{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:18:56Z","timestamp":1793110736861,"version":"4.5.0"},"reference-count":34,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"crossref","award":["1I01BX005307"],"award-info":[{"award-number":["1I01BX005307"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01AI100560"],"award-info":[{"award-number":["R01AI100560"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2025,5,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Tebipenem pivoxil has potent\n              <jats:italic>in vitro<\/jats:italic>\n              activity against\n              <jats:italic>Enterobacterales<\/jats:italic>\n              pathogens, but requires combination with \u03b2-lactamase inhibitor to achieve activity against carbapenemase producers, including metallo-\u03b2-lactamases (MBLs). Herein, we evaluate the potential of tebipenem pivoxil, alone and in combination with the prodrug of the experimental MBL inhibitor CS319 (CS319-piv-SAc), to disrupt the indigenous mice microbiota of the colon and promote colonization by pathogens. The effect of antibiotic treatment (daily for 3 days with subcutaneous saline [control], subcutaneous clindamycin, oral tebipenem pivoxil alone and in combination with CS319-piv-Sac, or oral CS319-piv-Sac) on the intestinal microbiota was assessed by culture for enterococci and facultative Gram-negative bacilli and by 16S rRNA amplicon sequencing. Mice were also challenged with 10,000 colony-forming units (CFU) of multidrug-resistant (MDR) strain\n              <jats:italic>Klebsiella pneumoniae bla<\/jats:italic>\n              <jats:sub>NDM-1<\/jats:sub>\n              , 6 h after the second dose. The concentrations of the MDR\n              <jats:italic>K. pneumoniae<\/jats:italic>\n              in stool were measured on days 1, 3, and 6 after challenge. In comparison to saline controls, clindamycin (\n              <jats:italic>P<\/jats:italic>\n              = 0.001) and tebipenem pivoxil plus CS319-piv-SAc (\n              <jats:italic>P<\/jats:italic>\n              = 0.02) treatment resulted in significant changes in the alpha diversity patterns, whereas tebipenem pivoxil and CS319-piv-SAc individual treatments did not (\n              <jats:italic>P<\/jats:italic>\n              &gt; 0.05). Moreover, clindamycin treatment resulted in substantial overgrowth of MDR\n              <jats:italic>K. pneumoniae<\/jats:italic>\n              (mean concentration after 6 days of infection, 6.1 vs 2.9 log\n              <jats:sub>10<\/jats:sub>\n              CFU\/g stool), whereas the other treatments did not (\u22643.6 log10 CFU\/g). Although tebipenem pivoxil alone or in combination with an MBL inhibitor, CS319, caused alteration of the mice intestinal microbiota, neither treatment promoted overgrowth of carbapenem-resistant\n              <jats:italic>K. pneumoniae<\/jats:italic>\n              .\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                In this work, we used a mouse model to determine the impact of tebipenem pivoxil alone and in combination with a prodrug of an experimental metallo-\u03b2-lactamase inhibitor, CS319, on the intestinal microbiota and on the establishment of colonization with carbapenem-resistant\n                <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                . We found that while treatment with tebipenem pivoxil plus the prodrug of CS319 caused alteration of the intestinal microbiota, it did not promote the overgrowth of carbapenem-resistant\n                <jats:italic>K. pneumoniae<\/jats:italic>\n                . Although additional studies are needed to examine the impact of tebipenem pivoxil treatment on other multidrug-resistant Gram-negative bacilli,\n                <jats:italic>Clostridioides difficile<\/jats:italic>\n                , and\n                <jats:italic>Candida<\/jats:italic>\n                spp., our study is a step forward in the understanding of the potential effect of this oral carbapenem on the indigenous microbiota of the colon and on the promotion of colonization by pathogens.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.02346-24","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T13:00:24Z","timestamp":1741957224000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Impact of tebipenem pivoxil on the intestinal microbiota and on establishment of colonization with carbapenem-resistant\n            <i>Klebsiella pneumoniae<\/i>\n            in mice"],"prefix":"10.1128","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1380-9824","authenticated-orcid":true,"given":"Maria F.","family":"Mojica","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]},{"name":"Research Service, Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]},{"name":"CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES)","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan S.","family":"Hausman","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basya S.","family":"Pearlmutter","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]},{"name":"Ohio State College of Medicine, The Ohio State University","place":["Columbus, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth G.","family":"Zink","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education and Clinical Center, Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigid M.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education and Clinical Center, Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Villamil","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Farmac\u00e9utica, Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica (UdelaR)","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Saiz","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Farmac\u00e9utica, Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica (UdelaR)","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graciela","family":"Mahler","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Farmac\u00e9utica, Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica (UdelaR)","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7978-3233","authenticated-orcid":true,"given":"Alejandro A.","family":"Vila","sequence":"additional","affiliation":[{"name":"CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES)","place":["Cleveland, USA"]},{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (IBR, CONICET-UNR)","place":["Rosario, Argentina"]},{"name":"Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas, Universidad Nacional de Rosario","place":["Rosario, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naseer","family":"Sangwan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]},{"name":"Lerner Research Institute\/Lerner College of Medicine of Case Western Reserve University","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0990-4498","authenticated-orcid":true,"given":"Curtis J.","family":"Donskey","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education and Clinical Center, Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]},{"name":"Department of Medicine, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3299-894X","authenticated-orcid":true,"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]},{"name":"CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES)","place":["Cleveland, USA"]},{"name":"Geriatric Research, Education and Clinical Center, Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]},{"name":"Department of Medicine, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]},{"name":"Department of Pharmacology, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]},{"name":"Department of Biochemistry, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]},{"name":"Department of Proteomics and Bioinformatics, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00421-024-05496-1"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/422002"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(01)00066-4"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076269"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1080\/14787210.2018.1496821"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jacamr\/dlad132"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01051-12"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules21010062"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02396-21"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.5b00046"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5b00106"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1601368113"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2105462"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2023.106733"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00618-19"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01509-22"},{"key":"e_1_3_4_18_2","first-page":"214","article-title":"Pharmacokinetics 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