{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T15:21:47Z","timestamp":1784128907469,"version":"3.55.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:00:00Z","timestamp":1697414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017639","name":"Entasis Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017639","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Sulbactam-durlobactam is a potent combination active against Acinetobacter baumannii; however, it lacks activity against other nosocomial pathogens. Cefepime is a common first-line therapy for hospital\/ventilator-associated pneumonia caused by Gram-negative pathogens including Pseudomonas aeruginosa and Enterobacterales. With increasing resistance to cefepime, and the significant proportion of polymicrobial nosocomial infections, effective therapy for infections caused by Acinetobacter baumannii, P. aeruginosa and Enterobacterales is needed. This study investigated the in vitro synergy of sulbactam-durlobactam plus cefepime against relevant pathogens.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Static time\u2013kills assays were performed in duplicate against 14 cefepime-resistant isolates (A. baumannii, n\u200a=\u200a4; P. aeruginosa, n\u200a=\u200a4; Escherichia coli, n\u200a=\u200a3; Klebsiella pneumoniae, n\u200a=\u200a3). One WT K. pneumoniae isolate was included. Antibiotic concentrations simulated the free-steady state average concentration of clinically administered doses in patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Sulbactam-durlobactam alone showed significant activity against A. baumannii consistent with the MIC values. Sulbactam-durlobactam plus cefepime showed synergy against one A. baumannii isolate with an elevated MIC to sulbactam-durlobactam (32 mg\/L). Against all P. aeruginosa isolates, synergy was observed with sulbactam-durlobactam plus cefepime. For the Enterobacterales, one E. coli isolate demonstrated synergy while the others were indifferent due to significant kill from sulbactam-durlobactam alone. The combination of sulbactam-durlobactam plus cefepime showed synergy against one of the K. pneumoniae and additive effects against the other two K. pneumoniae tested. No antagonism was observed in any isolates including the WT strain.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Synergy and no antagonism was observed with a combination of sulbactam-durlobactam and cefepime; further in vivo pharmacokinetic\/pharmacodynamics data and clinical correlation are necessary to support our findings.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkad244","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T01:44:42Z","timestamp":1697420682000},"page":"2801-2809","source":"Crossref","is-referenced-by-count":16,"title":["<i>In vitro<\/i> synergy of the combination of sulbactam-durlobactam and cefepime at clinically relevant concentrations against <i>A. baumannii<\/i>, <i>P. aeruginosa<\/i> and Enterobacterales"],"prefix":"10.1093","volume":"78","author":[{"given":"Aliaa","family":"Fouad","sequence":"first","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P","family":"Nicolau","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, CT , USA"},{"name":"Division of Infectious Diseases, Hartford Hospital , Hartford, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3606-0761","authenticated-orcid":false,"given":"Christian M","family":"Gill","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,16]]},"reference":[{"key":"2023120106063772700_dkad244-B1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.4161\/viru.19700","article-title":"Acinetobacter baumannii: an emerging opportunistic pathogen","volume":"3","author":"Howard","year":"2012","journal-title":"Virulence"},{"key":"2023120106063772700_dkad244-B2","article-title":"New treatment options against carbapenem-resistant Acinetobacter baumannii infections","volume":"63","author":"Isler","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2023120106063772700_dkad244-B3","author":"Doherty News","year":"2021"},{"key":"2023120106063772700_dkad244-B4","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.3390\/pathogens10101310","article-title":"Bacterial antibiotic resistance: the most critical pathogens","volume":"10","author":"Mancuso","year":"2021","journal-title":"Pathogens"},{"key":"2023120106063772700_dkad244-B5","doi-asserted-by":"crossref","first-page":"e61","DOI":"10.1093\/cid\/ciw353","article-title":"Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society","volume":"63","author":"Kalil","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2023120106063772700_dkad244-B6","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fphar.2019.00092","article-title":"Acinetobacter baumannii ventilator-associated pneumonia: clinical efficacy of combined antimicrobial therapy and in vitro drug sensitivity test results","volume":"10","author":"Huang","year":"2019","journal-title":"Front Pharmacol"},{"key":"2023120106063772700_dkad244-B7","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1186\/s12879-022-07436-w","article-title":"Epidemiology and outcomes associated with carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Pseudomonas aeruginosa: a retrospective cohort study","volume":"22","author":"Vivo","year":"2022","journal-title":"BMC Infect Dis"},{"key":"2023120106063772700_dkad244-B8","doi-asserted-by":"crossref","DOI":"10.3389\/fcimb.2022.919414","article-title":"Predictors of occurrence and 30-day mortality for co-infection of carbapenem-resistant Klebsiella pneumoniae and carbapenem-resistant Acinetobacter baumannii","volume":"12","author":"Lv","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"2023120106063772700_dkad244-B9","doi-asserted-by":"crossref","first-page":"17104","DOI":"10.1038\/nmicrobiol.2017.104","article-title":"ETX2514 is a broad-spectrum \u03b2-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii","volume":"2","author":"Durand-R\u00e9ville","year":"2017","journal-title":"Nat Microbiol"},{"key":"2023120106063772700_dkad244-B10","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1093\/jac\/dkaa208","article-title":"In vitro activity of sulbactam\/durlobactam against global isolates of carbapenem-resistant Acinetobacter baumannii","volume":"75","author":"Seifert","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2023120106063772700_dkad244-B11","doi-asserted-by":"crossref","DOI":"10.1128\/aac.00781-22","article-title":"In vitro activity of sulbactam-durlobactam against global isolates of Acinetobacter baumannii-calcoaceticus complex collected from 2016 to 2021","volume":"66","author":"Karlowsky","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"key":"2023120106063772700_dkad244-B12","doi-asserted-by":"crossref","article-title":"Efficacy and safety of sulbactam-durlobactam are consistent across regions in the global ATTACK Phase 3 trial in the treatment of carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRABC) infections","author":"Miller","DOI":"10.1093\/ofid\/ofac492.303"},{"key":"2023120106063772700_dkad244-B13","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jcrc.2009.02.014","article-title":"Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia","volume":"25","author":"Nicasio","year":"2010","journal-title":"J Crit Care"},{"key":"2023120106063772700_dkad244-B14","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.chest.2020.03.087","article-title":"A systematic review of the effect of delayed appropriate antibiotic treatment on the outcomes of patients with severe bacterial infections","volume":"158","author":"Zasowski","year":"2020","journal-title":"Chest"},{"key":"2023120106063772700_dkad244-B15","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.02146-18","article-title":"The novel \u03b2-lactam enhancer zidebactam augments the in vivo pharmacodynamic activity of cefepime in a neutropenic mouse lung Acinetobacter baumannii infection model","volume":"63","author":"Bhagwat","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2023120106063772700_dkad244-B16","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1093\/jac\/dkaa036","article-title":"Effective inhibition of PBPs by cefepime and zidebactam in the presence of VIM-1 drives potent bactericidal activity against MBL-expressing Pseudomonas aeruginosa","volume":"75","author":"Moya","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2023120106063772700_dkad244-B17","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1007\/s10096-021-04308-0","article-title":"The ERACE-PA Global Surveillance Program: ceftolozane\/tazobactam and ceftazidime\/avibactam in vitro activity against a global collection of carbapenem-resistant Pseudomonas aeruginosa","volume":"40","author":"Gill","year":"2021","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"2023120106063772700_dkad244-B18","volume-title":"Performance Standards for Antimicrobial Susceptibility Testing\u2014Thirty-Second Edition: M100","author":"CLSI","year":"2022"},{"key":"2023120106063772700_dkad244-B19","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00997-19","article-title":"In vitro activity of imipenem-relebactam alone or in combination with amikacin or colistin against Pseudomonas aeruginosa","volume":"63","author":"Asempa","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2023120106063772700_dkad244-B20","doi-asserted-by":"crossref","article-title":"Population pharmacokinetic (PPK), pharmacokinetic\/pharmacodynamic attainment (PTA), clinical pharmacokinetic\/pharmacodynamic (PK\/PD) analyses for sulbactam-durlobactam (SUL-DUR) to support dose selection for the treatment of Acinetobacter baumannii\u2013calcoaceticus complex (ABC) infections","author":"Bhavnani","DOI":"10.1093\/ofid\/ofac492.1896"},{"key":"2023120106063772700_dkad244-B21","doi-asserted-by":"crossref","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":"2023120106063772700_dkad244-B22","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s40121-017-0179-5","article-title":"Antimicrobial stewardship opportunities in critically ill patients with Gram-negative lower respiratory tract infections: a multicenter cross-sectional analysis","volume":"7","author":"Claeys","year":"2018","journal-title":"Infect Dis Ther"},{"key":"2023120106063772700_dkad244-B23","doi-asserted-by":"crossref","first-page":"114833","DOI":"10.1016\/j.diagmicrobio.2019.05.005","article-title":"Comparison of ceftazidime-avibactam and ceftolozane-tazobactam in vitro activities when tested against gram-negative bacteria isolated from patients hospitalized with pneumonia in United States medical centers (2017\u20132018)","volume":"96","author":"Sader","year":"2020","journal-title":"Diagn Microbiol Infect Dis"},{"key":"2023120106063772700_dkad244-B24","doi-asserted-by":"crossref","DOI":"10.1093\/ofid\/ofab320","article-title":"Ceftolozane\/tazobactam and imipenem\/relebactam cross-susceptibility among clinical isolates of Pseudomonas aeruginosa from patients with respiratory tract infections in ICU and non-ICU wards\u2014SMART United States 2017\u20132019","volume-title":"Open Forum Infect Dis","author":"Lob","year":"2021"},{"key":"2023120106063772700_dkad244-B25","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1093\/jac\/dkaa511","article-title":"An update on cefepime and its future role in combination with novel \u03b2-lactamase inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa","volume":"76","author":"Isler","year":"2021","journal-title":"J Antimicrob Chemother"},{"key":"2023120106063772700_dkad244-B26","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.ijantimicag.2018.07.011","article-title":"Assessing the in vitro activity of ceftazidime\/avibactam and aztreonam among carbapenemase-producing Enterobacteriaceae: defining the zone of hope","volume":"52","author":"Avery","year":"2018","journal-title":"Int J Antimicrob Agents"},{"key":"2023120106063772700_dkad244-B27","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.2147\/IDR.S402275","article-title":"A simple disk stacking plus micro-elution method for rapid detection of the synergistic effect of aztreonam and ceftazidime\/avibactam against metallo-\u03b2-lactamase producing Enterobacterales","volume":"16","author":"Liu","year":"2023","journal-title":"Infect Drug Resist"},{"key":"2023120106063772700_dkad244-B28","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00948-18","article-title":"Assessment of the in vivo efficacy of WCK 5222 (cefepime-zidebactam) against carbapenem-resistant Acinetobacter baumannii in the neutropenic murine lung infection model","volume":"62","author":"Avery","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2023120106063772700_dkad244-B29","article-title":"In vivo efficacy of humanized WCK 5222 (cefepime-zidebactam) exposures against carbapenem-resistant Acinetobacter baumannii in the neutropenic thigh model","volume":"63","author":"Abuhussain","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2023120106063772700_dkad244-B30","first-page":"149","article-title":"Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model","volume":"75","author":"Kidd","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2023120106063772700_dkad244-B31","article-title":"ETX2514, a novel, rationally designed inhibitor of class A, C and D \u03b2-lactamases, for the treatment of Gram-negative infections","author":"Shapiro"},{"key":"2023120106063772700_dkad244-B32","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1128\/AAC.04819-14","article-title":"Amdinocillin (mecillinam) resistance mutations in clinical isolates and laboratory-selected mutants of Escherichia coli","volume":"59","author":"Thulin","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2023120106063772700_dkad244-B33","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.1093\/jac\/dkw230","article-title":"New insights into the regulatory pathways associated with the activation of the stringent response in bacterial resistance to the PBP2-targeted antibiotics, mecillinam and OP0595\/RG6080","volume":"71","author":"Doumith","year":"2016","journal-title":"J Antimicrob Chemother"},{"key":"2023120106063772700_dkad244-B34","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1186\/s13054-015-1165-5","article-title":"Polymicrobial intensive care unit-acquired pneumonia: prevalence, microbiology and outcome","volume":"19","author":"Ferrer","year":"2015","journal-title":"J Crit Care"},{"key":"2023120106063772700_dkad244-B35","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1378\/chest.121.5.1618","article-title":"Incidence and outcome of polymicrobial ventilator-associated pneumonia","volume":"121","author":"Combes","year":"2002","journal-title":"Chest"},{"key":"2023120106063772700_dkad244-B36","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.ajic.2011.10.013","article-title":"\u201cSwimming in resistance\u201d: co-colonization with carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii or Pseudomonas aeruginosa","volume":"40","author":"Marchaim","year":"2012","journal-title":"Am J Infect Control"},{"key":"2023120106063772700_dkad244-B37","doi-asserted-by":"crossref","DOI":"10.1016\/j.infpip.2022.100255","article-title":"Clinical outcomes associated with co-infection of carbapenem-resistant Enterobacterales and other multidrug-resistant organisms","volume":"4","author":"Tadese","year":"2022","journal-title":"Infection Prevention in Practice"},{"key":"2023120106063772700_dkad244-B38","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1186\/s12879-022-07755-y","article-title":"The risk of inappropriate empiric treatment and its outcomes based on pathogens in non-ventilated (nvHABP), ventilated (vHABP) hospital-acquired and ventilator-associated (VABP) bacterial pneumonia in the US, 2012\u20132019","volume":"22","author":"Zilberberg","year":"2022","journal-title":"BMC Infect Dis"},{"key":"2023120106063772700_dkad244-B39","doi-asserted-by":"crossref","first-page":"e0667","DOI":"10.1097\/CCE.0000000000000667","article-title":"Inappropriate empiric therapy impacts complications and hospital resource utilization differentially among different types of bacterial nosocomial pneumonia: a cohort study, United States, 2014\u20132019","volume":"4","author":"Zilberberg","year":"2022","journal-title":"Crit Care Explor"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/78\/12\/2801\/53850570\/dkad244.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/78\/12\/2801\/53850570\/dkad244.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T06:07:50Z","timestamp":1701410870000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/78\/12\/2801\/7236921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,16]]},"references-count":39,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,10,16]]},"published-print":{"date-parts":[[2023,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkad244","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,12]]},"published":{"date-parts":[[2023,10,16]]}}}