{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T06:15:39Z","timestamp":1782627339704,"version":"3.54.5"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013281","name":"the Joint Programming Initiative on Antimicrobial Resistance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Antibiotic combination therapy is increasingly used to treat MDR pathogens. In vitro studies suggest that the polymyxin B\/rifampicin combination might be synergistic. Therefore, the pharmacodynamics of rifampicin as monotherapy and combined with polymyxin B were studied in Escherichia coli- and Klebsiella pneumoniae-infected mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The rifampicin pharmacokinetics (oral doses 0.5\u201364 mg\/kg) in murine plasma were studied to estimate the exposures to rifampicin. These exposures were subsequently correlated with the antibacterial effect in a sigmoid maximum-effect model. The minimum exposures needed for a static, 1 log10 and 2 log10 kill effect in two E. coli and two K. pneumoniae strains were determined for monotherapy and the combination. The pharmacodynamic interactions between polymyxin B and rifampicin were assessed using Loewe additivity and Bliss independence in both an E. coli and a K. pneumoniae strain.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Rifampicin monotherapy resulted in a static effect in E. coli but not against K. pneumoniae. When combined with polymyxin B, rifampicin fAUC\/MIC needed for stasis, 1 log10 and 2 log10 kill effect decreased with increasing polymyxin B exposures for all strains. Synergy was confirmed in Loewe additivity (interaction indices 0.11\u20130.51 for E. coli and 0.04\u20130.19 for K. pneumoniae) and Bliss independence (267% and 863%). Maximal killing (&amp;gt;2 log10 kill) in combination therapy was found at rifampicin\/polymyxin B fAUC\/MIC of 0.68\/32.56 for E. coli and 0.169\/16.28 for K. pneumoniae.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These in vivo studies confirmed that there is a clear synergistic effect between polymyxin B and rifampicin, which was stronger for the K. pneumoniae strain than for the E. coli strain.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkaf056","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T20:39:02Z","timestamp":1741120742000},"page":"1248-1255","source":"Crossref","is-referenced-by-count":4,"title":["The synergistic effect of the combination of polymyxin B and rifampicin in a murine neutropenic thigh infection model with <i>E. coli<\/i> and <i>K. pneumoniae<\/i>"],"prefix":"10.1093","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9209-0178","authenticated-orcid":false,"given":"Sanne","family":"Van Den Berg","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center , Dr. Molewaterplein 40, 3015 GD Rotterdam ,","place":["The Netherlands"]},{"name":"CATOR, Center for Antimicrobial Treatment Optimization Rotterdam , Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-638X","authenticated-orcid":false,"given":"Sebastiaan D T","family":"Sassen","sequence":"additional","affiliation":[{"name":"CATOR, Center for Antimicrobial Treatment Optimization Rotterdam , Rotterdam ,","place":["The Netherlands"]},{"name":"Department of Hospital Pharmacy, Erasmus MC, University Medical Center , Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Couet","sequence":"additional","affiliation":[{"name":"INSERM U1070, CHU de Poitiers et Universit\u00e9 de Poitiers , Poitiers ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Marchand","sequence":"additional","affiliation":[{"name":"INSERM U1070, CHU de Poitiers et Universit\u00e9 de Poitiers , Poitiers ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heleen","family":"Van Der Spek","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center , Dr. Molewaterplein 40, 3015 GD Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian T","family":"Ten Kate","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center , Dr. Molewaterplein 40, 3015 GD Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8869-1509","authenticated-orcid":false,"given":"Joseph","family":"Meletiadis","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center , Dr. Molewaterplein 40, 3015 GD Rotterdam ,","place":["The Netherlands"]},{"name":"Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Clinical Microbiology Laboratory , Athens ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5042-6251","authenticated-orcid":false,"given":"Anouk E","family":"Muller","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center , Dr. Molewaterplein 40, 3015 GD Rotterdam ,","place":["The Netherlands"]},{"name":"CATOR, Center for Antimicrobial Treatment Optimization Rotterdam , Rotterdam ,","place":["The Netherlands"]},{"name":"Department of Medical Microbiology, Haaglanden MC , The Hague ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"2025050205523920700_dkaf056-B1","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1007\/s40265-024-02102-8","article-title":"The challenge of treating infections caused by metallo-\u03b2-lactamase-producing Gram-negative bacteria: a narrative review","volume":"84","author":"Hidalgo-Tenorio","year":"2024","journal-title":"Drugs"},{"key":"2025050205523920700_dkaf056-B2","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1093\/jac\/dkm357","article-title":"Polymyxin B for the treatment of multidrug-resistant pathogens: a critical 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