{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T23:15:44Z","timestamp":1769555744849,"version":"3.49.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009947","name":"Merck Sharp and Dohme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009947","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales are common causes of bloodstream infection. ESBL-producing bacteria are typically resistant to third-generation cephalosporins and result in a sizeable economic and public health burden. AmpC-producing Enterobacterales may develop third-generation cephalosporin resistance through enzyme hyper-expression. In no observational study has the outcome of treatment of these infections been surpassed by carbapenems. Widespread use of carbapenems may drive the development of carbapenem-resistant Gram-negative bacilli.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This study will use a multicentre, parallel group open-label non-inferiority trial design comparing ceftolozane-tazobactam and meropenem in adult patients with bloodstream infection caused by ESBL or AmpC-producing Enterobacterales. Trial recruitment will occur in up to 40 sites in six countries (Australia, Singapore, Italy, Spain, Saudi Arabia and Lebanon). The sample size is determined by a predefined quantity of ceftolozane-tazobactam to be supplied by Merck, Sharpe and Dohme (MSD). We anticipate that a trial with 600 patients contributing to the primary outcome analysis would have 80% power to declare non-inferiority with a 5% non-inferiority margin, assuming a 30-day mortality of 5% in both randomised groups. Once randomised, definitive treatment will be for a minimum of 5\u2009days and a maximum of 14\u2009days with the total duration determined by treating clinicians. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>Participants will have bloodstream infection due to third-generation cephalosporin non-susceptible <jats:italic>E. coli<\/jats:italic> and <jats:italic>Klebsiella<\/jats:italic> spp. or <jats:italic>Enterobacter<\/jats:italic> spp., <jats:italic>Citrobacter freundii<\/jats:italic>, <jats:italic>Morganella morganii<\/jats:italic>, <jats:italic>Providencia<\/jats:italic> spp. or <jats:italic>Serratia marcescens<\/jats:italic>. They will be randomised 1:1 to ceftolozane-tazobactam 3\u2009g versus meropenem 1\u2009g, both every 8\u2009h. Secondary outcomes will be a comparison of 14-day all-cause mortality, clinical and microbiological success at day 5, functional bacteraemia score, microbiological relapse, new bloodstream infection, length of hospital stay, serious adverse events, <jats:italic>C. difficile<\/jats:italic> infection, multidrug-resistant organism colonisation. The estimated trial completion date is December 2024.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>The MERINO-3 trial is registered under the US National Institute of Health <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link> register, reference number: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04238390?cond=ceftolozane+meropenem&amp;draw=2&amp;rank=1\">NCT04238390<\/jats:ext-link>. Registered on 23 January 2020.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-021-05206-8","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T12:03:36Z","timestamp":1619093016000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Ceftolozane-tazobactam versus meropenem for definitive treatment of bloodstream infection due to extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales (\u201cMERINO-3\u201d): study protocol for a multicentre, open-label randomised non-inferiority trial"],"prefix":"10.1186","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7262-7529","authenticated-orcid":false,"given":"Adam G.","family":"Stewart","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick N. A.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark D.","family":"Chatfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Littleford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David L.","family":"Paterson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,22]]},"reference":[{"issue":"4","key":"5206_CR1","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1128\/CMR.18.4.657-686.2005","volume":"18","author":"DL Paterson","year":"2005","unstructured":"Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. 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Clin Infect Dis. 2004;38(Suppl 4):S341\u20135.","journal-title":"Clin Infect Dis"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-021-05206-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-021-05206-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-021-05206-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T12:08:39Z","timestamp":1619093319000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-021-05206-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,22]]},"references-count":24,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["5206"],"URL":"https:\/\/doi.org\/10.1186\/s13063-021-05206-8","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,22]]},"assertion":[{"value":"9 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval was given by The Royal Brisbane and Women\u2019s Hospital HREC (HREC\/2019\/QRBW\/59232 as part of the National Mutual Acceptance Scheme in Australia. International sites will seek local HREC\/IRB approval as per local procedures. The protocol has been given ethical approval by the Royal Brisbane and Women\u2019s Hospital on 28th February 2020 (HREC\/2019\/QRBW\/59232). This study will be conducted in accordance with the ICH-GCP Guidelines and the principles in the Declaration of Helsinki. Potential participants or substitute decision-makers will be approached and provided with information sheets outlining the risks, benefits and procedures of the trial, and then will be invited to provide written informed consent prior to enrolment. This was conducted to ICH-GCP standards and all other regulatory requirements.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate {24}"}},{"value":"See Supplementary material.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication {32}"}},{"value":"DLP has received funding from AstraZeneca, Leo Pharmaceuticals, Bayer, GlaxoSmithKline (GSK), Cubist, Venatorx and Accelerate; reports board membership from Entasis, Qpex, Merck, Shionogi, Achaogen, AstraZeneca, Leo Pharmaceuticals, Bayer, GSK, Cubist, Venatorx, and Accelerate; reports grants\/grants pending from Shionogi and Merck; and has received payment for lectures including service on speaker\u2019s bureaus from Pfizer, outside the submitted work. PNAH has received research grants from MSD. All other authors have no competing interests to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests {28}"}}],"article-number":"301"}}