{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T20:16:16Z","timestamp":1778530576299,"version":"3.51.4"},"reference-count":32,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"unspecified","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,6,11]]},"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Amoxicillin-clavulanate is commonly used to prevent infections following snakebites despite the lack of clinical evidence. We aimed to demonstrate that clinically directed initiation of amoxicillin-clavulanate would be non-inferior to routine use in this setting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Open-label, randomised, non-inferiority trial with blinded adjudication of endpoints.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>Emergency department of a teaching hospital in southern India.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>Adults with local swelling following snakebites within 24 hours of bite.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interventions<\/jats:title>\n                    <jats:p>In the routine use strategy, intravenous followed by oral amoxicillin-clavulanate was administered for at least 5\u2009days. In the clinically directed strategy, the antibiotic was only initiated for clinical failures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Primary and secondary outcome measures<\/jats:title>\n                    <jats:p>Primary outcomes were protocol-defined clinical failure and total antibiotic consumption. Non-inferiority margin was prespecified as 10%. Secondary outcomes were the length of hospital stay, total antivenom consumption, new-onset organ failure, bleeding requiring transfusion, death\/need for surgical intervention and drug-related adverse events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The trial was prematurely stopped due to the COVID-19 situation after randomising 66 patients\u201434 to clinically directed initiation and 32 to routine use arms. Russell\u2019s viper was the most common (21 (32%)) biting snake species identified; 52 (79%) patients had evidence of haemotoxic envenomation at baseline, and 24 (36%) patients developed AKI. There were 10 clinical failures\u2014six in the clinically directed initiation arm and four in the routine use arm. The difference in clinical failure between the two arms was 5.2% (\u221212.0%\u201321.7%; p=0.291); the upper bound of the CI exceeded the prespecified non-inferiority margin. Total antibiotic consumption, expressed in DDDs, was significantly lower in the clinically directed initiation arm (0 (0\u20131) vs 5.31 (4.67\u20136.17); p&lt;0.001). Three serious adverse events resulting in two deaths (one in each arm) were observed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We could not demonstrate the non-inferiority of clinically directed initiation compared with routine use of amoxicillin-clavulanate among patients with local swelling caused by haemotoxic snakebites. However, the frequency of clinical failures was similar, and antibiotic consumption was substantially lower with the clinically directed initiation strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.gov;\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02570347\">NCT02570347<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2024-094409","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T14:20:21Z","timestamp":1750688421000},"page":"e094409","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Clinically directed initiation versus routine use of amoxicillin-clavulanate and the risk of local complications among patients with haemotoxic snakebite envenomation treated at a teaching hospital in southern India: a randomised, non-inferiority trial"],"prefix":"10.1136","volume":"15","clinical-trial-number":[{"clinical-trial-number":"nct02570347","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02570347","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Aditya","family":"Gautam","sequence":"first","affiliation":[{"name":"Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malayil B","family":"Indu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinchan","family":"Bhardwaj","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paramasivam","family":"Sabitha","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surendran","family":"Deepanjali","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bettadpura Shamanna","family":"Suryanarayana","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chanaveerappa","family":"Bammigatti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4676-743X","authenticated-orcid":false,"given":"Tamilarasu","family":"Kadhiravan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"2025120619063035000_15.6.e094409.1","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.23-0278"},{"key":"2025120619063035000_15.6.e094409.2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.4038\/cmj.v50i4.1405","article-title":"Routine antibiotic therapy in the management of the local inflammatory swelling in venomous snakebites: results of a placebo-controlled study","volume":"50","author":"Kularatne","year":"2005","journal-title":"Ceylon Med J"},{"key":"2025120619063035000_15.6.e094409.3","doi-asserted-by":"publisher","DOI":"10.1007\/PL00012255"},{"key":"2025120619063035000_15.6.e094409.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.trstmh.2003.12.009"},{"key":"2025120619063035000_15.6.e094409.5","unstructured":"Warrell AD . Guidelines for management of snakebites. New Delhi: WHO Regional Office South East Asia, 2010."},{"key":"2025120619063035000_15.6.e094409.6","unstructured":"WHO Regional Office for Africa . Guidelines for the prevention and clinical management of snakebite in Africa. Brazaville: WHO Regional Office for Africa, 2010."},{"key":"2025120619063035000_15.6.e094409.7","unstructured":"Directorate General of Health Services, Ministry of Health and Family Welfare . National snakebite management protocol. New Delhi: Government of India, 2009."},{"key":"2025120619063035000_15.6.e094409.8","first-page":"OC05","article-title":"Pattern of Use of Antibiotics Following Snake Bite in a Tertiary Care Hospital","volume":"9","author":"Palappallil","year":"2015","journal-title":"J Clin Diagn Res"},{"key":"2025120619063035000_15.6.e094409.9","doi-asserted-by":"crossref","DOI":"10.1186\/1472-6904-1-4","article-title":"Routine prophylactic antibiotic use in the management of snakebite","volume":"1","author":"Tagwireyi","year":"2001","journal-title":"BMC Clin Pharmacol"},{"key":"2025120619063035000_15.6.e094409.10","doi-asserted-by":"crossref","DOI":"10.3390\/toxins16010037","article-title":"Use of Antibiotics following Snakebite in the Era of Antimicrobial Stewardship","volume":"16","author":"Brenes-Chacon","year":"2024","journal-title":"Toxins (Basel)"},{"key":"2025120619063035000_15.6.e094409.11","doi-asserted-by":"crossref","first-page":"734","DOI":"10.4236\/jbise.2011.411090","article-title":"Implementation of an open-source customizable minimization program for allocation of patients to parallel groups in clinical trials","volume":"04","author":"Saghaei","year":"2011","journal-title":"JBiSE"},{"key":"2025120619063035000_15.6.e094409.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2019.103208"},{"key":"2025120619063035000_15.6.e094409.13","unstructured":"WHO Collaborating Centre for Drug Statistics Methodology . Guidelines for ATC classification and DDD assignment 2015. Oslo: WHO, 2014."},{"key":"2025120619063035000_15.6.e094409.14","unstructured":"Sealed Envelope Ltd . Power calculator for binary outcome non-inferiority trial, 2012. Available: https:\/\/www.sealedenvelope.com\/power\/binary-noninferior\/"},{"key":"2025120619063035000_15.6.e094409.15","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)62220-0"},{"key":"2025120619063035000_15.6.e094409.16","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(14)71018-7"},{"key":"2025120619063035000_15.6.e094409.17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1411162"},{"key":"2025120619063035000_15.6.e094409.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61233-2"},{"key":"2025120619063035000_15.6.e094409.19","doi-asserted-by":"publisher","DOI":"10.1037\/0033-2909.112.1.155"},{"key":"2025120619063035000_15.6.e094409.20","unstructured":"Food and Drug Administration, U.S. Department of Health and Human Services . Multiple Endpoints in Clinical Trials. Guidance for Industry, 2022. Available: https:\/\/www.fda.gov\/media\/162416\/download"},{"key":"2025120619063035000_15.6.e094409.21","unstructured":"Food and Drug Administration, U.S. Department of Health and Human Services . Complicated Urinary Tract Infections: Developing Drugs for Treatment Guidance for Industry, 2015. Available: https:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/UCM070981.pdf"},{"key":"2025120619063035000_15.6.e094409.22","unstructured":"Infectious Diseases Society of America . IDSA Comments on cUTI Draft Guidance 052412, 2012. Available: https:\/\/www.regulations.gov\/comment\/FDA-2012-D-0148-0008"},{"key":"2025120619063035000_15.6.e094409.23","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu444"},{"key":"2025120619063035000_15.6.e094409.24","doi-asserted-by":"crossref","first-page":"e296","DOI":"10.1016\/S2214-109X(22)00479-X","article-title":"A global core outcome measurement set for snakebite clinical trials","volume":"11","author":"Abouyannis","year":"2023","journal-title":"Lancet Glob Health"},{"key":"2025120619063035000_15.6.e094409.25","doi-asserted-by":"crossref","unstructured":"Bhaumik S , Beri D , Santra V , et al . Core outcome set for intervention research on snakebite envenomation in South Asia. Inj Prev 2024.:ip-2023-045155. doi:10.1136\/ip-2023-045155","DOI":"10.1136\/ip-2023-045155"},{"key":"2025120619063035000_15.6.e094409.26","article-title":"Antibiotics for preventing wound infections after snakebite","volume":"2022","author":"Bhaumik","year":"2022","journal-title":"Cochrane Database Syst Rev"},{"key":"2025120619063035000_15.6.e094409.27","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0005745","article-title":"Poor efficacy of preemptive amoxicillin clavulanate for preventing secondary infection from Bothrops snakebites in the Brazilian Amazon: A randomized controlled clinical trial","volume":"11","author":"Sachett","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"key":"2025120619063035000_15.6.e094409.28","article-title":"Antimicrobial prophylaxis for colorectal surgery","volume":"2014","author":"Nelson","year":"2014","journal-title":"Cochrane Database Syst Rev"},{"key":"2025120619063035000_15.6.e094409.29","unstructured":"Global guidelines for the prevention of surgical site infection. 2nd edn. Geneva: World Health Organization, 2018."},{"key":"2025120619063035000_15.6.e094409.30","doi-asserted-by":"crossref","DOI":"10.1590\/1678-9199-jvatitd-2019-0098","article-title":"Antibiotic therapy for snakebite envenoming","volume":"26","author":"Resiere","year":"2020","journal-title":"J Venom Anim Toxins Incl Trop Dis"},{"key":"2025120619063035000_15.6.e094409.31","doi-asserted-by":"crossref","first-page":"845","DOI":"10.4269\/ajtmh.24-0033","article-title":"Antibiotic Therapy and Prophylaxis for Snake-Bitten Patients","volume":"110","author":"Kallel","year":"2024","journal-title":"Am J Trop Med Hyg"},{"key":"2025120619063035000_15.6.e094409.32","doi-asserted-by":"publisher","DOI":"10.1136\/emj.6.4.251"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2024-094409","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T03:06:45Z","timestamp":1765076805000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2024-094409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":32,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,23]]},"published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1136\/bmjopen-2024-094409"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2024-094409","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6]]}}}