{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T12:22:09Z","timestamp":1790338929437,"version":"4.1.0"},"reference-count":14,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2019,10,26]],"date-time":"2019-10-26T00:00:00Z","timestamp":1572048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Australian National Health and Medical Research Council for Centre of Research Excellence","award":["APP1099452"],"award-info":[{"award-number":["APP1099452"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To determine the \u03b2-lactam exposure associated with positive clinical outcomes for Gram-negative blood stream infection (BSI) in critically ill patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Patients and methods<\/jats:title>\n                  <jats:p>Pooled data of critically ill patients with mono-microbial Gram-negative BSI treated with \u03b2-lactams were collected from two databases. Free minimum concentrations (fCmin) of aztreonam, cefepime, ceftazidime, ceftriaxone, piperacillin (co-administered with tazobactam) and meropenem were interpreted in relation to the measured MIC for targeted bacteria (fCmin\/MIC). A positive clinical outcome was defined as completion of the treatment course or de-escalation, without other change of antibiotic therapy, and with no additional antibiotics commenced within 48\u2009h of cessation. Drug exposure breakpoints associated with positive clinical outcome were determined by classification and regression tree (CART) analysis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Data from 98 patients were included. Meropenem (46.9%) and piperacillin\/tazobactam (36.7%) were the most commonly prescribed antibiotics. The most common pathogens were Escherichia coli (28.6%), Pseudomonas aeruginosa (19.4%) and Klebsiella pneumoniae (13.3%). In all patients, 87.8% and 71.4% achieved fCmin\/MIC \u22651 and fCmin\/MIC &gt;5, respectively. Seventy-eight patients (79.6%) achieved positive clinical outcome. Two drug exposure breakpoints were identified: fCmin\/MIC &gt;1.3 for all \u03b2-lactams (predicted difference in positive outcome 84.5% versus 15.5%, P\u2009&lt;\u20090.05) and fCmin\/MIC &gt;4.95 for meropenem, aztreonam or ceftriaxone (predicted difference in positive outcome 97.7% versus 2.3%, P\u2009&lt;\u20090.05).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A \u03b2-lactam fCmin\/MIC &gt;1.3 was a significant predictor of a positive clinical outcome in critically ill patients with Gram-negative BSI and could be considered an antibiotic dosing target.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkz437","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T15:51:46Z","timestamp":1570722706000},"source":"Crossref","is-referenced-by-count":11,"title":["\u03b2-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill"],"prefix":"10.1093","author":[{"given":"Gloria","family":"Wong","sequence":"first","affiliation":[{"name":"UQ Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia"},{"name":"Royal Brisbane and Women\u2019s Hospital, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Taccone","sequence":"additional","affiliation":[{"name":"Department of Intensive Care, Erasme Hospital, Universit\u00e9 Libre de Bruxelles, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Villois","sequence":"additional","affiliation":[{"name":"Department of Intensive Care, Erasme Hospital, Universit\u00e9 Libre de Bruxelles, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1091-6130","authenticated-orcid":false,"given":"Marc H","family":"Scheetz","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA"},{"name":"Department of Pharmacy Practice and Pharmacometrics Center of Excellence, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA"},{"name":"Department of Pharmacology, College of Graduate Studies, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel J","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA"},{"name":"Department of Pharmacy Practice and Pharmacometrics Center of Excellence, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA"},{"name":"Department of Pharmacology, College of Graduate Studies, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA"},{"name":"Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA"},{"name":"Department of Pharmacy Practice and Pharmacometrics Center of Excellence, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Briscoe","sequence":"additional","affiliation":[{"name":"Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"McWhinney","sequence":"additional","affiliation":[{"name":"Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Nunez-Nunez","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Department of Infectious Diseases, University Hospital San Cecilio, Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacobus","family":"Ungerer","sequence":"additional","affiliation":[{"name":"Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia"},{"name":"Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Lipman","sequence":"additional","affiliation":[{"name":"UQ Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia"},{"name":"Royal Brisbane and Women\u2019s Hospital, Brisbane, Queensland, Australia"},{"name":"Division of Anaesthesiology Critical Care Emergency and Pain Medicine, N\u00eemes University Hospital, University of Montpellier, N\u00eemes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6218-435X","authenticated-orcid":false,"given":"Jason A","family":"Roberts","sequence":"additional","affiliation":[{"name":"UQ Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia"},{"name":"Royal Brisbane and Women\u2019s Hospital, Brisbane, Queensland, Australia"},{"name":"Division of Anaesthesiology Critical Care Emergency and Pain Medicine, N\u00eemes University Hospital, University of Montpellier, N\u00eemes, France"},{"name":"Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,10,26]]},"reference":[{"key":"2019103013331028100_dkz437-B1","doi-asserted-by":"crossref","first-page":"e0194210.","DOI":"10.1371\/journal.pone.0194210","article-title":"ICU mortality following ICU-acquired primary bloodstream infections according to the type of pathogen: a prospective cohort study in 937 Germany ICUs (2006\u20132015)","volume":"13","author":"Schwab","year":"2018","journal-title":"PLoS One"},{"key":"2019103013331028100_dkz437-B2","doi-asserted-by":"crossref","first-page":"R100.","DOI":"10.1186\/cc10114","article-title":"Acquired bloodstream infection in the intensive care unit: incidence and attributable mortality","volume":"15","author":"Prowle","year":"2011","journal-title":"Crit Care"},{"key":"2019103013331028100_dkz437-B3","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.ijantimicag.2014.12.018","article-title":"Cefepime free minimum concentration to minimum inhibitory concentration (fCmin\/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia","volume":"45","author":"Aitken","year":"2015","journal-title":"Int J Antimicrob Agents"},{"key":"2019103013331028100_dkz437-B4","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1093\/jac\/dkf130","article-title":"Pharmacodynamics of cefepime in patients with Gram-negative infections","volume":"50","author":"Tam","year":"2002","journal-title":"J Antimicrob Chemother"},{"key":"2019103013331028100_dkz437-B5","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1128\/AAC.00294-06","article-title":"Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections","volume":"51","author":"Li","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"2019103013331028100_dkz437-B6","doi-asserted-by":"crossref","first-page":"e02534-17","DOI":"10.1128\/AAC.02534-17","article-title":"\u03b2-Lactam dosage regimens in septic patients with augmented renal clearance","volume":"62","author":"Jacobs","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2019103013331028100_dkz437-B7","doi-asserted-by":"crossref","first-page":"3087","DOI":"10.1093\/jac\/dky314","article-title":"Therapeutic drug monitoring of \u03b2-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures","volume":"73","author":"Wong","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2019103013331028100_dkz437-B8","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.talanta.2012.10.024","article-title":"Rapid quantification of six \u03b2-lactams to optimize dosage regimens in severely septic patients","volume":"103","author":"Wolff","year":"2013","journal-title":"Talanta"},{"key":"2019103013331028100_dkz437-B9","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jchromb.2012.09.016","article-title":"A method for determining the free (unbound) concentration of ten \u03b2-lactam antibiotics in human plasma using high performance liquid chromatography with ultraviolet detection","volume":"907","author":"Briscoe","year":"2012","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"2019103013331028100_dkz437-B10","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.diagmicrobio.2017.03.008","article-title":"Relationship between vancomycin exposure and outcomes among patients with MRSA bloodstream infections with vancomycin Etest\u00ae MIC values of 1.5mg\/L: a pilot study","volume":"88","author":"Martirosov","year":"2017","journal-title":"Diagn Microbiol Infect Dis"},{"key":"2019103013331028100_dkz437-B11","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1128\/AAC.01956-15","article-title":"Defining clinical exposures of cefepime for Gram-negative bloodstream infections that are associated with improved survival","volume":"60","author":"Rhodes","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2019103013331028100_dkz437-B12","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1046\/j.1365-2125.2003.01797.x","article-title":"Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis","volume":"55","author":"Tomaselli","year":"2002","journal-title":"Br J Clin Pharmacol"},{"key":"2019103013331028100_dkz437-B13","doi-asserted-by":"crossref","first-page":"4390","DOI":"10.1128\/AAC.01487-06","article-title":"Failure of current cefepime breakpoints to predict clinical outcomes of bacteremia caused by Gram-negative organisms","volume":"51","author":"Bhat","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"2019103013331028100_dkz437-B14","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.ijantimicag.2017.04.023","article-title":"Defining the impact of severity of illness on time above the MIC threshold for cefepime in Gram-negative bacteraemia: a \u2018Goldilocks\u2019 window","volume":"50","author":"Miglis","year":"2017","journal-title":"Int J Antimicrob Agents"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jac\/advance-article-pdf\/doi\/10.1093\/jac\/dkz437\/30313993\/dkz437.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jac\/advance-article-pdf\/doi\/10.1093\/jac\/dkz437\/30313993\/dkz437.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,30]],"date-time":"2019-10-30T14:15:21Z","timestamp":1572444921000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/advance-article\/doi\/10.1093\/jac\/dkz437\/5607718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,26]]},"references-count":14,"URL":"https:\/\/doi.org\/10.1093\/jac\/dkz437","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,26]]},"article-number":"dkz437"}}