We have addressed each point ... Continue reading Response to Reviewer We thank the reviewer for their thoughtful and constructive comments, which have helped improve the clarity and interpretation of the manuscript. We have addressed each point below. Comment 1: Discrepancies in guideline recommendations for oral antibiotics Reviewer comment: I recommend revising the final paragraph of this section, as there are discrepancies among existing recommendations regarding the use of oral antibiotics in the population studied in this trial… Response: We thank the reviewer for highlighting this important point. We have revised the final paragraph to explicitly acknowledge ongoing international variation in recommendations regarding the route of antibiotic administration in young infants with suspected UTI. The amended text now contrasts American Academy of Pediatrics guidance, which supports oral antibiotic treatment in infants older than 28 days, with Swiss consensus recommendations, which advise oral therapy only in infants over 60 days of age. We now explicitly state that this lack of consensus represents a key motivation for conducting this randomised controlled trial (references 2, 23, 24). Comment 2: Inclusion of infants with parent-reported (subjective) fever Reviewer comment: Among the inclusion criteria, I am slightly concerned about the inclusion of patients with “subjective” fever… Response: We agree that this is a reasonable concern. While parent-reported fever has lower specificity for measured fever, existing literature in febrile infants suggests that caregiver-reported fever is nevertheless associated with both documented fever and invasive bacterial infection, particularly in younger infants. Inclusion of infants with a history of fever therefore reflects real-world clinical decision-making at the point of presentation. Furthermore NICE in the UK advises that caregiver reports of subjective fever are taken seriously. Reporting the proportion of participants included solely on the basis of subjective fever would indeed have been informative, and a sensitivity analysis excluding these infants was planned for the definitive trial. However, following early termination of the study after the pilot phase, the sample size was insufficient to support a meaningful sensitivity analysis. Comment 3: Method of urine collection Reviewer comment: In addition, the method of urine collection should be clearly described; I assume urethral catheterization was used in this age group. Response: Thank you for this comment. In contrast to some international guidance, UK NICE recommendations advise against routine invasive urine sampling in young children, and in UK practice the majority of urine samples are obtained using non-invasive clean-catch methods where feasible. Given the pragmatic, multicentre design of this trial, sites were permitted to collect urine according to local clinical policy and the treating clinician’s judgement. Mandating a single method of urine collection was not considered pragmatic or reflective of real-world UK practice. The method of urine collection was recorded on the case report form, and this has now been clarified in the Trial Interventions section. Comment 4: Definition of treatment failure at day 28 Reviewer comment: Finally, treatment failure at day 28 is listed as a secondary outcome. Could the authors clarify how this outcome was defined? Response: Thank you for highlighting this potential ambiguity. Treatment failure at day 28 was defined using the same criteria as the primary outcome at day 7, namely the requirement for additional parenteral antibiotic therapy, but assessed at a later time point. To avoid ambiguity, we have revised the manuscript to explicitly define the day-28 secondary outcome as “requirement for additional parenteral antibiotics” rather than using the term treatment failure.Response to ReviewerCompeting Interests: None Close We thank the reviewer for their thoughtful and constructive comments, which have helped improve the clarity and interpretation of the manuscript. We have addressed each point below. Comment 1: Discrepancies in guideline recommendations for oral antibiotics Reviewer comment: I recommend revising the final paragraph of this section, as there are discrepancies among existing recommendations regarding the use of oral antibiotics in the population studied in this trial… Response: We thank the reviewer for highlighting this important point. We have revised the final paragraph to explicitly acknowledge ongoing international variation in recommendations regarding the route of antibiotic administration in young infants with suspected UTI. The amended text now contrasts American Academy of Pediatrics guidance, which supports oral antibiotic treatment in infants older than 28 days, with Swiss consensus recommendations, which advise oral therapy only in infants over 60 days of age. We now explicitly state that this lack of consensus represents a key motivation for conducting this randomised controlled trial (references 2, 23, 24). Comment 2: Inclusion of infants with parent-reported (subjective) fever Reviewer comment: Among the inclusion criteria, I am slightly concerned about the inclusion of patients with “subjective” fever… Response: We agree that this is a reasonable concern. While parent-reported fever has lower specificity for measured fever, existing literature in febrile infants suggests that caregiver-reported fever is nevertheless associated with both documented fever and invasive bacterial infection, particularly in younger infants. Inclusion of infants with a history of fever therefore reflects real-world clinical decision-making at the point of presentation. Furthermore NICE in the UK advises that caregiver reports of subjective fever are taken seriously. Reporting the proportion of participants included solely on the basis of subjective fever would indeed have been informative, and a sensitivity analysis excluding these infants was planned for the definitive trial. However, following early termination of the study after the pilot phase, the sample size was insufficient to support a meaningful sensitivity analysis. Comment 3: Method of urine collection Reviewer comment: In addition, the method of urine collection should be clearly described; I assume urethral catheterization was used in this age group. Response: Thank you for this comment. In contrast to some international guidance, UK NICE recommendations advise against routine invasive urine sampling in young children, and in UK practice the majority of urine samples are obtained using non-invasive clean-catch methods where feasible. Given the pragmatic, multicentre design of this trial, sites were permitted to collect urine according to local clinical policy and the treating clinician’s judgement. Mandating a single method of urine collection was not considered pragmatic or reflective of real-world UK practice. The method of urine collection was recorded on the case report form, and this has now been clarified in the Trial Interventions section. Comment 4: Definition of treatment failure at day 28 Reviewer comment: Finally, treatment failure at day 28 is listed as a secondary outcome. Could the authors clarify how this outcome was defined? Response: Thank you for highlighting this potential ambiguity. Treatment failure at day 28 was defined using the same criteria as the primary outcome at day 7, namely the requirement for additional parenteral antibiotic therapy, but assessed at a later time point. To avoid ambiguity, we have revised the manuscript to explicitly define the day-28 secondary outcome as “requirement for additional parenteral antibiotics” rather than using the term treatment failure. COMMENTS ON THIS REPORT - Author Response 12 Feb 2026Thomas Waterfield, Queen's University Belfast, Belfast, UK12 Feb 2026Author ResponseResponse to Reviewer We thank the reviewer for their thoughtful and constructive comments, which have helped improve the clarity and interpretation of the manuscript. We have addressed each point ... Continue reading Response to Reviewer We thank the reviewer for their thoughtful and constructive comments, which have helped improve the clarity and interpretation of the manuscript. We have addressed each point below. Comment 1: Discrepancies in guideline recommendations for oral antibiotics Reviewer comment: I recommend revising the final paragraph of this section, as there are discrepancies among existing recommendations regarding the use of oral antibiotics in the population studied in this trial… Response: We thank the reviewer for highlighting this important point. We have revised the final paragraph to explicitly acknowledge ongoing international variation in recommendations regarding the route of antibiotic administration in young infants with suspected UTI. The amended text now contrasts American Academy of Pediatrics guidance, which supports oral antibiotic treatment in infants older than 28 days, with Swiss consensus recommendations, which advise oral therapy only in infants over 60 days of age. We now explicitly state that this lack of consensus represents a key motivation for conducting this randomised controlled trial (references 2, 23, 24). Comment 2: Inclusion of infants with parent-reported (subjective) fever Reviewer comment: Among the inclusion criteria, I am slightly concerned about the inclusion of patients with “subjective” fever… Response: We agree that this is a reasonable concern. While parent-reported fever has lower specificity for measured fever, existing literature in febrile infants suggests that caregiver-reported fever is nevertheless associated with both documented fever and invasive bacterial infection, particularly in younger infants. Inclusion of infants with a history of fever therefore reflects real-world clinical decision-making at the point of presentation. Furthermore NICE in the UK advises that caregiver reports of subjective fever are taken seriously. Reporting the proportion of participants included solely on the basis of subjective fever would indeed have been informative, and a sensitivity analysis excluding these infants was planned for the definitive trial. However, following early termination of the study after the pilot phase, the sample size was insufficient to support a meaningful sensitivity analysis. Comment 3: Method of urine collection Reviewer comment: In addition, the method of urine collection should be clearly described; I assume urethral catheterization was used in this age group. Response: Thank you for this comment. In contrast to some international guidance, UK NICE recommendations advise against routine invasive urine sampling in young children, and in UK practice the majority of urine samples are obtained using non-invasive clean-catch methods where feasible. Given the pragmatic, multicentre design of this trial, sites were permitted to collect urine according to local clinical policy and the treating clinician’s judgement. Mandating a single method of urine collection was not considered pragmatic or reflective of real-world UK practice. The method of urine collection was recorded on the case report form, and this has now been clarified in the Trial Interventions section. Comment 4: Definition of treatment failure at day 28 Reviewer comment: Finally, treatment failure at day 28 is listed as a secondary outcome. Could the authors clarify how this outcome was defined? Response: Thank you for highlighting this potential ambiguity. Treatment failure at day 28 was defined using the same criteria as the primary outcome at day 7, namely the requirement for additional parenteral antibiotic therapy, but assessed at a later time point. To avoid ambiguity, we have revised the manuscript to explicitly define the day-28 secondary outcome as “requirement for additional parenteral antibiotics” rather than using the term treatment failure.Response to ReviewerCompeting Interests: None Close We thank the reviewer for their thoughtful and constructive comments, which have helped improve the clarity and interpretation of the manuscript. We have addressed each point below. Comment 1: Discrepancies in guideline recommendations for oral antibiotics Reviewer comment: I recommend revising the final paragraph of this section, as there are discrepancies among existing recommendations regarding the use of oral antibiotics in the population studied in this trial… Response: We thank the reviewer for highlighting this important point. We have revised the final paragraph to explicitly acknowledge ongoing international variation in recommendations regarding the route of antibiotic administration in young infants with suspected UTI. The amended text now contrasts American Academy of Pediatrics guidance, which supports oral antibiotic treatment in infants older than 28 days, with Swiss consensus recommendations, which advise oral therapy only in infants over 60 days of age. We now explicitly state that this lack of consensus represents a key motivation for conducting this randomised controlled trial (references 2, 23, 24). Comment 2: Inclusion of infants with parent-reported (subjective) fever Reviewer comment: Among the inclusion criteria, I am slightly concerned about the inclusion of patients with “subjective” fever… Response: We agree that this is a reasonable concern. While parent-reported fever has lower specificity for measured fever, existing literature in febrile infants suggests that caregiver-reported fever is nevertheless associated with both documented fever and invasive bacterial infection, particularly in younger infants. Inclusion of infants with a history of fever therefore reflects real-world clinical decision-making at the point of presentation. Furthermore NICE in the UK advises that caregiver reports of subjective fever are taken seriously. Reporting the proportion of participants included solely on the basis of subjective fever would indeed have been informative, and a sensitivity analysis excluding these infants was planned for the definitive trial. However, following early termination of the study after the pilot phase, the sample size was insufficient to support a meaningful sensitivity analysis. Comment 3: Method of urine collection Reviewer comment: In addition, the method of urine collection should be clearly described; I assume urethral catheterization was used in this age group. Response: Thank you for this comment. In contrast to some international guidance, UK NICE recommendations advise against routine invasive urine sampling in young children, and in UK practice the majority of urine samples are obtained using non-invasive clean-catch methods where feasible. Given the pragmatic, multicentre design of this trial, sites were permitted to collect urine according to local clinical policy and the treating clinician’s judgement. Mandating a single method of urine collection was not considered pragmatic or reflective of real-world UK practice. The method of urine collection was recorded on the case report form, and this has now been clarified in the Trial Interventions section. Comment 4: Definition of treatment failure at day 28 Reviewer comment: Finally, treatment failure at day 28 is listed as a secondary outcome. Could the authors clarify how this outcome was defined? Response: Thank you for highlighting this potential ambiguity. Treatment failure at day 28 was defined using the same criteria as the primary outcome at day 7, namely the requirement for additional parenteral antibiotic therapy, but assessed at a later time point. To avoid ambiguity, we have revised the manuscript to explicitly define the day-28 secondary outcome as “requirement for additional parenteral antibiotics” rather than using the term treatment failure. Views 0 How to cite this report: Ghssein G. Reviewer Report For: Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.15336.r37956) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-104/v1#referee-response-37956 https://openresearch.nihr.ac.uk/articles/5-104/v1#referee-response-37956 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 12 Nov 2025 Ghassan Ghssein, Lebanese University, Beirut, Lebanon Not Approved VIEWS 0 Dear Authors, Your Manuscript entitled "Empirical oral Antibiotics for possible UTI in well appearing Young febrile infants (EASY)" has been carefully reviewed. This paper deserves attention since it highlights on a very important topic ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close Your Manuscript entitled "Empirical oral Antibiotics for possible UTI in well appearing Young febrile infants (EASY)" has been carefully reviewed. This paper deserves attention since it highlights on a very important topic ... Continue reading Dear Authors, Your Manuscript entitled "Empirical oral Antibiotics for possible UTI in well appearing Young febrile infants (EASY)" has been carefully reviewed. This paper deserves attention since it highlights on a very important topic from medical point of view, this paper compare the effect of Empirical Oral Antibiotics with the effect of normal IV Empirical Antibiotics that can be used for possible UTI in well appearing young febrile infants in the UK. The study shows a good potential ad advantages of using Oral ATB when compared to IV antibiotics in the participant patients. But we can not generalize these findings since the sample size of the study is very low 24 infants. So Authors suggest to work on a larger population in a future study before generalizing their findings. The Article is well written in English language, Tables are clear for readers, but the statistical analyses are poor and do not compare statistically the main results of the study. Kindly find below my list of comments regarding this work: 01- The Title of the Manuscript should be modified, Since it is just limited to 27 samples, I suggest to put "A Pilot Study" in the title. 02- In the abstract, section "setting" you mentioned the follow (Twenty one paediatric emergency departments and assessment units across the UK.) then in your Plain Language Summary, you mentioned the follow (Researchers ran a trial in 10 hospitals across the UK). Here the information is not clear, the study was done in 10 hospitals, in 21 pediatric emergency departments? Please make it more clear for readers. 03- In your Background section, first point (Urinary tract infections (UTIs) are the most common serious bacterial infection (SBI) in febrile infants, accounting for over 90% of all SBIs in this age group) You are using 7 references just for this point. I think it is a large number of references for a small idea. You are invited to remove some of these references. 04- In the Background section, when you are talking about clinical symptoms related to UTI in infant, I invite you to add Jaundice as possible symptom related to UTI in infant and newborns. You can refer to the following article for this point: -- Prevalence and Clinical Significance of Urinary Tract Infection among Neonates Presenting with Unexplained Hyperbilirubinemia in Lebanon: A Retrospective Study 05- When talking about the treatment for Infants suspected to have UTI, why the period of treatment was limited to 36-48 hours? This is not very clear in the manuscript. 06- Some information are not clear in your Figure 1 (CONSORT Diagram), you mention that you lost to follow up 2 infants in the first group (n=14), and you lost to follow up in 1 infant in the second group (n=13). But you mention below that you Analyzed (n=14) and (n=13) how can you explain this point? 07- When you are comparing results between the two groups, why you are not calculating the P-value to see if there is a significance for your results or not? 08- You sample size (n=27) is very small, it doesn't meat the minimum required number for a pilot study. So why are trying to publish these results? I suggest to make the result longer and work to recruit the number required for a Pilot Study which is 99 participants. 09- In your Materials and Methods section, you should more elaborate about the statistical tool, you used in this study. Best Regards Your Manuscript entitled "Empirical oral Antibiotics for possible UTI in well appearing Young febrile infants (EASY)" has been carefully reviewed. This paper deserves attention since it highlights on a very important topic from medical point of view, this paper compare the effect of Empirical Oral Antibiotics with the effect of normal IV Empirical Antibiotics that can be used for possible UTI in well appearing young febrile infants in the UK. The study shows a good potential ad advantages of using Oral ATB when compared to IV antibiotics in the participant patients. But we can not generalize these findings since the sample size of the study is very low 24 infants. So Authors suggest to work on a larger population in a future study before generalizing their findings. The Article is well written in English language, Tables are clear for readers, but the statistical analyses are poor and do not compare statistically the main results of the study. Kindly find below my list of comments regarding this work: 01- The Title of the Manuscript should be modified, Since it is just limited to 27 samples, I suggest to put "A Pilot Study" in the title. 02- In the abstract, section "setting" you mentioned the follow (Twenty one paediatric emergency departments and assessment units across the UK.) then in your Plain Language Summary, you mentioned the follow (Researchers ran a trial in 10 hospitals across the UK). Here the information is not clear, the study was done in 10 hospitals, in 21 pediatric emergency departments? Please make it more clear for readers. 03- In your Background section, first point (Urinary tract infections (UTIs) are the most common serious bacterial infection (SBI) in febrile infants, accounting for over 90% of all SBIs in this age group) You are using 7 references just for this point. I think it is a large number of references for a small idea. You are invited to remove some of these references. 04- In the Background section, when you are talking about clinical symptoms related to UTI in infant, I invite you to add Jaundice as possible symptom related to UTI in infant and newborns. You can refer to the following article for this point: -- Prevalence and Clinical Significance of Urinary Tract Infection among Neonates Presenting with Unexplained Hyperbilirubinemia in Lebanon: A Retrospective Study 05- When talking about the treatment for Infants suspected to have UTI, why the period of treatment was limited to 36-48 hours? This is not very clear in the manuscript. 06- Some information are not clear in your Figure 1 (CONSORT Diagram), you mention that you lost to follow up 2 infants in the first group (n=14), and you lost to follow up in 1 infant in the second group (n=13). But you mention below that you Analyzed (n=14) and (n=13) how can you explain this point? 07- When you are comparing results between the two groups, why you are not calculating the P-value to see if there is a significance for your results or not? 08- You sample size (n=27) is very small, it doesn't meat the minimum required number for a pilot study. So why are trying to publish these results? I suggest to make the result longer and work to recruit the number required for a Pilot Study which is 99 participants. 09- In your Materials and Methods section, you should more elaborate about the statistical tool, you used in this study. Best Regards - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Partly - Are sufficient details of methods and analysis provided to allow replication by others? Partly - If applicable, is the statistical analysis and its interpretation appropriate? No - Are all the source data underlying the results available to ensure full reproducibility? No source data required - Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Clinical Epidemiology, Infectious Diseases, Microbiology, Bacteriology, Bacterial Metallophores, Antimicrobial Resistance CITE HOW TO CITE THIS REPORT Ghssein G. Reviewer Report For: Empirical oral AntibioticS for possible UTI in well appearing Young febrile infants (EASY) [version 2; peer review: 2 approved, 1 approved with reservations]. NIHR Open Res 2026, 5:104 (https://doi.org/10.3310/nihropenres.15336.r37956) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-104/v1#referee-response-37956 https://openresearch.nihr.ac.uk/articles/5-104/v1#referee-response-37956 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 12 Feb 2026Thomas Waterfield, Queen's University Belfast, Belfast, UK12 Feb 2026Author ResponseComment 01: Thank you for your suggestion regarding the title. The EASY trial was not a pilot study; it was a full trial with an internal pilot phase, which ... Continue reading Comment 01: Thank you for your suggestion regarding the title. The EASY trial was not a pilot study; it was a full trial with an internal pilot phase, which was terminated early due to poor recruitment. Presenting it as a pilot study in the title would be inaccurate. Therefore, we will retain the current title. Comment 02: We appreciate your observation. To clarify: 21 sites were signed up to participate, but only 10 opened before the trial was closed due to poor recruitment. Comment 03: Thank you for your comment. We believe the current number of references is appropriate to support the statement. Comment 04: We appreciate your suggestion regarding jaundice and the reference provided. However, as this reference is authored by the reviewer, it would be inappropriate to add it at peer review. We will retain the current content. Comment 05: Thank you for raising this point. The 36–48 hour period refers only to the pre-culture phase when the trial stipulated either IV or oral antibiotics. This is already clear in the manuscript, so no changes are required. Comment 06: We appreciate your observation. The infants lost to follow-up were for secondary outcome measures only; all infants were followed up for primary outcome data. Comment 07: Thank you for your suggestion regarding P-values. The study was underpowered and therefore, formal hypothesis testing was not appropriate. The analysis is descriptive and observational, and this is already stated in the manuscript. Comment 08: We appreciate your concern about sample size. The trial was terminated early due to poor recruitment, and further recruitment is not possible. The purpose of publishing these findings is to highlight the challenges of conducting this type of research, inform future trial design, and provide data for meta-analyses. Publishing negative or terminated studies is important for transparency and scientific progress. We believe this rationale is clear in the manuscript. Comment 09: Thank you for your comment on statistical methods. The reviewer appears to view this as a definitive trial with adequate power, which is not the case. Due to the small sample size, formal statistical comparisons were not appropriate. This rationale is already explained in the manuscript.Comment 01:Competing Interests: No competing interests were disclosed. Close Thank you for your suggestion regarding the title. The EASY trial was not a pilot study; it was a full trial with an internal pilot phase, which was terminated early due to poor recruitment. Presenting it as a pilot study in the title would be inaccurate. Therefore, we will retain the current title. Comment 02: We appreciate your observation. To clarify: 21 sites were signed up to participate, but only 10 opened before the trial was closed due to poor recruitment. Comment 03: Thank you for your comment. We believe the current number of references is appropriate to support the statement. Comment 04: We appreciate your suggestion regarding jaundice and the reference provided. However, as this reference is authored by the reviewer, it would be inappropriate to add it at peer review. We will retain the current content. Comment 05: Thank you for raising this point. The 36–48 hour period refers only to the pre-culture phase when the trial stipulated either IV or oral antibiotics. This is already clear in the manuscript, so no changes are required. Comment 06: We appreciate your observation. The infants lost to follow-up were for secondary outcome measures only; all infants were followed up for primary outcome data. Comment 07: Thank you for your suggestion regarding P-values. The study was underpowered and therefore, formal hypothesis testing was not appropriate. The analysis is descriptive and observational, and this is already stated in the manuscript. Comment 08: We appreciate your concern about sample size. The trial was terminated early due to poor recruitment, and further recruitment is not possible. The purpose of publishing these findings is to highlight the challenges of conducting this type of research, inform future trial design, and provide data for meta-analyses. Publishing negative or terminated studies is important for transparency and scientific progress. We believe this rationale is clear in the manuscript. Comment 09: Thank you for your comment on statistical methods. The reviewer appears to view this as a definitive trial with adequate power, which is not the case. Due to the small sample size, formal statistical comparisons were not appropriate. This rationale is already explained in the manuscript. COMMENTS ON THIS REPORT - Author Response 12 Feb 2026Thomas Waterfield, Queen's University Belfast, Belfast, UK12 Feb 2026Author ResponseComment 01: Thank you for your suggestion regarding the title. The EASY trial was not a pilot study; it was a full trial with an internal pilot phase, which ... Continue reading Comment 01: Thank you for your suggestion regarding the title. The EASY trial was not a pilot study; it was a full trial with an internal pilot phase, which was terminated early due to poor recruitment. Presenting it as a pilot study in the title would be inaccurate. Therefore, we will retain the current title. Comment 02: We appreciate your observation. To clarify: 21 sites were signed up to participate, but only 10 opened before the trial was closed due to poor recruitment. Comment 03: Thank you for your comment. We believe the current number of references is appropriate to support the statement. Comment 04: We appreciate your suggestion regarding jaundice and the reference provided. However, as this reference is authored by the reviewer, it would be inappropriate to add it at peer review. We will retain the current content. Comment 05: Thank you for raising this point. The 36–48 hour period refers only to the pre-culture phase when the trial stipulated either IV or oral antibiotics. This is already clear in the manuscript, so no changes are required. Comment 06: We appreciate your observation. The infants lost to follow-up were for secondary outcome measures only; all infants were followed up for primary outcome data. Comment 07: Thank you for your suggestion regarding P-values. The study was underpowered and therefore, formal hypothesis testing was not appropriate. The analysis is descriptive and observational, and this is already stated in the manuscript. Comment 08: We appreciate your concern about sample size. The trial was terminated early due to poor recruitment, and further recruitment is not possible. The purpose of publishing these findings is to highlight the challenges of conducting this type of research, inform future trial design, and provide data for meta-analyses. Publishing negative or terminated studies is important for transparency and scientific progress. We believe this rationale is clear in the manuscript. Comment 09: Thank you for your comment on statistical methods. The reviewer appears to view this as a definitive trial with adequate power, which is not the case. Due to the small sample size, formal statistical comparisons were not appropriate. This rationale is already explained in the manuscript.Comment 01:Competing Interests: No competing interests were disclosed. Close Thank you for your suggestion regarding the title. The EASY trial was not a pilot study; it was a full trial with an internal pilot phase, which was terminated early due to poor recruitment. Presenting it as a pilot study in the title would be inaccurate. Therefore, we will retain the current title. Comment 02: We appreciate your observation. To clarify: 21 sites were signed up to participate, but only 10 opened before the trial was closed due to poor recruitment. Comment 03: Thank you for your comment. We believe the current number of references is appropriate to support the statement. Comment 04: We appreciate your suggestion regarding jaundice and the reference provided. However, as this reference is authored by the reviewer, it would be inappropriate to add it at peer review. We will retain the current content. Comment 05: Thank you for raising this point. The 36–48 hour period refers only to the pre-culture phase when the trial stipulated either IV or oral antibiotics. This is already clear in the manuscript, so no changes are required. Comment 06: We appreciate your observation. The infants lost to follow-up were for secondary outcome measures only; all infants were followed up for primary outcome data. Comment 07: Thank you for your suggestion regarding P-values. The study was underpowered and therefore, formal hypothesis testing was not appropriate. The analysis is descriptive and observational, and this is already stated in the manuscript. Comment 08: We appreciate your concern about sample size. The trial was terminated early due to poor recruitment, and further recruitment is not possible. The purpose of publishing these findings is to highlight the challenges of conducting this type of research, inform future trial design, and provide data for meta-analyses. Publishing negative or terminated studies is important for transparency and scientific progress. We believe this rationale is clear in the manuscript. Comment 09: Thank you for your comment on statistical methods. The reviewer appears to view this as a definitive trial with adequate power, which is not the case. Due to the small sample size, formal statistical comparisons were not appropriate. This rationale is already explained in the manuscript. Alongside their report, reviewers assign a status to the article: - Approved - Approved with reservations - Not approved | Invited Reviewers | ||| |---|---|---|---| | 1 | 2 | 3 | | | Version 2 (revision) 12 Feb 26 | read | read | | | Version 1 17 Oct 25 | read | read | - Ghassan Ghssein, Lebanese University, Beirut, Lebanon Sign up for content alerts You are now signed up to receive this alert Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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