{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T13:54:16Z","timestamp":1791467656802,"version":"4.3.4"},"reference-count":26,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP23K16313"],"award-info":[{"award-number":["JP23K16313"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Treatment options for New Delhi metallo-\u03b2-lactamase-producing Enterobacterales (NDME) remain limited, and the clinical relevance of fosfomycin\u2013carbapenem combinations has not been fully established. We evaluated whether biapenem\u2013fosfomycin provides greater\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      activity than meropenem\u2013fosfomycin. A total of 54 clinical NDME isolates (\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 22;\n                      <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 21;\n                      <jats:italic toggle=\"yes\">Enterobacter cloacae<\/jats:italic>\n                      complex,\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 11) collected in Bangladesh and Japan were analyzed. Antimicrobial susceptibility testing, checkerboard assays, checkerboard-derived cumulative inhibition analyses, time\u2013kill assays, and assessment of fosfomycin-resistant subpopulations were performed. Biapenem exhibited lower MICs than meropenem across all species. Biapenem\u2013fosfomycin demonstrated higher rates of synergy than meropenem\u2013fosfomycin, particularly in\n                      <jats:italic toggle=\"yes\">E. coli<\/jats:italic>\n                      (73% vs 45%). At concentration pairs corresponding to median minimum Fractional Inhibitory Concentration Index (mFICI) values, a greater proportion of isolates was inhibited at low biapenem concentrations in the presence of fosfomycin, whereas this effect was more limited with meropenem. At a fixed carbapenem concentration of 1 \u03bcg\/mL, \u226590% inhibition was achieved at lower fosfomycin concentrations with biapenem\u2013fosfomycin than with meropenem\u2013fosfomycin. Time\u2013kill analyses demonstrated that mFICI-based conditions resulted in regrowth, whereas MIC\/MIC combinations of biapenem\u2013fosfomycin maintained bacterial suppression over 24 h. Fosfomycin alone was associated with frequent recovery of fosfomycin-resistant subpopulations, whereas biapenem\u2013fosfomycin reduced their recovery under the tested conditions. Biapenem\u2013fosfomycin demonstrated favorable\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      activity compared with meropenem\u2013fosfomycin against NDME. These findings indicate that checkerboard-defined synergy should be interpreted together with cumulative inhibition profiles, killing kinetics, and resistant-subpopulation data.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Treating infections caused by New Delhi metallo-\u03b2-lactamase (NDM)-producing Enterobacterales remains a major global challenge because therapeutic options are limited. Fosfomycin\u2013carbapenem combinations are frequently assessed using checkerboard-based Fractional Inhibitory Concentration Index (FICI), but this screening approach does not fully describe time-dependent killing, regrowth, or the recovery of resistant subpopulations. In this study, we compared biapenem\u2013fosfomycin with meropenem\u2013fosfomycin using checkerboard assays and checkerboard-derived cumulative inhibition analysis and further characterized biapenem\u2013fosfomycin using time\u2013kill assays and fosfomycin-resistant subpopulation assessment. Biapenem\u2013fosfomycin showed more favorable\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        activity than meropenem\u2013fosfomycin under the tested conditions. These findings support further evaluation of biapenem\u2013fosfomycin using dynamic pharmacokinetic models that better reproduce human drug exposure profiles.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01350-26","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T13:00:42Z","timestamp":1791464442000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Biapenem\u2013fosfomycin shows enhanced\n                    <i>in vitro<\/i>\n                    activity compared with meropenem\u2013fosfomycin against NDM-producing Enterobacterales"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5640-5811","authenticated-orcid":true,"given":"Takashi","family":"Okanda","sequence":"first","affiliation":[{"name":"Department of Microbiology, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daishu","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Microbiology, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsuki","family":"Yumura","sequence":"additional","affiliation":[{"name":"Department of Microbiology, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niinyo","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Microbiology, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuro","family":"Koshikawa","sequence":"additional","affiliation":[{"name":"Department of Microbiology, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadatomo","family":"Oyanagi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Technology, St. Marianna University Hospital","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonori","family":"Takano","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kunishima","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuo","family":"Kaku","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromu","family":"Takemura","sequence":"additional","affiliation":[{"name":"Department of Microbiology, St. Marianna University School of Medicine","place":["Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1080\/14787210.2024.2303028"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciae403"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1039\/d5sc02122g"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiac.2026.102903"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12088-024-01293-8"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2025.1702881"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a025262"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics2020217"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2009.11.011"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00749-17"},{"key":"e_1_3_4_12_2","first-page":"264","article-title":"Fosfomycin-meropenem synergistic combination against NDM carbapenemase-producing Klebsiella pneumoniae strains","volume":"46","author":"Della Rocca MT","year":"2023","unstructured":"Della Rocca MT, Di Caprio G, Colucci F, Merola F, Panetta V, Cordua E, Greco R. 2023. 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