{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T09:05:58Z","timestamp":1791450358758,"version":"4.3.3"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T00:00:00Z","timestamp":1585785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Instituto de Salud Carlos III, Proyectos de Investigaci\u00f3n en Salud","award":["PI16\/01378"],"award-info":[{"award-number":["PI16\/01378"]}]},{"name":"Instituto de Salud Carlos III, Proyectos de Investigaci\u00f3n en Salud","award":["PI16\/01306"],"award-info":[{"award-number":["PI16\/01306"]}]},{"name":"Instituto de Salud Carlos III, Subdirecci\u00f3n General de Redes y Centros de Investigaci\u00f3n Cooperativa, Ministerio de Ciencia, Innovaci\u00f3n y Universidades"},{"name":"Spanish Network for Research in Infectious Diseases","award":["REIPI RD16\/0016\/0009"],"award-info":[{"award-number":["REIPI RD16\/0016\/0009"]}]},{"name":"European Development Regional Fund"},{"name":"Subprograma Miguel Servet Tipo I from the Ministerio de Econom\u00eda y Competitividad of Spain","award":["CP15\/01358"],"award-info":[{"award-number":["CP15\/01358"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Repurposing drugs provides a new approach to the fight against MDR Gram-negative bacilli (MDR-GNB). Rafoxanide, a veterinary antihelminthic drug, has shown antibacterial activity in vitro against Gram-positive bacteria. We aimed to analyse the in vitro and in vivo efficacy of rafoxanide in combination with colistin against colistin-susceptible (Col-S) and colistin-resistant (Col-R) GNB.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A collection of Col-S and Col-R Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae were used. Chequerboard and time\u2013kill curve analyses were performed to determine the synergy between rafoxanide and colistin. Changes in membrane structure and permeability were analysed using transmission electron microscopy and fluorescence assays. A murine peritoneal sepsis model using Col-R strains of these pathogens was performed to study the efficacy of rafoxanide (10\u2009mg\/kg\/24\u2009h, IV), colistimethate sodium (CMS) (20\u2009mg\/kg\/8\u2009h, intraperitoneally) and rafoxanide (10\u2009mg\/kg\/24\u2009h, IV) plus CMS (20\u2009mg\/kg\/8\u2009h, intraperitoneally) for 72\u2009h.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Rafoxanide showed MICs \u2265256\u2009mg\/L for all Col-S and Col-R strains. Chequerboard and time\u2013kill curve analyses showed that rafoxanide (1\u2009mg\/L) is more synergistic with colistin against Col-R than Col-S strains. Col-R, but not Col-S, strains treated with rafoxanide demonstrated higher membrane permeabilization. Transmission electron microscopy visualization confirmed that Col-R strains suffer morphological changes. In the murine peritoneal sepsis model with Col-R strains, rafoxanide plus CMS, compared with CMS alone, increased mouse survival to 53.8% and 73.3%, and reduced bacterial loads in tissues and blood between 2.34 and 4.99 log10\u2009cfu\/g or mL, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Rafoxanide repurposing, as monotherapy and in combination with CMS, may address the urgent need for new treatments for infections caused by MDR-GNB.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkaa103","type":"journal-article","created":{"date-parts":[[2020,2,29]],"date-time":"2020-02-29T12:21:53Z","timestamp":1582978913000},"page":"1895-1905","source":"Crossref","is-referenced-by-count":35,"title":["Repositioning rafoxanide to treat Gram-negative bacilli infections"],"prefix":"10.1093","volume":"75","author":[{"given":"Andrea","family":"Mir\u00f3-Canturri","sequence":"first","affiliation":[{"name":"Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Roc\u00edo, Seville, Spain"},{"name":"Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Ayerbe-Algaba","sequence":"first","affiliation":[{"name":"Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Roc\u00edo, Seville, Spain"},{"name":"Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngel Rodr\u00edguez","family":"Villodres","sequence":"first","affiliation":[{"name":"Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Roc\u00edo, Seville, Spain"},{"name":"Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jer\u00f3nimo","family":"Pach\u00f3n","sequence":"first","affiliation":[{"name":"Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville, Seville, Spain"},{"name":"Department of Medicine, University of Seville, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9302-8384","authenticated-orcid":false,"given":"Younes","family":"Smani","sequence":"first","affiliation":[{"name":"Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Roc\u00edo, Seville, Spain"},{"name":"Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,2]]},"reference":[{"key":"2020061904540876500_dkaa103-B1"},{"key":"2020061904540876500_dkaa103-B2","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1185\/03007995.2015.1018989","article-title":"Colistin, mechanisms and prevalence of resistance","volume":"31","author":"Bialvaei","year":"2015","journal-title":"Curr Med Res Opin"},{"key":"2020061904540876500_dkaa103-B3","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.ijantimicag.2014.07.020","article-title":"Worldwide emergence of colistin resistance in Klebsiella pneumoniae from healthy humans and patients in Lao PDR, Thailand, Israel, Nigeria and France owing to inactivation of the PhoP\/PhoQ regulator 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