{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T00:46:43Z","timestamp":1759538803580,"version":"build-2065373602"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001704","name":"European Society of Clinical Microbiology and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001704","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>We investigated the use of time-to-positivity (Tpos), a readily available parameter measured from automated blood culture incubators, as a surrogate marker for serum antimicrobial activity during antibiotic treatment against ESBL- and carbapenemase-producing Klebsiella pneumoniae.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Banked human serum spiked with clinically representative concentrations of different antibiotics was injected into aerobic blood culture bottles containing 1\u200a\u00d7\u200a104 mL inoculum of K. pneumoniae isolates. The time required for the test inoculum to \u2018grow through\u2019 serum antibacterial activity (Tpos) was then measured over 24 h. Serum containing combinations of antibiotics were also tested using an 8\u200a\u00d7\u200a8 combination array to assess synergistic or antagonistic interactions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Tpos increased from &amp;lt;10 to &amp;gt;24 h with increasing serum antibiotic concentrations for all drug-isolate combinations tested with the EC50 Tpos of \u223c17 h for all isolates. The EC50 for ceftazidime\/avibactam (4:1) ranged from 5.73 mg\/L (95% CI, 5.60\u20135.37) for a WT strain (MIC 0.125 mg\/L) to 377 mg\/L (95% CI, 356.26\u2013398.41) for a resistant KPC-3-producing isolate (MIC 16 mg\/L). Variation in observed Tpos was linked to isolate MIC (R2\u200a=\u200a0.94). Antibiotic combinations marginally increased serum Tpos (1\u20133 h) for most isolates with the exception of ceftazidime\/avibactam\u200a+\u200ameropenem or aztreonam against KPC-3-producing isolates (increase of 10.36\u201311.61 h) or ceftazidime\/avibactam\u200a+\u200aaztreonam against an NDM-2 isolate (increase of 10.33 h).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Tpos is a simple, reproducible marker of serum antibiotic activity against ESBL- and carbapenemase-producing K. pneumoniae. With further clinical validation, Tpos could be developed as a complementary surrogate marker for early detection of inadequate antimicrobial therapy in patients receiving antibiotic therapy for bloodstream infections caused by MDR Gram-negative bacteria.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkaf276","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T09:00:26Z","timestamp":1755162026000},"page":"2705-2713","source":"Crossref","is-referenced-by-count":0,"title":["Development of blood culture time-to-positivity as a pharmacodynamic indicator for monitoring antibiotic therapy against MDR Gram-negative bacteria"],"prefix":"10.1093","volume":"80","author":[{"given":"Irene","family":"Zaghi","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, University Hospital of Galway , Newcastle Road, Galway H91YR71 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Cricca","sequence":"additional","affiliation":[{"name":"Unit of Microbiology, The Greater Romagna Area Hub Laboratory , Piazza della Liberazione 60, Cesena 47522 ,","place":["Italy"]},{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna , via Massarenti 9, Bologna 40138 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason A","family":"Roberts","sequence":"additional","affiliation":[{"name":"University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland , Building 71\/918 RBWH Herston, Brisbane ,","place":["Australia"]},{"name":"Herston Infectious Diseases Institute (HeiDI), Metro North Health, UQ Centre for Clinical Research Royal Brisbane and Women's Hospital , Herston, Brisbane, QLD 4029 ,","place":["Australia"]},{"name":"Department of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women\u2019s Hospital , Butterfield St., Herston, Brisbane, QLD 4029 ,","place":["Australia"]},{"name":"Division of Anaesthesiology Critical Care Emergency and Pain Medicine, N\u00eemes University Hospital, University of Montpellier , 4 Rue du Professeur Robert Debr\u00e9, N\u00eemes 30900 ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Brandolini","sequence":"additional","affiliation":[{"name":"Unit of Microbiology, The Greater Romagna Area Hub Laboratory , Piazza della Liberazione 60, Cesena 47522 ,","place":["Italy"]},{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna , via Massarenti 9, Bologna 40138 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4135-9402","authenticated-orcid":false,"given":"Claudia","family":"Colosimo","sequence":"additional","affiliation":[{"name":"Unit of Microbiology, The Greater Romagna Area Hub Laboratory , Piazza della Liberazione 60, Cesena 47522 ,","place":["Italy"]},{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna , via Massarenti 9, Bologna 40138 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Montanari","sequence":"additional","affiliation":[{"name":"Unit of Microbiology, The Greater Romagna Area Hub Laboratory , Piazza della Liberazione 60, Cesena 47522 ,","place":["Italy"]},{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna , via Massarenti 9, Bologna 40138 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vittorio","family":"Sambri","sequence":"additional","affiliation":[{"name":"Unit of Microbiology, The Greater Romagna Area Hub Laboratory , Piazza della Liberazione 60, Cesena 47522 ,","place":["Italy"]},{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna , via Massarenti 9, Bologna 40138 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell E","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine , University of Padua, Via Gabelli 63, Padua 35121 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"2025100314262245400_dkaf276-B1","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1093\/cid\/ciu027","article-title":"DALI: defining antibiotic levels in intensive care unit patients: are current \u03b2-lactam antibiotic doses sufficient for critically ill patients?","volume":"58","author":"Roberts","year":"2014","journal-title":"Clin Infect Dis"},{"key":"2025100314262245400_dkaf276-B2","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s00134-021-06609-6","article-title":"Effect of therapeutic drug monitoring-based dose optimization of piperacillin\/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial","volume":"48","author":"Hagel","year":"2022","journal-title":"Intensive Care Med"},{"key":"2025100314262245400_dkaf276-B3","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1007\/s00134-022-06921-9","article-title":"Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial","volume":"48","author":"Ewoldt","year":"2022","journal-title":"Intensive Care Med"},{"key":"2025100314262245400_dkaf276-B4","doi-asserted-by":"publisher","first-page":"e0726","DOI":"10.1097\/CCE.0000000000000726","article-title":"\u03b2-Lactam therapeutic drug monitoring in critically ill patients: weighing the challenges and opportunities to assess clinical value","volume":"4","author":"Dilworth","year":"2022","journal-title":"Crit Care Explor"},{"key":"2025100314262245400_dkaf276-B5","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/s13054-023-04527-1","article-title":"International survey of antibiotic dosing and monitoring in adult intensive care units","volume":"27","author":"Williams","year":"2023","journal-title":"Crit Care"},{"key":"2025100314262245400_dkaf276-B6","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1097\/FTD.0000000000001059","article-title":"Why is the implementation of beta-lactam therapeutic drug monitoring for the critically ill falling short? A multicenter mixed-methods study","volume":"45","author":"Barreto","year":"2023","journal-title":"Ther Drug Monit"},{"key":"2025100314262245400_dkaf276-B7","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1016\/j.cmi.2020.04.036","article-title":"Serum bactericidal titres for monitoring antimicrobial therapy: current status and potential role in the management of multidrug-resistant Gram-negative infections","volume":"26","author":"Zaghi","year":"2020","journal-title":"Clin Microbiol Infect"},{"key":"2025100314262245400_dkaf276-B8","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1111\/j.1469-0691.2004.01054.x","article-title":"Development of a time-to-positivity assay as a tool in the antibiotic management of septic patients","volume":"11","author":"Kaltsas","year":"2005","journal-title":"Clin Microbiol Infect"},{"key":"2025100314262245400_dkaf276-B9","doi-asserted-by":"publisher","first-page":"320.e1","DOI":"10.1016\/j.jcrc.2011.06.009","article-title":"A pilot clinical trial to evaluate a novel time-to-positivity assay to measure the effectiveness of antibiotic therapy for septic patients in intensive care","volume":"27","author":"Jerwood","year":"2012","journal-title":"J Crit Care"},{"key":"2025100314262245400_dkaf276-B10","volume-title":"Methodology for the Serum Bactericidal Test; Approved Guidelines: M21-A","author":"CLSI","year":"1999"},{"key":"2025100314262245400_dkaf276-B11","volume-title":"Methods for Determining Bactericidal Activity of Antimicrobial Agents: Approved Guideline","author":"National Committee for Clinical Laboratory Standards","year":"1999"},{"key":"2025100314262245400_dkaf276-B12","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2020"},{"key":"2025100314262245400_dkaf276-B13","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-98141-3","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"Wickham","year":"2009"},{"key":"2025100314262245400_dkaf276-B14","doi-asserted-by":"publisher","first-page":"17935","DOI":"10.1038\/s41598-017-18068-5","article-title":"BIGL: biochemically intuitive generalized Loewe null model for prediction of the expected combined effect compatible with partial agonism and antagonism","volume":"7","author":"Van der Borght","year":"2017","journal-title":"Sci Rep"},{"key":"2025100314262245400_dkaf276-B15","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1002\/pst.2173","article-title":"Statistical detection of synergy: new methods and a comparative study","volume":"21","author":"Thas","year":"2022","journal-title":"Pharm Stat"},{"key":"2025100314262245400_dkaf276-B16","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-022-07098-8","article-title":"Short time to positivity of blood culture predicts mortality and septic shock in bacteremic patients: a systematic review and meta-analysis","volume":"22","author":"Hsieh","year":"2022","journal-title":"BMC Infect Dis"},{"key":"2025100314262245400_dkaf276-B17","doi-asserted-by":"publisher","first-page":"17","DOI":"10.2217\/fmb-2021-0004","article-title":"A longitudinal population-based study of predictors of mortality from bloodstream infections in Calgary, Alberta, Canada","volume":"17","author":"Church","year":"2022","journal-title":"Future Microbiol"},{"key":"2025100314262245400_dkaf276-B18","doi-asserted-by":"publisher","first-page":"136.e7","DOI":"10.1016\/j.cmi.2021.05.043","article-title":"Time to positivity in bloodstream infection is not a prognostic marker for mortality: analysis of a prospective multicentre randomized control trial","volume":"28","author":"Hamilton","year":"2022","journal-title":"Clin Microbiol Infect"},{"key":"2025100314262245400_dkaf276-B19","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.cmi.2024.03.032","article-title":"Time to positivity is a risk factor for death among patients with bloodstream infections: a population-based cohort","volume":"30","author":"Laupland","year":"2024","journal-title":"Clin Microbiol Infect"},{"key":"2025100314262245400_dkaf276-B20","doi-asserted-by":"publisher","first-page":"3502","DOI":"10.1128\/JCM.01241-17","article-title":"Effects of clinically meaningful concentrations of antipseudomonal \u03b2-lactams on time to detection and organism growth in blood culture bottles","volume":"55","author":"Grupper","year":"2017","journal-title":"J Clin Microbiol"},{"key":"2025100314262245400_dkaf276-B21","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1128\/JCM.02064-06","article-title":"Comparison of BACTEC PLUS blood culture media to BacT\/Alert FA blood culture media for detection of bacterial pathogens in samples containing therapeutic levels of antibiotics","volume":"45","author":"Flayhart","year":"2007","journal-title":"J Clin Microbiol"},{"key":"2025100314262245400_dkaf276-B22","doi-asserted-by":"publisher","first-page":"e00849-19","DOI":"10.1128\/JCM.00849-19","article-title":"Recovery of gram-negative bacteria from aerobic blood culture bottles containing antibiotic binding resins after exposure to \u03b2-lactam and fluoroquinolone concentrations","volume":"57","author":"Chen","year":"2019","journal-title":"J Clin Microbiol"},{"key":"2025100314262245400_dkaf276-B23","doi-asserted-by":"publisher","first-page":"e02273-17","DOI":"10.1128\/AAC.02273-17","article-title":"Population pharmacokinetics of high-dose tigecycline in patients with sepsis or septic shock","volume":"62","author":"Borsuk-De Moor","year":"2018","journal-title":"Antimicrob Agents Chemother"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/80\/10\/2705\/64043514\/dkaf276.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/80\/10\/2705\/64043514\/dkaf276.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T18:26:35Z","timestamp":1759515995000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/80\/10\/2705\/8234236"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,14]]},"references-count":23,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,8,14]]},"published-print":{"date-parts":[[2025,10,3]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkaf276","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,8,14]]}}}