{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T17:42:59Z","timestamp":1781890979086,"version":"3.54.5"},"reference-count":26,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,1,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Sulbactam\u2013durlobactam is a \u03b2-lactam\/\u03b2-lactamase inhibitor combination approved in the United States for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of\n              <jats:italic>Acinetobacter baumannii\u2013calcoaceticus<\/jats:italic>\n              in adults. A population pharmacokinetic (PK) model of sulbactam\u2013durlobactam in plasma was developed using data from eight Phase 1\u20133 studies. A total of 432 subjects and 8,100 plasma concentrations were available for the population PK data set. The combined model was a four-compartment (two compartments per drug) model with linear kinetics. Both renal clearance and nonrenal clearance were estimated, and total clearance was calculated as the sum of renal and nonrenal clearance. Individual renal clearances were scaled by baseline creatinine clearance. The sampling\u2013importance\u2013resampling analysis indicated that the parameters were estimated reliably with adequate precision. Hemodialysis (HD) and epithelial lining fluid (ELF) sub-models were developed for each analyte separately. Intermittent HD resulted in an approximately 30% decrease in the daily area under the concentration\u2013time curve (AUC\n              <jats:sub>0\u201324<\/jats:sub>\n              ) when HD was started 1 hour after the end of the infusion. Assuming protein binding estimates of 10% and 38% for durlobactam and sulbactam, respectively, ELF penetration ratios were found to be 41.3% for durlobactam and 86.0% for sulbactam. Of the statistically significant covariates of PK identified, which included body weight, body mass index, infection type, and region of origin, renal function was the only clinically relevant covariate. Overall, a robust description of the plasma PK of sulbactam and durlobactam was achieved. The resultant population PK model was expected to be appropriate for model-based simulations and assessment of pharmacokinetic\u2013pharmacodynamic relationships.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.00485-24","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T13:30:21Z","timestamp":1732195821000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Population pharmacokinetic analyses for sulbactam\u2013durlobactam using Phase 1, 2, and 3 data"],"prefix":"10.1128","volume":"69","author":[{"given":"Anthony P.","family":"Cammarata","sequence":"first","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Inc.","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0452-682X","authenticated-orcid":true,"given":"M. Courtney","family":"Safir","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Inc.","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Trang","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Inc.","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kajal B.","family":"Larson","sequence":"additional","affiliation":[{"name":"Entasis Therapeutics, Inc., an affiliate of Innoviva Specialty Therapeutics, Inc.","place":["Waltham, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2762-451X","authenticated-orcid":true,"given":"John P.","family":"O'Donnell","sequence":"additional","affiliation":[{"name":"Entasis Therapeutics, Inc., an affiliate of Innoviva Specialty Therapeutics, Inc.","place":["Waltham, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4891-6467","authenticated-orcid":true,"given":"Sujata M.","family":"Bhavnani","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Inc.","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3172-0847","authenticated-orcid":true,"given":"Christopher M.","family":"Rubino","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Inc.","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00058-16"},{"key":"e_1_3_3_3_2","unstructured":"CDC. 2019. Antibiotic resistance threats in the United States 2019. U.S. Department of Health and Human Services Atlanta GA CDC. Available from: https:\/\/www.cdc.gov\/drugresistance\/pdf\/threats-report\/2019-ar-threats-report-508.pdf. Retrieved 14 Aug 2024."},{"key":"e_1_3_3_4_2","unstructured":"CDC. 2022. Antimicrobial resistance threats in the United States 2021-2022. U.S. Department of Health and Human Services Atlanta GA CDC. Available from: https:\/\/www.cdc.gov\/antimicrobial-resistance\/media\/pdfs\/antimicrobial-resistance-threats-update-2022-508.pdf. Retrieved 14 Aug 2024."},{"key":"e_1_3_3_5_2","unstructured":"WHO. 2024. WHO bacterial priority pathogens list 2024: bacterial pathogens of public health importance to guide research development and strategies to prevent and control antimicrobial resistance. Geneva World Health Organization. Available from: https:\/\/iris.who.int\/bitstream\/handle\/10665\/376776\/9789240093461-eng.pdf?sequence=1. Retrieved 14 Aug 2024."},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2017.104"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00159-19"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01576-17"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics11081136"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00781-22"},{"key":"e_1_3_3_11_2","unstructured":"XACDURO (sulbactam for injection; durlobactam for injection [prescribing information]. 2023. Waltham MA: Entasis Therapeutics Ltd"},{"key":"e_1_3_3_12_2","unstructured":"Onufrak NJ Rubino CM Ambrose PG Isaacs R Srinivasan S O\u2019Donnell J. 2019. Population pharmacokinetic and pharmacokinetic-pharmacodynamic target attainment analyses of ETX2514SUL to support dosing regimens in patients with varying renal function. Poster P1953. Presented at: 29th European Congress of Clinical Microbiology and Infectious Diseases; April 13-16 2019. Amsterdam Netherlands"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiac.2014.12.005"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01089-18"},{"key":"e_1_3_3_15_2","unstructured":"Study to determine the excretion and metabolism of 14C-ETX2514 administered intravenously in healthy male subjects. ClinicalTrials.gov identifier: NCT04018950. Updated August 30 2019. Available from: https:\/\/clinicaltrials.gov\/study\/NCT04018950. Retrieved 14 Aug 2024."},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12991"},{"key":"e_1_3_3_17_2","unstructured":"Data on file. Entasis therapeutics Inc. an affiliate of innoviva specialty therapeutics Inc. Waltham MA."},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01506-19"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(23)00184-6"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1159\/000180580"},{"key":"e_1_3_3_21_2","doi-asserted-by":"crossref","unstructured":"Bhavnani SM Rubino CM Hammel JP Cammarata A Larson KB Liolios K McLeod SM Miller AA Ambrose PG Tommasi R O\u2019Donnell JP. 2022. Population pharmacokinetic pharmacokinetic-pharmacodynamic attainment and clinical pharmacokinetic-pharmacodynamic analyses for sulbactam-durlobactam to support dose selection for the treatment of Acinetobacter baumannii-calcoaceticus complex infections. Slide presentation LB2306. Presented at: IDWeek; October 19\u201323 2022. Washington DC","DOI":"10.1093\/ofid\/ofac492.1896"},{"key":"e_1_3_3_22_2","doi-asserted-by":"crossref","unstructured":"Larson KB Bhavnani SM Hammel JP Cammarata AP O\u2019Donnell JP Rubino CM. 2023. Pharmacometric analyses to support sulbactam-durlobactam dosing regimens in patients with altered renal function. Poster 2549. Presented at: IDWeek; October 11\u201315 2023. Boston MA","DOI":"10.1093\/ofid\/ofad500.2166"},{"key":"e_1_3_3_23_2","unstructured":"UNASYN (ampicillin sodium\/sulbactam sodium). 2024. Prescribing information. New York NY Pfizer Inc"},{"key":"e_1_3_3_24_2","volume-title":"NONMEM users guides; Introduction to NONMEM 7.4.1","author":"Bauer RJ.","year":"2017","unstructured":"Bauer RJ. NONMEM users guides; Introduction to NONMEM 7.4.1. ICON Plc, Gaithersburg, MD. 2017."},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-016-9487-8"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9542-0"},{"key":"e_1_3_3_27_2","doi-asserted-by":"crossref","unstructured":"Baron KT. 2017. mrgsolve: simulate from ODE-based population PK\/PD and systems pharmacology models. R package Version 0.8.6","DOI":"10.32614\/CRAN.package.mrgsolve"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00485-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00485-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T14:04:15Z","timestamp":1738332255000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.00485-24"}},"subtitle":[],"editor":[{"given":"James E.","family":"Leggett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,31]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,31]]}},"alternative-id":["10.1128\/aac.00485-24"],"URL":"https:\/\/doi.org\/10.1128\/aac.00485-24","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,31]]},"assertion":[{"value":"2024-03-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00485-24"}}