{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T11:35:32Z","timestamp":1765884932344,"version":"3.48.0"},"reference-count":44,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"unspecified","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"Netherlands Organisation for Health Research and Development","doi-asserted-by":"crossref","award":["84801"],"award-info":[{"award-number":["84801"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2021,11,26]]},"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Around 15%\u201320% of children with acute otitis media present with ear discharge due to a spontaneous tear or perforation of the eardrum (AOMd). Current guidance recommends clinicians to consider oral antibiotics as first-line treatment in this condition. The opening in the eardrum however should allow topical antibiotics to enter the middle ear directly. Local administration of antibiotics does not expose children to systemic side effects and may put less selective resistance pressure on bacteria. Evidence on the effectiveness of this approach in children with AOMd is lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>A primary care-based, open, individually randomised, controlled, non-inferiority trial. The trial aims to recruit 350 children aged 6 months to 12 years with AOMd and ear pain and\/or fever. Participants will be randomised to 7 days of hydrocortisone-bacitracin-colistin eardrops five drops three times daily or amoxicillin oral suspension 50 mg\/kg body weight per day, divided over three doses. Parents will keep a daily diary of AOM symptoms, adverse events and complications for 2 weeks. In addition, they will record AOM recurrences, healthcare utilisation and societal costs for 3 months. The primary outcome is the proportion of children without ear pain and fever at day 3. Secondary outcomes include ear pain and fever intensity\/severity; days with ear discharge; eardrum perforation at 2 weeks; adverse events during first 2 weeks; costs; and cost effectiveness at 2 weeks and 3 months. The primary analyses will be intention-to-treat and per-protocol analyses will be conducted as well.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The medical research ethics committee Utrecht, The Netherlands has given ethical approval (17-400\/G-M). Parents\/guardians of participants will provide written informed consent. Study results will be submitted for publication in peer-reviewed medical journals and presented at relevant (inter)national scientific meetings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>The Netherlands National Trial Register; NTR6723. Date of registration: 27 November 2017.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-052128","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T11:33:55Z","timestamp":1639654435000},"page":"e052128","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Topical or oral antibiotics for children with acute otitis media presenting with ear discharge: study protocol of a randomised controlled non-inferiority trial"],"prefix":"10.1136","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3413-1423","authenticated-orcid":false,"given":"Saskia","family":"Hullegie","sequence":"first","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1446-9614","authenticated-orcid":false,"given":"Roderick P","family":"Venekamp","sequence":"additional","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thijs M A","family":"van Dongen","sequence":"additional","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanne","family":"Mulder","sequence":"additional","affiliation":[{"name":"Parent and PPI contributor, Utrecht, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Willem","family":"van Schaik","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G Ardine","family":"de Wit","sequence":"additional","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"Centre for Nutrition, Prevention and Healthcare, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alastair D","family":"Hay","sequence":"additional","affiliation":[{"name":"Centre for Academic Primary Care, School of Social and Community Medicine, University of Bristol, Bristol, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3664-1873","authenticated-orcid":false,"given":"Paul","family":"Little","sequence":"additional","affiliation":[{"name":"Primary Care Population Science and Medical Education, Aldemoor Health Centre, University of Southampton, Southampton, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5127-4509","authenticated-orcid":false,"given":"Michael V","family":"Moore","sequence":"additional","affiliation":[{"name":"Primary Care Population Science and Medical Education, Aldemoor Health Centre, University of Southampton, Southampton, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth A M","family":"Sanders","sequence":"additional","affiliation":[{"name":"Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"Centre for Infectious Disease Control, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc J M","family":"Bonten","sequence":"additional","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debby","family":"Bogaert","sequence":"additional","affiliation":[{"name":"Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"Centre for Inflammation Research, Queen\"s Medical Research Institute, University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne GM","family":"Schilder","sequence":"additional","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK"},{"name":"evidENT, Ear Institute, University College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger A M J","family":"Damoiseaux","sequence":"additional","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"2025121603320152000_11.12.e052128.1","doi-asserted-by":"publisher","DOI":"10.1186\/s12913-018-3139-1"},{"key":"2025121603320152000_11.12.e052128.2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku005"},{"key":"2025121603320152000_11.12.e052128.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69606-2"},{"key":"2025121603320152000_11.12.e052128.4","doi-asserted-by":"publisher","DOI":"10.3399\/bjgp10X483148"},{"key":"2025121603320152000_11.12.e052128.5","unstructured":"Centre for Clinical Practice at NICE (UK) . Guideline, otitis media (acute): antimicrobial prescribing, 2018. Available: https:\/\/www.nice.org.uk\/guidance\/ng91\/resources\/otitis-media-acute-antimicrobial-prescribing-pdf-1837750121413 [Accessed 30 Sep 2021]."},{"key":"2025121603320152000_11.12.e052128.6","article-title":"NHG-Standaard otitis media acuta bij kinderen (derde herziening)","volume":"57","author":"RAMJ","year":"2014","journal-title":"Huisarts Wet"},{"key":"2025121603320152000_11.12.e052128.7","first-page":"CD000219","article-title":"Antibiotics for acute otitis media in children","volume":"303","author":"Venekamp","year":"2015","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"2025121603320152000_11.12.e052128.8","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(13)70318-9"},{"key":"2025121603320152000_11.12.e052128.9","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c2096"},{"key":"2025121603320152000_11.12.e052128.10","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1001\/archotol.125.3.337","article-title":"Ofloxacin otic solution in patients with otitis media: an analysis of drug concentrations","volume":"125","author":"Ohyama","year":"1999","journal-title":"Arch Otolaryngol Head Neck Surg"},{"key":"2025121603320152000_11.12.e052128.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.otohns.2003.12.009"},{"key":"2025121603320152000_11.12.e052128.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1301630"},{"key":"2025121603320152000_11.12.e052128.13","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2014-3141"},{"key":"2025121603320152000_11.12.e052128.14","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.i308"},{"key":"2025121603320152000_11.12.e052128.15","doi-asserted-by":"crossref","DOI":"10.1186\/s13063-020-04419-7","article-title":"A multi-centre, pragmatic, three-arm, individually randomised, non-inferiority, open trial to compare immediate orally administered, immediate topically administered or delayed orally administered antibiotics for acute otitis media with discharge in children: The Runny Ear Study (REST): study protocol","volume":"21","author":"Curtis","year":"2020","journal-title":"Trials"},{"key":"2025121603320152000_11.12.e052128.16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0150949"},{"key":"2025121603320152000_11.12.e052128.17","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0000000000003134"},{"key":"2025121603320152000_11.12.e052128.18","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200312000-00011"},{"key":"2025121603320152000_11.12.e052128.19","doi-asserted-by":"publisher","DOI":"10.1542\/peds.113.1.e40"},{"key":"2025121603320152000_11.12.e052128.20","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1177\/0194599811399711","article-title":"Assessing the efficacy of tragal pumping: a randomized controlled trial","volume":"144","author":"Boyd","year":"2011","journal-title":"Otolaryngol Head Neck Surg"},{"key":"2025121603320152000_11.12.e052128.21","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2019-035343"},{"key":"2025121603320152000_11.12.e052128.22","unstructured":"Nederlands Kenniscentrum voor Farmacotherapie bij Kinderen, Kinderformularium. Available: https:\/\/www.kinderformularium.nl\/geneesmiddel\/7\/amoxicilline [Accessed 18 Mar 2021]."},{"key":"2025121603320152000_11.12.e052128.23","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.322.7282.336"},{"key":"2025121603320152000_11.12.e052128.24","doi-asserted-by":"publisher","DOI":"10.1093\/fampra\/18.5.553"},{"key":"2025121603320152000_11.12.e052128.25","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.1997.01900100019002"},{"key":"2025121603320152000_11.12.e052128.26","doi-asserted-by":"crossref","unstructured":"Bouwmans C , Hakkaart-van Roijen L , Koopmanschap M . Manual of the iMTA productivity cost questionnaire (iPCQ). Rotterdam: iMTA. Rotterdam: Erasmus University, 2013. www.imta.nl","DOI":"10.1016\/j.jval.2014.08.1791"},{"key":"2025121603320152000_11.12.e052128.27","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5876(03)00198-8"},{"key":"2025121603320152000_11.12.e052128.28","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5876(98)00185-2"},{"key":"2025121603320152000_11.12.e052128.29","doi-asserted-by":"publisher","DOI":"10.1097\/01.inf.0000049347.42983.77"},{"key":"2025121603320152000_11.12.e052128.30","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2014.0087"},{"key":"2025121603320152000_11.12.e052128.31","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2010.134"},{"key":"2025121603320152000_11.12.e052128.32","unstructured":"U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) . Non-Inferiority Clinical Trials to Establish Effectiveness. Guidance for Industry 2016."},{"key":"2025121603320152000_11.12.e052128.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013550"},{"key":"2025121603320152000_11.12.e052128.34","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2012.87802"},{"key":"2025121603320152000_11.12.e052128.35","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c332"},{"key":"2025121603320152000_11.12.e052128.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2006.01.014"},{"key":"2025121603320152000_11.12.e052128.37","doi-asserted-by":"crossref","unstructured":"Rubin D . Multiple imputation for non-response in surveys. New York: John Wiley, 1987.","DOI":"10.1002\/9780470316696"},{"key":"2025121603320152000_11.12.e052128.38","unstructured":"Nederland Z . Kostenhandleiding: Methodologie van kostenonderzoek en referentieprijzen voor economische evaluaties in de gezondheidszorg. Diemen: Zorginstituut Nederland, 2016."},{"key":"2025121603320152000_11.12.e052128.39","unstructured":"Nederland Z . Richtlijn voor het uitvoeren van economische evaluaties in de gezondheidszorg. Diemen: Zorginstituut Nederland, 2016."},{"key":"2025121603320152000_11.12.e052128.40","unstructured":"Farmacotherapeutisch Kompas - CVZ. Available: http:\/\/www.fk.cvz.nl\/"},{"key":"2025121603320152000_11.12.e052128.41","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.133.11.1083"},{"key":"2025121603320152000_11.12.e052128.42","unstructured":"National Institute for Family Finance Information website. Available: https:\/\/www.nibud.nl\/beroepsmatig\/"},{"key":"2025121603320152000_11.12.e052128.43","unstructured":"Hay AF , Moore M , Taylor J . Results, lessons learned and recommendations from the REST randomised controlled trial of antibiotic strategies for children with acute otitis media with discharge. 2021 Submitted to Health Technol Assess; provisionally accepted 2021."},{"key":"2025121603320152000_11.12.e052128.44","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l6802"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2021-052128","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T11:32:09Z","timestamp":1765884729000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2021-052128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12,16]]},"published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1136\/bmjopen-2021-052128"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2021-052128","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"type":"print","value":"2044-6055"},{"type":"electronic","value":"2044-6055"}],"subject":[],"published":{"date-parts":[[2021,12]]}}}