{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:31:56Z","timestamp":1787016716309,"version":"build-2736575974"},"reference-count":22,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["HHSN272201700020I\/75N93021F00002"],"award-info":[{"award-number":["HHSN272201700020I\/75N93021F00002"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP17pc0101002"],"award-info":[{"award-number":["JP17pc0101002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"ABSTRACT<\/jats:title>\n \n \n \n KSP-1007 is a novel bicyclic boronate-based broad-spectrum \u03b2-lactamase inhibitor that improves meropenem (MEM) efficacy against gram-negative bacteria (GNB) producing serine- and metallo-type carbapenemases. We investigated which pharmacokinetics (PK)\/pharmacodynamics (PD) parameters of KSP-1007 correlated with MEM\/KSP-1007 efficacy against carbapenemase-producing (CP)\n Enterobacterales<\/jats:italic>\n (CPE) and\n Acinetobacter baumannii<\/jats:italic>\n (CPAB) in a neutropenic murine thigh infection model. Infected neutropenic mice were subcutaneously treated with MEM every 3 h for 24 h alone or in combination with KSP-1007 administered at 3-, 6-, 12-, or 24-h dosing intervals. The bacterial burden in the thigh was assessed 2 h and 26 h after infection. The percentage of the dosing interval at which the free drug concentration exceeded the threshold concentration (%\n f<\/jats:italic>\n T>C\n T<\/jats:sub>\n ) was a good predictor of activity against serine- and metallo-CPE and CPAB based on coefficients of determinations (R\n 2<\/jats:sup>\n = 0.5\u20130.8) and a visual inspection of the plots showing %\n f<\/jats:italic>\n T>C\n T<\/jats:sub>\n against the change in log\n 10<\/jats:sub>\n CFU\/thigh, although the area under the 24-h free drug concentration time-curve yielded similar R\n 2<\/jats:sup>\n values. The required values for %\n f<\/jats:italic>\n T>C\n T<\/jats:sub>\n at 0.25\u20134 \u03bcg\/mL were 20.4%\u20134.2% (stasis) and 45.1%\u201314.1% (1-log\n 10<\/jats:sub>\n kill) for serine-CPE and 48.6%\u201313.3% (stasis) and 97.9%\u201342.3% (1-log\n 10<\/jats:sub>\n kill) for metallo-CPE. The corresponding values for CPAB at thresholds of 0.5\u20138 \u03bcg\/mL were 15.3%\u20134.3% and 33.9%\u20138.7%. Frequent dosing of KSP 1007 maximized its potentiation of MEM activity against most of the tested CP-GNB strains. Therefore, the\n in vivo<\/jats:italic>\n efficacy of KSP-1007 with MEM against CP-GNB was not dependent on the peak free drug concentration of KSP-1007, making KSP-1007 an optimal partner for MEM, which exhibits time-dependent activity.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1128\/aac.01852-25","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T14:55:37Z","timestamp":1772549737000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacokinetics\/pharmacodynamics of KSP-1007 in combination with meropenem against carbapenemase-producing gram-negative bacteria in a neutropenic murine thigh infection model"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0894-8624","authenticated-orcid":true,"given":"Koji","family":"Takemoto","sequence":"first","affiliation":[{"name":"Corporate Regulatory Compliance & Quality Assurance Division, Sumitomo Pharma Co., Ltd.","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mami","family":"Kamada","sequence":"additional","affiliation":[{"name":"Research and Development Division, Sumitomo Pharma Co., Ltd.","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keizo","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Research and Development Division, Sumitomo Pharma Co., Ltd.","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidehito","family":"Matsui","sequence":"additional","affiliation":[{"name":"\u014cmura Satoshi Memorial Institute, Kitasato University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hidaka","sequence":"additional","affiliation":[{"name":"Research and Development Division, Sumitomo Pharma Co., Ltd.","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Hanaki","sequence":"additional","affiliation":[{"name":"\u014cmura Satoshi Memorial Institute, Kitasato University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1177\/2049936115621709"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0159-8"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01602-23"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/516284"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2010.06.012"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/phar.2210"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01659-18"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01764-20"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1177\/0091270003257225"},{"key":"e_1_3_5_11_2","series-title":"CLSI Supplement M100","volume-title":"Performance standards for antimicrobial susceptibility testing","author":"CLSI","year":"2025","unstructured":"CLSI. 2025. Performance standards for antimicrobial susceptibility testing. 35th ed. CLSI Supplement M100. Clinical and Laboratory Standards Institute.","edition":"35"},{"key":"e_1_3_5_12_2","volume-title":"ASM Microbe 2023, Houston, TX","author":"Dansky H","year":"2023","unstructured":"Dansky H, Naik H, Shen S, Bordelon N, Meyer J, Tomita Y, Azoulay S. 2023. Safety, tolerability, and pharmacokinetics of KSP-1007, after single and multiple ascending doses alone or in combination with meropenem in healthy subjects, Abstr AAR-FRIDAY-519. ASM Microbe 2023, Houston, TX."},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.7.1577"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02056-16"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01446-17"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02228-17"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00130-20"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkaf431"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkac446"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofac492.667"},{"key":"e_1_3_5_21_2","series-title":"CLSI Standard M07","volume-title":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically","author":"CLSI","year":"2018","unstructured":"CLSI. 2018. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 11th ed. CLSI Standard M07. Clinical and Laboratory Standards Institute, Wayne, PA.","edition":"11"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dky404"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.10.2083"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01852-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01852-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T13:00:55Z","timestamp":1775048455000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.01852-25"}},"subtitle":[],"editor":[{"given":"James E.","family":"Leggett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":22,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4,1]]}},"alternative-id":["10.1128\/aac.01852-25"],"URL":"https:\/\/doi.org\/10.1128\/aac.01852-25","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]},"assertion":[{"value":"2025-12-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01852-25"}}