{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:07:15Z","timestamp":1786975635395,"version":"build-2736575974"},"reference-count":42,"publisher":"American Medical Association (AMA)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Current evidence is conflicting for associations of extended-infusion \u03b2-lactam (EI-BL) therapy with clinical outcomes.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To investigate the association of EI-BL therapy with survival, adverse events, and emergence of antibiotic resistance in adults with gram-negative bloodstream infections (GN-BSI).<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This cohort study of consecutive adults with GN-BSI admitted to 24 United States hospitals between January 1, 2019, and December 31, 2019, receiving EI-BL were compared with adults with GN-BSI receiving the same agents as intermittent infusion \u03b2-lactam (II-BL; \u22641-hour infusions). Statistical analysis was performed from January to October 2023.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n EI-BL (ie, \u22653-hour infusion).<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n EI-BL and II-BL groups underwent 1:3 nearest-neighbor propensity score matching (PSM) without replacement. Multivariable regression was applied to the PSM cohort to investigate outcomes, all censored at day 90. The primary outcome was mortality; secondary outcomes included antibiotic adverse events and emergence of resistance (\u22654-fold increase in the minimum inhibitory concentration of the \u03b2-lactam used to treat the index GN-BSI).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among the 4861 patients included, 2547 (52.4%) were male; and the median (IQR) age was 67 (55-77) years. There were 352 patients in the EI-BL 1:3 PSM group, and 1056 patients in the II-BL 1:3 PSM group. Among 1408 PSM patients, 373 (26.5%) died by day 90. The odds of mortality were lower in the EI-BL group (adjusted odds ratio [aOR], 0.71 [95% CI, 0.52-0.97]). In a stratified analysis, a survival benefit was only identified in patients with severe illness or elevated minimum inhibitory concentrations (ie, in the intermediate range for the antibiotic administered). There were increased odds of catheter complications (aOR, 3.14 [95% CI, 1.66-5.96]) and antibiotic discontinuation because of adverse events (eg, acute kidney injury, cytopenias, seizures) in the EI-BL group (aOR, 3.66 [95% CI, 1.68-7.95]). Emergence of resistance was similar in the EI-BL and II-BL groups at 2.9% vs 7.2%, respectively (\n P<\/jats:italic>\n \u2009=\u2009.35).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this cohort study of patients with GN-BSI, EI-BL therapy was associated with reduced mortality for patients with severe illness or those infected with nonsusceptible organisms; potential advantages in other groups remain unclear and need to be balanced with potential adverse events. The subsequent emergence of resistance warrants investigation in a larger cohort.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2024.18234","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T11:38:29Z","timestamp":1719920309000},"page":"e2418234","source":"Crossref","is-referenced-by-count":22,"title":["Extended-Infusion \u03b2-Lactam Therapy, Mortality, and Subsequent Antibiotic Resistance Among Hospitalized Adults With Gram-Negative Bloodstream Infections"],"prefix":"10.1001","volume":"7","author":[{"given":"Sara M.","family":"Karaba","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Cosgrove","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Hyoung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suiyini","family":"Fiawoo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily L.","family":"Heil","sequence":"additional","affiliation":[{"name":"Department of Practice, Sciences, and Health-Outcomes Research, University of Maryland School of Pharmacy, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelyn S.","family":"Quartuccio","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Rochester Medical Center, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine C.","family":"Shihadeh","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Denver Health Medical Center, Denver, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranita D.","family":"Tamma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"issue":"4","key":"zoi240602r1","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1128\/AAC.01141-08","article-title":"Population pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically ill patients with ventilator-associated pneumonia.","volume":"53","author":"Nicasio","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"zoi240602r2","doi-asserted-by":"publisher","first-page":"S42","DOI":"10.1086\/344653","article-title":"Prevention of resistance: a goal for dose selection for antimicrobial agents.","volume":"36","author":"Drusano","year":"2003","journal-title":"Clin Infect Dis"},{"issue":"2","key":"zoi240602r3","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.ijantimicag.2009.10.008","article-title":"First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis.","volume":"35","author":"Roberts","year":"2010","journal-title":"Int J Antimicrob Agents"},{"issue":"2","key":"zoi240602r4","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.ijantimicag.2013.10.021","article-title":"Prolonging \u00df-lactam infusion: a review of the rationale and evidence, and guidance for implementation.","volume":"43","author":"MacVane","year":"2014","journal-title":"Int J Antimicrob Agents"},{"issue":"2","key":"zoi240602r5","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1345\/aph.1G467","article-title":"Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli.","volume":"40","author":"Lorente","year":"2006","journal-title":"Ann Pharmacother"},{"issue":"11","key":"zoi240602r6","doi-asserted-by":"publisher","first-page":"2433","DOI":"10.1016\/j.clinthera.2007.11.003","article-title":"Comparison of clinical cure rates in adults with ventilator-associated pneumonia treated with intravenous ceftazidime administered by continuous or intermittent infusion: a retrospective, nonrandomized, open-label, historical chart review.","volume":"29","author":"Lorente","year":"2007","journal-title":"Clin Ther"},{"issue":"5","key":"zoi240602r7","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1016\/j.ijantimicag.2008.10.025","article-title":"Clinical cure of ventilator-associated pneumonia treated with piperacillin\/tazobactam administered by continuous or intermittent infusion.","volume":"33","author":"Lorente","year":"2009","journal-title":"Int J Antimicrob Agents"},{"issue":"2","key":"zoi240602r8","doi-asserted-by":"publisher","first-page":"187","DOI":"10.5863\/1551-6776-26.2.187","article-title":"Extended infusion of beta-lactams is associated with improved outcomes in pediatric patients.","volume":"26","author":"Zembles","year":"2021","journal-title":"J Pediatr Pharmacol Ther"},{"issue":"9","key":"zoi240602r9","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1093\/cid\/ciab176","article-title":"Ceftazidime-avibactam use for Klebsiella pneumoniae carbapenemase-producing K. pneumoniae infections: a retrospective observational multicenter study.","volume":"73","author":"Tumbarello","year":"2021","journal-title":"Clin Infect Dis"},{"issue":"3","key":"zoi240602r10","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofad034","article-title":"High-dose cefepime vs carbapenems for bacteremia caused by enterobacterales with moderate to high risk of clinically significant AmpC \u00df-lactamase production.","volume":"10","author":"Kunz Coyne","year":"2023","journal-title":"Open Forum Infect Dis"},{"issue":"4","key":"zoi240602r11","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofad170","article-title":"Clinical outcomes with extended versus intermittent infusion of anti-pseudomonal beta-lactams in patients with gram-negative bacteremia.","volume":"10","author":"Tran","year":"2023","journal-title":"Open Forum Infect Dis"},{"issue":"6","key":"zoi240602r12","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/S0002-9610(00)00388-3","article-title":"Intermittent and continuous ceftazidime infusion for critically ill trauma patients.","volume":"179","author":"Hanes","year":"2000","journal-title":"Am J Surg"},{"issue":"6","key":"zoi240602r13","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0924-8579(01)00329-6","article-title":"Continuous versus intermittent administration of ceftazidime in intensive care unit patients with nosocomial pneumonia.","volume":"17","author":"Nicolau","year":"2001","journal-title":"Int J Antimicrob Agents"},{"issue":"11","key":"zoi240602r14","doi-asserted-by":"publisher","first-page":"3556","DOI":"10.1128\/AAC.00329-06","article-title":"Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection.","volume":"50","author":"Lau","year":"2006","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"zoi240602r15","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.ijantimicag.2006.02.020","article-title":"Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients.","volume":"28","author":"Rafati","year":"2006","journal-title":"Int J Antimicrob Agents"},{"issue":"2","key":"zoi240602r16","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1093\/jac\/dkl478","article-title":"Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? a randomized controlled pilot study.","volume":"59","author":"Roberts","year":"2007","journal-title":"J Antimicrob Chemother"},{"issue":"9","key":"zoi240602r17","doi-asserted-by":"publisher","first-page":"3304","DOI":"10.1128\/AAC.01318-06","article-title":"Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial.","volume":"51","author":"Sakka","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"zoi240602r18","doi-asserted-by":"publisher","first-page":"R113","DOI":"10.1186\/cc11405","article-title":"Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial.","volume":"16","author":"Chytra","year":"2012","journal-title":"Crit Care"},{"issue":"2","key":"zoi240602r19","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1093\/cid\/cis856","article-title":"Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial.","volume":"56","author":"Dulhunty","year":"2013","journal-title":"Clin Infect Dis"},{"issue":"11","key":"zoi240602r20","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1164\/rccm.201505-0857OC","article-title":"A multicenter randomized trial of continuous versus intermittent \u00df-lactam infusion in severe sepsis.","volume":"192","author":"Dulhunty","year":"2015","journal-title":"Am J Respir Crit Care Med"},{"issue":"10","key":"zoi240602r21","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1007\/s00134-015-4188-0","article-title":"Beta-lactam infusion in severe sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis.","volume":"42","author":"Abdul-Aziz","year":"2016","journal-title":"Intensive Care Med"},{"issue":"1","key":"zoi240602r22","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S1441-2772(23)00582-3","article-title":"A protocol for a phase 3 multicentre randomised controlled trial of continuous versus intermittent \u00df-lactam antibiotic infusion in critically ill patients with sepsis: BLING III.","volume":"21","author":"Lipman","year":"2019","journal-title":"Crit Care Resusc"},{"issue":"11","key":"zoi240602r23","doi-asserted-by":"publisher","first-page":"e4599","DOI":"10.1093\/cid\/ciaa1306","article-title":"Modifiable risk factors for the emergence of ceftolozane-tazobactam resistance.","volume":"73","author":"Tamma","year":"2021","journal-title":"Clin Infect Dis"},{"issue":"7","key":"zoi240602r24","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofad265","article-title":"Epidemiology of gram-negative bloodstream infections in the United States: results from a cohort of 24 hospitals.","volume":"10","author":"Ince","year":"2023","journal-title":"Open Forum Infect Dis"},{"issue":"6","key":"zoi240602r25","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1097\/EDE.0b013e3181577654","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.","volume":"18","author":"von Elm","year":"2007","journal-title":"Epidemiology"},{"issue":"2","key":"zoi240602r27","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1097\/SHK.0b013e318182f98f","article-title":"Scoring systems for prediction of mortality in patients with intensive care unit-acquired sepsis: a comparison of the Pitt bacteremia score and the Acute Physiology and Chronic Health Evaluation II scoring systems.","volume":"31","author":"Rhee","year":"2009","journal-title":"Shock"},{"issue":"9","key":"zoi240602r28","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1001\/jamainternmed.2017.1938","article-title":"Association of adverse events with antibiotic use in hospitalized patients.","volume":"177","author":"Tamma","year":"2017","journal-title":"JAMA Intern Med"},{"issue":"9","key":"zoi240602r29","doi-asserted-by":"publisher","first-page":"e497","DOI":"10.1093\/cid\/ciaa169","article-title":"Comparing propensity score methods versus traditional regression analysis for the evaluation of observational data: a case study evaluating the treatment of gram-negative bloodstream infections.","volume":"71","author":"Amoah","year":"2020","journal-title":"Clin Infect Dis"},{"issue":"3","key":"zoi240602r30","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1086\/510590","article-title":"Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy.","volume":"44","author":"Lodise","year":"2007","journal-title":"Clin Infect Dis"},{"issue":"8","key":"zoi240602r31","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1592\/phco.31.8.767","article-title":"The Retrospective Cohort of Extended-Infusion Piperacillin-Tazobactam (RECEIPT) study: a multicenter study.","volume":"31","author":"Yost","year":"2011","journal-title":"Pharmacotherapy"},{"issue":"6","key":"zoi240602r32","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1164\/rccm.201601-0024OC","article-title":"Continuous versus intermittent \u00df-lactam infusion in severe sepsis. a meta-analysis of individual patient data from randomized trials.","volume":"194","author":"Roberts","year":"2016","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"zoi240602r33","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/S1473-3099(17)30615-1","article-title":"Prolonged versus short-term intravenous infusion of antipseudomonal \u00df-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials.","volume":"18","author":"Vardakas","year":"2018","journal-title":"Lancet Infect Dis"},{"issue":"2","key":"zoi240602r34","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1097\/CCM.0000000000002836","article-title":"Prolonged infusion piperacillin-tazobactam decreases mortality and improves outcomes in severely ill patients: results of a systematic review and meta-analysis.","volume":"46","author":"Rhodes","year":"2018","journal-title":"Crit Care Med"},{"issue":"9","key":"zoi240602r36","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1093\/jac\/dkad215","article-title":"Loading dose plus continuous\/extended infusion versus intermittent bolus of \u00df-lactams for the treatment of Gram-negative bacteria bloodstream infections: a propensity score-adjusted retrospective cohort study.","volume":"78","author":"Bavaro","year":"2023","journal-title":"J Antimicrob Chemother"},{"issue":"8","key":"zoi240602r37","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 \u00df-lactam antibiotic doses sufficient for critically ill patients?","volume":"58","author":"Roberts","year":"2014","journal-title":"Clin Infect Dis"},{"issue":"12","key":"zoi240602r38","doi-asserted-by":"publisher","first-page":"3644","DOI":"10.1093\/jac\/dkaa359","article-title":"Early therapeutic monitoring of \u00df-lactams and associated therapy outcomes in critically ill patients.","volume":"75","author":"Al-Shaer","year":"2020","journal-title":"J Antimicrob Chemother"},{"issue":"8","key":"zoi240602r39","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1002\/phar.v43.8","article-title":"International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists.","volume":"43","author":"Hong","year":"2023","journal-title":"Pharmacotherapy"},{"key":"zoi240602r40","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.jcrc.2018.07.003","article-title":"Emergence of antimicrobial resistance to piperacillin\/tazobactam or meropenem in the ICU: intermittent versus continuous infusion. a retrospective cohort study.","volume":"47","author":"Dhaese","year":"2018","journal-title":"J Crit Care"},{"issue":"1","key":"zoi240602r41","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s13613-017-0296-z","article-title":"Emergence of antimicrobial resistance to Pseudomonas aeruginosa in the intensive care unit: association with the duration of antibiotic exposure and mode of administration.","volume":"7","author":"Yusuf","year":"2017","journal-title":"Ann Intensive Care"},{"issue":"1","key":"zoi240602r42","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":"zoi240602r26","volume-title":"M100 Performance Standards for Antimicrobial Susceptibility Testing","author":"Clinical Laboratory Standards Institute","year":"2023","edition":"33rd ed"},{"key":"zoi240602r35","author":"Monti","year":"2023"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2820673\/karaba_2024_oi_240602_1719332769.43152.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T11:38:35Z","timestamp":1719920315000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2820673"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,2]]},"references-count":42,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2024.18234","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,2]]}}}