{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:30:35Z","timestamp":1788363035856,"version":"build-2803163510"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T00:00:00Z","timestamp":1686096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M008665\/1"],"award-info":[{"award-number":["MR\/M008665\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Infection with ESBL-producing Enterobacteriaceae infection is ubiquitous in some neonatal ICUs and increasing levels of antibiotic resistance are a cause for urgent concern. Delineation of bacterial and viral sepsis can be challenging, often leading to patients receiving empirical antibiotics without or whilst waiting for a definitive causal diagnosis. Empirical therapy is often dependent on broad-spectrum \u2018Watch\u2019 antibiotics, contributing to further resistance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>ESBL-producing Enterobacteriaceae clinical isolates found to have caused neonatal sepsis and meningitis underwent a detailed in vitro screening including susceptibility testing, chequerboard combination analysis and hollow-fibre infection model dynamic analyses using combinations of cefotaxime, ampicillin and gentamicin in combination with \u03b2-lactamase inhibitors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Additivity or synergy was found for all antibiotic combinations against seven Escherichia coli and three Klebsiella pneumoniae clinical isolates. Cefotaxime or ampicillin plus sulbactam combined with gentamicin was able to consistently inhibit the growth of ESBL-producing isolates at typical neonatal doses, and the combination cleared the hollow-fibre infection model system of organisms resistant to each agent alone. The combination of cefotaxime\/sulbactam and gentamicin was consistently bactericidal at clinically achievable concentrations (Cmax of 180, 60 and 20 mg\/L for cefotaxime, sulbactam and gentamicin, respectively).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The addition of sulbactam to cefotaxime or ampicillin to the typical first-line empirical therapy could obviate the need for carbapenems and amikacin in settings with high ESBL-infection prevalence.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkad177","type":"journal-article","created":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T00:44:02Z","timestamp":1686185042000},"page":"1882-1890","source":"Crossref","is-referenced-by-count":8,"title":["Cefotaxime\/sulbactam plus gentamicin as a potential carbapenem- and amikacin-sparing first-line combination for neonatal sepsis in high ESBL prevalence settings"],"prefix":"10.1093","volume":"78","author":[{"given":"J B","family":"Readman","sequence":"first","affiliation":[{"name":"Institute of Infection and Immunity, St George\u2019s, University of London , London , UK"},{"name":"Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Acman","sequence":"additional","affiliation":[{"name":"UCL Genetics Institute, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Hamawandi","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity, St George\u2019s, University of London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Hsun","family":"Chiu","sequence":"additional","affiliation":[{"name":"Chang Gung Memorial Hospital, Chang Gung University , Taoyuan , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Sharland","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity, St George\u2019s, University of London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J A","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity, St George\u2019s, University of London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4561-7173","authenticated-orcid":false,"given":"J F","family":"Standing","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity, St George\u2019s, University of London , London , UK"},{"name":"Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health , London , UK"},{"name":"Department of Pharmacy, Great Ormond Street Hospital for Children , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,6,7]]},"reference":[{"key":"2023080202250255600_dkad177-B1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/s13756-019-0673-5","article-title":"Bacterial pathogens and resistance causing community acquired paediatric bloodstream infections in low- and middle-income countries: a systematic review and meta-analysis","volume":"8","author":"Droz","year":"2019","journal-title":"Antimicrob Resist Infect Control"},{"key":"2023080202250255600_dkad177-B2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1093\/cid\/ciy834","article-title":"Emerging resistance to empiric antimicrobial regimens for pediatric bloodstream infections in Malawi (1998\u20132017)","volume":"69","author":"Tam","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2023080202250255600_dkad177-B3","doi-asserted-by":"crossref","first-page":"e752","DOI":"10.1016\/S2214-109X(16)30148-6","article-title":"Characterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: a cohort study","volume":"4","author":"Investigators of the Delhi Neonatal Infection Study (DeNIS) collaboration","year":"2016","journal-title":"Lancet Global Health"},{"key":"2023080202250255600_dkad177-B4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41390-020-0785-x","article-title":"Challenges in developing a consensus definition of neonatal sepsis","volume":"88","author":"McGovern","year":"2020","journal-title":"Pediatr Res"},{"key":"2023080202250255600_dkad177-B5","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1186\/s13054-018-2236-1","article-title":"The combination of procalcitonin and C-reactive protein or presepsin alone improves the accuracy of diagnosis of neonatal sepsis: a meta-analysis and systematic review","volume":"22","author":"Ruan","year":"2018","journal-title":"Crit Care"},{"key":"2023080202250255600_dkad177-B6","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0229380","article-title":"Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): a randomised controlled trial","volume":"15","author":"Lutsar","year":"2020","journal-title":"PLoS One"},{"key":"2023080202250255600_dkad177-B7","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/S1473-3099(17)30724-7","article-title":"Classifying antibiotics in the WHO essential medicines list for optimal use\u2014be AWaRe","volume":"18","author":"Sharland","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"2023080202250255600_dkad177-B8","author":"WHO","year":"2019"},{"key":"2023080202250255600_dkad177-B9","author":"EUCAST"},{"key":"2023080202250255600_dkad177-B10","author":"EUCAST"},{"key":"2023080202250255600_dkad177-B11","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1093\/jac\/dkp498","article-title":"Development of a set of multiplex PCR assays for the detection of genes encoding important \u03b2-lactamases in Enterobacteriaceae","volume":"65","author":"Dallenne","year":"2010","journal-title":"J Antimicrob Chemother"},{"key":"2023080202250255600_dkad177-B12","doi-asserted-by":"crossref","DOI":"10.1155\/2016\/1875865","article-title":"Identification of genes coding aminoglycoside modifying enzymes in E. coli of UTI patients in India","volume":"2016","author":"Mir","year":"2016","journal-title":"Scientific World Journal"},{"key":"2023080202250255600_dkad177-B13","author":"MicrobesNG.","year":"2021"},{"key":"2023080202250255600_dkad177-B14","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1005595","article-title":"Unicycler: resolving bacterial genome assemblies from short and long sequencing reads","volume":"13","author":"Wick","year":"2017","journal-title":"PLoS Comput Biol"},{"key":"2023080202250255600_dkad177-B15","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1093\/jac\/dkaa345","article-title":"ResFinder 4.0 for predictions of phenotypes from genotypes","volume":"75","author":"Bortolaia","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2023080202250255600_dkad177-B16","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/S0732-8893(02)00473-X","article-title":"Comparison of methods of interpretation of checkerboard synergy testing","volume":"44","author":"Bonapace","year":"2002","journal-title":"Diagn Microbiol Infect Dis"},{"key":"2023080202250255600_dkad177-B17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jac\/dkg301","article-title":"Synergy, antagonism, and what the chequerboard puts between them","volume":"52","author":"Odds","year":"2003","journal-title":"J Antimicrob Chemother"},{"key":"2023080202250255600_dkad177-B18","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.bcp.2019.03.001","article-title":"The FICI paradigm: correcting flaws in antimicrobial in vitro synergy screens at their inception","volume":"163","author":"G\u00f3mara","year":"2019","journal-title":"Biochem Pharmacol"},{"key":"2023080202250255600_dkad177-B19","article-title":"Three dimensional checkerboard synergy analysis of colistin, meropenem, tigecycline against multidrug-resistant clinical Klebsiella pneumonia isolates","volume":"11","author":"Stein","year":"2015","journal-title":"PLoS One"},{"key":"2023080202250255600_dkad177-B20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1093\/jac\/15.suppl_A.125","article-title":"In-vitro model for simultaneous simulation of the serum kinetics of two drugs with different half-lives","volume":"15","author":"Blaser","year":"1985","journal-title":"J Antimicrob Chemother"},{"key":"2023080202250255600_dkad177-B21","first-page":"6111","article-title":"Clinical pharmacology of cefotaxime in neonates and infants: effects and pharmacokinetics","volume":"5","author":"Pacifici","year":"2017","journal-title":"Int J Pediatr"},{"key":"2023080202250255600_dkad177-B22","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.1128\/AAC.02374-13","article-title":"Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design","volume":"58","author":"Tremoulet","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"2023080202250255600_dkad177-B23","doi-asserted-by":"crossref","first-page":"4869","DOI":"10.1128\/AAC.00577-16","article-title":"Development and evaluation of a gentamicin pharmacokinetic model that facilitates opportunistic gentamicin therapeutic drug monitoring in neonates and infants","volume":"60","author":"Germovsek","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"key":"2023080202250255600_dkad177-B24","first-page":"4575","article-title":"Clinical pharmacokinetics of gentamicin in neonates","volume":"5","author":"Pacifici","year":"2017","journal-title":"Int J Pediatr"},{"key":"2023080202250255600_dkad177-B25","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1128\/AAC.48.7.2599-2603.2004","article-title":"Antibacterial effects of amoxicillin-clavulanate against Streptococcus pneumoniae and Haemophilus influenzae strains for which MICs are high, in an in vitro pharmacokinetic model","volume":"48","author":"MacGowan","year":"2004","journal-title":"Antimicrob Agents Chemother"},{"key":"2023080202250255600_dkad177-B26","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.2174\/0929867023370031","article-title":"Resistance to \u03b2-lactam antibiotics: structure and mechanism based design of \u03b2-lactamase inhibitors","volume":"9","author":"Sandanayaka","year":"2002","journal-title":"Curr Med Chem"},{"key":"2023080202250255600_dkad177-B27","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1093\/clinids\/24.3.494","article-title":"\u03b2-Lactamase inhibition and in vitro activity of sulbactam and sulbactam\/cefoperazone","volume":"24","author":"Williams","year":"1997","journal-title":"Clin Infect Dis"},{"key":"2023080202250255600_dkad177-B28","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1128\/CMR.00037-09","article-title":"Three decades of \u03b2-lactamase inhibitors","volume":"23","author":"Drawz","year":"2010","journal-title":"Clin Microbiol Rev"},{"key":"2023080202250255600_dkad177-B29","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1007\/BF01704610","article-title":"A new plasmidic cefotaximase from patients infected with Salmonella typhimurium","volume":"20","author":"Bauernfeind","year":"1992","journal-title":"Infection"},{"key":"2023080202250255600_dkad177-B30","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/S0022-3476(74)80308-2","article-title":"Neonatal Escherichia coli septicemia\u2013bacterial counts in blood","volume":"85","author":"Dietzman","year":"1974","journal-title":"J Pediatr"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/78\/8\/1882\/50967481\/dkad177.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/78\/8\/1882\/50967481\/dkad177.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T02:25:38Z","timestamp":1690943138000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/78\/8\/1882\/7191459"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,7]]},"references-count":30,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,6,7]]},"published-print":{"date-parts":[[2023,8,2]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkad177","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,8]]},"published":{"date-parts":[[2023,6,7]]}}}