{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:50:43Z","timestamp":1791845443241,"version":"4.3.4"},"reference-count":72,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Society of Infectious Diseases Pharmacists","award":["3048116157"],"award-info":[{"award-number":["3048116157"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,11,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      High-inoculum\n                      <jats:italic toggle=\"yes\">Enterobacter cloacae<\/jats:italic>\n                      complex (ECC) infections challenge \u03b2-lactam therapy due to \u03b2-lactamase-mediated resistance and the inoculum effect, where high bacterial densities amplify resistance and worsen outcomes. We evaluated the pharmacodynamic efficacy of cefepime, meropenem, ertapenem, meropenem\u2013vaborbactam, and ceftazidime\u2013avibactam against three high-inoculum (10\u2079 colony-forming unit [CFU]\/g) ECC isolates (0008, 0032, and 0060) harboring diverse \u03b2-lactamases using a 96 h simulated endocardial vegetation (SEV) model with humanized exposures. Bactericidal activity, resistance emergence, and \u03b2-lactamase expression were assessed. Cefepime failed in all isolates, with SEV growth from +0.4 to +1.6 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g and minimum inhibitory concentrations (MICs) increasing from 2\u20138 \u00b5g\/mL to &gt;64 \u202f\u00b5g\/mL in 0008, 0032, and 0060, coinciding with AmpC \u03b2-lactamase (ACT) induction up to 16.1-fold (0032). In 0060, cefepime failed, whereas meropenem displayed infusion-dependent efficacy: the 3 h infusion achieved bactericidal killing (\u22124.6 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g), while the 30 min infusion produced partial killing (\u20132.9 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g). Meropenem failed in 0032 (+1.1 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g), with ACT-16 induction reaching 14.6-fold. Ertapenem produced initial bactericidal activity in 0060 (\u20133.2 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g) but regrowth to \u20131.9 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g by 96 h, accompanied by ACT-89 expression rising 26-fold. Meropenem\u2013vaborbactam was bactericidal in 0008 (\u20134.6 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g) and 0032 (\u20133.6 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g) with stable MICs and minimal \u03b2-lactamase induction. Ceftazidime\u2013avibactam achieved bactericidal activity in 0008 (\u20134.9 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g) but only bacteriostatic activity in 0032 (\u20131.2 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/g), with modest KPC-3 and ACT-16 upregulation (~1.7- to 2.3-fold). \u03b2-Lactamase diversity and inoculum effects limit \u03b2-lactam efficacy in high-inoculum ECC infections. Meropenem\u2013vaborbactam showed consistent activity, and prolonged meropenem infusion benefited select isolates. Variable ceftazidime\u2013avibactam efficacy reinforces aligning \u03b2-lactam selection with underlying \u03b2-lactamase mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01170-25","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T12:00:21Z","timestamp":1758542421000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Molecular and pharmacodynamic insights into \u03b2-lactam therapy for high-inoculum\n                    <i>Enterobacter cloacae<\/i>\n                    complex infections"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4891-8625","authenticated-orcid":true,"given":"Ashlan J.","family":"Kunz Coyne","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02k3smh20","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Kentucky College of Pharmacy","place":["Lexington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Gray","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02k3smh20","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Kentucky College of Pharmacy","place":["Lexington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"May","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02k3smh20","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Kentucky College of Pharmacy","place":["Lexington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunter","family":"Curry","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05vvzn852","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Kentucky HealthCare","place":["Lexington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Slain","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05vvzn852","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Kentucky HealthCare","place":["Lexington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Delcher","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02k3smh20","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Kentucky College of Pharmacy","place":["Lexington, USA"]},{"id":[{"id":"https:\/\/ror.org\/02k3smh20","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Pharmaceutical Outcomes and Policy, University of Kentucky College of Pharmacy","place":["Lexington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Shin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02k3smh20","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Kentucky College of Pharmacy","place":["Lexington, USA"]},{"id":[{"id":"https:\/\/ror.org\/02k3smh20","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Pharmaceutical Outcomes and Policy, University of Kentucky College of Pharmacy","place":["Lexington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00044"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciae403"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1080\/1120009X.2021.1959786"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10156-012-0376-9"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.idcr.2021.e01149"},{"key":"e_1_3_3_7_2","series-title":"M100Ed35","volume-title":"Performance standards for antimicrobial susceptibility testing","unstructured":"Performance standards for antimicrobial susceptibility testing. 35th ed. 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