{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:12:40Z","timestamp":1772169160122,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.16801.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T00:00:00Z","timestamp":1636675200000}}],"reference-count":38,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T00:00:00Z","timestamp":1636675200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/TOO5033\/1"],"award-info":[{"award-number":["MR\/TOO5033\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002992","name":"Department for International Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002992","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000276","name":"Department of Health and Social Care","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000276","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Typhoid and paratyphoid fever (enteric fever) is a common cause of non-specific febrile infection in adults and children presenting to health care facilities in low resource settings such as the South Asia. \u00a0A 7-day course of a single oral antimicrobial such as ciprofloxacin, cefixime, or azithromycin is commonly used for its treatment. Increasing antimicrobial resistance threatens the effectiveness of these treatment choices. We hypothesize that combined treatment with azithromycin (active mainly intracellularly) and cefixime (active mainly extracellularly) will be a better option for the treatment of clinically suspected and culture-confirmed typhoid fever in South Asia.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    This is a phase IV, international multi-center, multi-country, comparative participant-and observer-blind, 1:1 randomised clinical trial. Patients with suspected uncomplicated typhoid fever will be randomized to one of the two interventions: Arm A: azithromycin 20mg\/kg\/day oral dose once daily (maximum 1gm\/day) and cefixime 20mg\/kg\/day oral dose in two divided doses (maximum 400mg bd) for 7 days, Arm B: azithromycin 20mg\/kg\/day oral dose once daily (max 1gm\/day) for 7 days AND cefixime-matched placebo for 7 days. We will recruit 1500 patients across sites in Bangladesh, India, Nepal, and Pakistan. We will assess whether treatment outcomes are better with the combination after one week of treatment and at one- and three-months follow-up.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Discussion:<\/ns4:bold>\n                    Combined treatment may limit the emergence of resistance if one of the components is active against resistant sub-populations not covered by the other antimicrobial activity. If the combined treatment is better than the single antimicrobial treatment, this will be an important result for patients across South Asia and other typhoid endemic areas.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Clinicaltrials.gov registration:<\/ns4:bold>\n                    NCT04349826 (16\/04\/2020)\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.16801.2","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T06:20:07Z","timestamp":1636698007000},"page":"207","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Azithromycin and cefixime combination versus azithromycin alone for the out-patient treatment of clinically suspected or confirmed uncomplicated typhoid fever in South Asia: a randomised controlled trial protocol"],"prefix":"10.12688","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0670-1433","authenticated-orcid":false,"given":"Abhishek","family":"Giri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhilasha","family":"Karkey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabina","family":"Dongol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Arjyal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3144-802X","authenticated-orcid":false,"given":"Archana","family":"Maharjan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Balaji","family":"Veeraraghavan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5119-4082","authenticated-orcid":false,"given":"Buddhi","family":"Paudyal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christiane","family":"Dolecek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damodar","family":"Gajurel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dung Nguyen Thi","family":"Phuong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duy Pham","family":"Thanh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farah","family":"Qamar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3656-564X","authenticated-orcid":false,"given":"Gagandeep","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3609-8455","authenticated-orcid":false,"given":"Ho Van","family":"Hien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob","family":"John","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6180-9995","authenticated-orcid":false,"given":"Katrina","family":"Lawson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"Wolbers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-8639","authenticated-orcid":false,"given":"Md. 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J."},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"603-5","DOI":"10.1097\/00006454-199507000-00010","article-title":"Comparison of the efficacy, safety and cost of cefixime, ceftriaxone and aztreonam in the treatment of multidrug-resistant Salmonella typhi septicemia in children.","volume":"14","author":"N Girgis","year":"1995","journal-title":"Pediatr Infect Dis J."},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"245-8","DOI":"10.1097\/00006454-199903000-00007","article-title":"A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. 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Zmora","year":"2018","journal-title":"PLoS Negl Trop Dis."},{"key":"ref-18","doi-asserted-by":"publisher","first-page":"e2188","DOI":"10.1371\/journal.pone.0002188","article-title":"A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam.","volume":"3","author":"C Dolecek","year":"2008","journal-title":"PLoS One."},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"819-25","DOI":"10.1128\/AAC.00447-06","article-title":"Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever.","volume":"51","author":"C Parry","year":"2007","journal-title":"Antimicrob Agents Chemother."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"243-50","DOI":"10.1093\/jac\/44.2.243","article-title":"Treatment of typhoid fever with azithromycin versus chloramphenicol in a randomized multicentre trial in India.","volume":"44","author":"T Butler","year":"1999","journal-title":"J Antimicrob Chemother."},{"key":"ref-21","doi-asserted-by":"publisher","first-page":"1441-4","DOI":"10.1128\/AAC.43.6.1441","article-title":"Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance.","volume":"43","author":"N Girgis","year":"1999","journal-title":"Antimicrob Agents Chemother."},{"key":"ref-22","doi-asserted-by":"publisher","first-page":"1855-9","DOI":"10.1128\/AAC.44.7.1855-1859.2000","article-title":"A Randomized Controlled Comparison of Azithromycin and Ofloxacin for Treatment of Multidrug-Resistant or Nalidixic Acid-Resistant Enteric Fever.","volume":"44","author":"N Chinh","year":"2000","journal-title":"Antimicrob Agents Chemother."},{"key":"ref-23","doi-asserted-by":"publisher","first-page":"1134-8","DOI":"10.1086\/317450","article-title":"Azithromycin versus ceftriaxone for the treatment of uncomplicated typhoid fever in children.","volume":"31","author":"R Frenck","year":"2000","journal-title":"Clin Infect Dis."},{"key":"ref-24","doi-asserted-by":"publisher","first-page":"1571-6","DOI":"10.1128\/JCM.39.4.1571-1576.2001","article-title":"Quantitation of bacteria in bone marrow from patients with typhoid fever: relationship between counts and clinical features.","volume":"39","author":"J Wain","year":"2001","journal-title":"J Clin Microbiol."},{"key":"ref-25","doi-asserted-by":"publisher","first-page":"1683-7","DOI":"10.1128\/JCM.36.6.1683-1687.1998","article-title":"Quantitation of bacteria in blood of typhoid fever patients and relationship between counts and clinical features, transmissibility, and antibiotic resistance.","volume":"36","author":"J Wain","year":"1998","journal-title":"J Clin Microbiol."},{"key":"ref-26","doi-asserted-by":"publisher","first-page":"85-93","DOI":"10.1093\/jac\/35.1.85","article-title":"Factors affecting the intracellular accumulation and activity of azithromycin.","volume":"35","author":"A Pascual","year":"1995","journal-title":"J Antimicrob Chemother."},{"key":"ref-27","doi-asserted-by":"publisher","first-page":"2450-4","DOI":"10.1128\/AAC.45.9.2450-2454.2001","article-title":"Mechanism of Therapeutic Effectiveness of Cefixime against Typhoid Fever.","volume":"45","author":"Y Matsumoto","year":"2001","journal-title":"Antimicrob Agents Chemother."},{"key":"ref-28","doi-asserted-by":"publisher","first-page":"359-64","DOI":"10.1093\/cid\/cit723","article-title":"A large outbreak of Salmonella Paratyphi A infection among israeli travelers to Nepal.","volume":"58","author":"E Meltzer","year":"2014","journal-title":"Clin Infect Dis."},{"key":"ref-29","article-title":"Dataset for the ACT-South ASIA protocol manuscript.","author":"E 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Klemm","year":"2018","journal-title":"mBio."},{"key":"ref-36","doi-asserted-by":"publisher","first-page":"59-70","DOI":"10.1111\/bcp.13503","article-title":"Threats to global antimicrobial resistance control: Centrally approved and unapproved antibiotic formulations sold in India.","volume":"85","author":"P McGettigan","year":"2019","journal-title":"Br J Clin Pharmacol."},{"key":"ref-37","doi-asserted-by":"publisher","first-page":"k5322","DOI":"10.1136\/bmj.k5322","article-title":"Multidrug resistant enteric fever in South Asia: unmet medical needs and opportunities.","volume":"364","author":"C Parry","year":"2019","journal-title":"BMJ."},{"key":"ref-38","doi-asserted-by":"publisher","first-page":"875-8","DOI":"10.4269\/ajtmh.14-0709","article-title":"Undifferentiated febrile illness in Kathmandu, Nepal.","volume":"92","author":"C Thompson","year":"2015","journal-title":"Am J Trop Med Hyg."}],"container-title":["Wellcome Open 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.19206.r47063, Karin Leder, School of Public Health and Preventive Medicine, Monash University, Clayton, Vic, Australia, 16 Nov 2021, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-207\/v2#referee-response-47063","order":0,"name":"referee-response-47063","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.19206.r47062, Eli Schwartz, The Center for Geographic Medicine and Tropical Diseases, Sheba Medical Center, Ramat Gan, 52621, Israel, 08 Dec 2021, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-207\/v2#referee-response-47062","order":1,"name":"referee-response-47062","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Buddha Basnyat<\/b>; \n<i>Posted: 11 Dec 2021<\/i>; Thank you very much, Dr Eli Schwartz.&nbsp;  In answer to your first query, yes indeed those that are found to have another diagnosis will be included in the ITT analysis. And we will also have a sub-group analysis of just those who are culture positive for typhoid fever. So, this will be a wide-ranging study the results of which should impact the treatment of undifferentiated febrile illness in South Asia including typhoid fever.  In response to your second query regarding serological diagnosis of leptospirosis and other common ( often neglected) disease-causing organisms, we are taking this matter up seriously and actively looking for means to carry out these tests.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-207\/v2#referee-comment-4834","order":2,"name":"referee-comment-4834","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Buddha Basnyat<\/b>; \n<i>Posted: 24 Nov 2021<\/i>; \n<b>We beg Reviewer two's pardon in that we missed responding to his last 4 important queries. Our responses are in bold and the reviewers comments are in italics.<\/b> &nbsp; \n<i>There are lists of rapid tests that will be performed; one of the common febrile illnesses in these regions is&nbsp;Leptospirosis<b>&nbsp;<\/b>which is not mentioned on the list. Should a rapid test or PCR be added to the list?<\/i>  \n<b>The reviewer raises an important point but<\/b> t\n<b>here are no rapid reliable tests including PCR available for us at this stage to include this in the protocol. &nbsp;<\/b> &nbsp; \n<i>Blood culture- As I know there are different blood-culture bottles in these countries with different amount of blood, which gives different sensitivity.&nbsp; Are these centers going to be supplied from a central supplier? There is no clear instruction about the amount of blood.&nbsp;<\/i>  \n<b>Under lab testing we have indeed mentioned in the protocol that 3 to 8 ml will be sampled from the patient depending on the age of the patient (and BACTEC bottles will be used in all sites). There will be no central supplier.<\/b>  \n<i>The Placebo mentioned is sugar pills. I am concerned that this may prevent a real blinding of the study.<\/i>&nbsp;  \n<b>We have tasted both the&nbsp;placebo and the real cefixime and they taste no different.<\/b>  \n<i>There is redundancy in secondary end-point and the statement below appears 3 times.<\/i>&nbsp;  \n<i>To compare the time from onset of treatment to treatment failure in patients in each treatment arm<\/i> \n<i>To compare the time from onset of symptoms to treatment failure in patients in each treatment arm<\/i> \n<i>To compare the time from onset of symptoms to treatment failure in patients in each treatment arm<\/i>&nbsp; &nbsp;  \n<b>We did not see this redundancy in the Secondary&nbsp;Endpoints. Perhaps the Reviewer was referring to Secondary Objectives. But again there is no redundancy because we are trying&nbsp;to compare onset of symptoms as well as onset of treatment separately to treatment failure.<\/b>  \n<b>Thank you very much for your kind consideration.<\/b>  \n<b>Dr Basnyat, PI<\/b>","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-207\/v2#article-response-4817","order":3,"name":"article-response-4817","label":"Article Comment","group":{"name":"article-comments","label":"Article Comments"}},{"value":"This work was supported by the Joint Global Health Trials Scheme [MR\/TOO5033\/1, awarded to the University of Oxford] which is jointly funded by the Department of Health and Social Care, the Department for International Development, the Global Challenges Research Fund, the Medical Research Council and the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}