Impact of tebipenem pivoxil on the intestinal microbiota and on establishment of colonization with carbapenem-resistant Klebsiella pneumoniae in mice

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dc.citation.titleMicrobiology Spectrum
dc.citation.volume13
dc.contributor.orcidhttps://orcid.org/0000-0002-1380-9824
dc.contributor.orcidhttps://orcid.org/0000-0002-7978-3233
dc.contributor.orcidhttps://orcid.org/0000-0003-0990-4498
dc.contributor.orcidhttps://orcid.org/0000-0002-3299-894X
dc.creatorMojica, María F.
dc.creatorHausman, Bryan S.
dc.creatorPearlmutter, Basya S.
dc.creatorZink, Elizabeth G.
dc.creatorWilson, Brigid M.
dc.creatorVillamil, Valentina
dc.creatorSaiz, Cecilia
dc.creatorMahler, Graciela S.
dc.creatorVila, Alejandro J.
dc.creatorSangwan, Naseer
dc.creatorDonskey, Curtis J.
dc.creatorBonomo, Robert A.
dc.date.accessioned2025-06-17T13:56:00Z
dc.date.available2025-06-17T13:56:00Z
dc.date.issued2025-03-14
dc.description.abstractTebipenem pivoxil has potent in vitro activity against Enterobacterales pathogens, but requires combination with β-lactamase inhibitor to achieve activity against carbapenemase producers, including metallo-β-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 Klebsiella pneumoniae blaNDM-1, 6 h after the second dose. The concentrations of the MDR K. pneumoniae in stool were measured on days 1, 3, and 6 after challenge. In comparison to saline controls, clindamycin (P = 0.001) and tebipenem pivoxil plus CS319-piv-SAc (P = 0.02) treatment resulted in significant changes in the alpha diversity patterns, whereas tebipenem pivoxil and CS319-piv-SAc individual treatments did not (P > 0.05). Moreover, clindamycin treatment resulted in substantial overgrowth of MDR K. pneumoniae (mean concentration after 6 days of infection, 6.1 vs 2.9 log10 CFU/g stool), whereas the other treatments did not (≤3.6 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 K. pneumoniae. IMPORTANCE: 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-β-lactamase inhibitor, CS319, on the intestinal microbiota and on the establishment of colonization with carbapenem-resistant Klebsiella pneumoniae. 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 K. pneumoniae. Although additional studies are needed to examine the impact of tebipenem pivoxil treatment on other multidrug-resistant Gram-negative bacilli, Clostridioides difficile, and Candida 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.
dc.description.filFil: Mojica, María F. Case Western Reserve University. School of Medicine. Department of Molecular Biology and Microbiology; United States.
dc.description.filFil: Mojica, María F. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Research Service; United States.
dc.description.filFil: Mojica, María F. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Hausman, Bryan S. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Research Service; United States.
dc.description.filFil: Pearlmutter, Basya S. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Research Service; United States.
dc.description.filFil: Pearlmutter, Basya S. The Ohio State University. College of Medicine; United States.
dc.description.filFil: Zink, Elizabeth G. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Geriatric Research, Education and Clinical Centers (GRECC); United States.
dc.description.filFil: Wilson, Brigid M. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Geriatric Research, Education and Clinical Centers (GRECC); United States.
dc.description.filFil: Villamil, Valentina. Universidad de la República. Facultad de Química. Departamento de Química Orgánica. Laboratorio de Química Farmacéutica; Uruguay.
dc.description.filFil: Saiz, Cecilia. Universidad de la República. Facultad de Química. Departamento de Química Orgánica. Laboratorio de Química Farmacéutica; Uruguay.
dc.description.filFil: Mahler, Graciela S. Universidad de la República. Facultad de Química. Departamento de Química Orgánica. Laboratorio de Química Farmacéutica; Uruguay.
dc.description.filFil: Vila, Alejandro J. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Sangwan, Naseer. Case Western Reserve University. School of Medicine. Department of Medicine; United States.
dc.description.filFil: Sangwan, Naseer. Case Western Reserve University. School of Medicine. Cleveland Clinic Lerner College of Medicine (CCLCM-CCLRI); United States.
dc.description.filFil: Donskey, Curtis J. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Geriatric Research, Education and Clinical Centers (GRECC); United States.
dc.description.filFil: Donskey, Curtis J. Case Western Reserve University. School of Medicine. Department of Medicine; United States.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University. School of Medicine. Department of Molecular Biology and Microbiology; United States.
dc.description.filFil: Bonomo, Robert A. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Bonomo, Robert A. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Geriatric Research, Education and Clinical Centers (GRECC); United States.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University. School of Medicine. Department of Medicine; United States.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University. School of Medicine. Department of Pharmacology; United States.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University. School of Medicine. Department of Biochemistry; United States.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University. School of Medicine. Department of Proteomics and Bioinformatics; United States.
dc.description.sponsorshipCleveland Department of Veterans Affairs
dc.description.sponsorshipBiomedical Laboratory Research & Development Service of the VA Office of Research and Development: award number 1I01BX005307
dc.description.sponsorshipGeriatric Research Education and Clinical Center VISN 10
dc.description.sponsorshipNational Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH): award number R01AI100560
dc.description.versionpeerreviewed
dc.format.extent1-12
dc.identifier.e-issn2165-0497
dc.identifier.urihttps://hdl.handle.net/2133/29668
dc.language.isoen
dc.publisherAmerican Society for Microbiology
dc.relation.publisherversionhttps://doi.org/10.1128/spectrum.02346-24
dc.relation.publisherversionhttps://journals.asm.org/doi/10.1128/spectrum.02346-24
dc.rightsopenAccess
dc.rights.holderMojica, María F.
dc.rights.holderHausman, Bryan S.
dc.rights.holderPearlmutter, Basya S.
dc.rights.holderZink, Elizabeth G.
dc.rights.holderWilson, Brigid M.
dc.rights.holderVillamil, Valentina
dc.rights.holderSaiz, Cecilia
dc.rights.holderMahler, Graciela S.
dc.rights.holderVila, Alejandro J.
dc.rights.holderSangwan, Naseer
dc.rights.holderDonskey, Curtis J.
dc.rights.holderBonomo, Robert A.
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas
dc.rights.textAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectTebipenem
dc.subjectMetallo-β-lactamase inhibitor
dc.subjectGut microbiome
dc.subjectIntestinal colonization
dc.subjectCarbapenem-resistant Enterobacterales
dc.subjectGastrointestinal Microbiome
dc.subjectKlebsiella pneumoniae
dc.subjectTebipenem pivoxil
dc.titleImpact of tebipenem pivoxil on the intestinal microbiota and on establishment of colonization with carbapenem-resistant Klebsiella pneumoniae in mice
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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