{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:27:12Z","timestamp":1786699632051,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>New beta-lactam\/beta-lactamase inhibitor combinations (BL\/BLICs) are licensed for Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) infections. However, data regarding their efficacy against bacterial biofilms and the potential of synergistic combinations remain limited. This study evaluated their efficacy on planktonic and biofilm forms of KPC-Kp isolated from catheter-related bloodstream infections (CRBSIs), correlating findings with genomic and clinical data. Twelve KPC-3-harboring isolates (ST512, n = 7; ST307, n = 3; ST101, n = 2) were characterized via whole-genome sequencing. Ceftazidime\/avibactam (CAZ\/AVI), meropenem\/vaborbactam (MEM\/VAB), and imipenem\/relebactam (IMI\/REL) were tested alone or combined with fosfomycin (FOS), cefepime (FEP), meropenem (MEM), or imipenem (IMI) using checkerboard assays. All BL\/BLICs alone showed significant, comparable efficacy against biofilm-producing strains. However, combination testing revealed heterogeneous synergistic profiles. CAZ\/AVI combined with MEM, IMI, or FEP achieved 100% synergy in both planktonic and biofilm states. MEM\/VAB-based combinations demonstrated consistent synergy (50\u2013100%), whereas IMI\/REL showed higher synergistic rates in biofilm than in planktonic forms. Conversely, FOS-based regimens were significantly less effective against biofilms. These findings provide a clinical rationale for selecting optimized dual regimens to eradicate biofilms, offering a critical therapeutic strategy to preserve vascular devices when catheter removal is unfeasible.<\/jats:p>","DOI":"10.3390\/microorganisms14081790","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:08:29Z","timestamp":1786694909000},"page":"1790","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting KPC-Producing Klebsiella pneumoniae Biofilms: Genomic Profiles, Clinical Outcomes and Novel Combinations"],"prefix":"10.3390","volume":"14","author":[{"given":"Chiara","family":"Papalini","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, Section of Infectious Diseases, University of Perugia, 06129 Perugia, Italy"},{"name":"Infectious Diseases Clinic, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Bicchieraro","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery and Center of Functional Genomics (C.U.R.Ge.F), University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2150-5388","authenticated-orcid":false,"given":"Luigi","family":"Tordelli Ruda","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Medical Microbiology Section, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1169-7766","authenticated-orcid":false,"given":"Alicia Yoke Wei","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery and Center of Functional Genomics (C.U.R.Ge.F), University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Battistelli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Medical Microbiology Section, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Genga","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinic, Santa Maria Hospital, 05100 Terni, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2319-6774","authenticated-orcid":false,"given":"Andrea","family":"Tommasi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Section of Infectious Diseases, University of Perugia, 06129 Perugia, Italy"},{"name":"Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Gidari","sequence":"additional","affiliation":[{"name":"Infectious Diseases Clinic, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Francisci","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Section of Infectious Diseases, University of Perugia, 06129 Perugia, Italy"},{"name":"Infectious Diseases Clinic, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8774-4843","authenticated-orcid":false,"given":"Giuseppe Vittorio De","family":"Socio","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Section of Infectious Diseases, University of Perugia, 06129 Perugia, Italy"},{"name":"Infectious Diseases Clinic, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2100-6172","authenticated-orcid":false,"given":"Roberta","family":"Spaccapelo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery and Center of Functional Genomics (C.U.R.Ge.F), University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1572-4290","authenticated-orcid":false,"given":"Donatella","family":"Pietrella","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Medical Microbiology Section, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9221-6172","authenticated-orcid":false,"given":"Antonella","family":"Mencacci","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Medical Microbiology Section, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5027-9367","authenticated-orcid":false,"given":"Claudia","family":"Monari","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Medical Microbiology Section, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8334-8325","authenticated-orcid":false,"given":"Samuele","family":"Sabbatini","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Health and Health Professions, Link Campus University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","unstructured":"European Centre for Disease Prevention and Control (2024). Antimicrobial Resistance in the EU\/EEA (EARS-Net)-Annual Epidemiological Report 2023, ECDC."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Guerra, M.E.S., Destro, G., Vieira, B., Lima, A.S., Ferraz, L.F.C., Hakansson, A.P., Darrieux, M., and Converso, T.R. (2022). Klebsiella pneumoniae Biofilms and Their Role in Disease Pathogenesis. Front. Cell. Infect. Microbiol., 12, Erratum in Front. Cell. Infect. Microbiol.\u00a02025, 15, 1564010. https:\/\/doi.org\/10.3389\/fcimb.2025.1564010.","DOI":"10.3389\/fcimb.2025.1564010"},{"key":"ref_3","unstructured":"European Centre for Disease Prevention and Control (2024). Point Prevalence Survey of Healthcare-Associated Infections and Antimicrobial Use in European Acute Care Hospitals, ECDC."},{"key":"ref_4","unstructured":"European Centre for Disease Prevention and Control (2025, September 05). Healthcare-Associated Infections. Available online: https:\/\/www.ecdc.europa.eu\/en\/healthcare-associated-infections."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1093\/jac\/dkz156","article-title":"KPC-31 expressed in a ceftazidime\/avibactam-resistant Klebsiella pneumoniae is associated with relevant detection issues","volume":"74","author":"Antonelli","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e0044722","DOI":"10.1128\/aac.00447-22","article-title":"Klebsiella pneumoniae Carbapenemase Variants Resistant to Ceftazidime-Avibactam: An Evolutionary Overview","volume":"66","author":"Hobson","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.jgar.2021.04.001","article-title":"Resistance to ceftazidime\/avibactam in infections and colonisations by KPC-producing Enterobacterales: A systematic review of observational clinical studies","volume":"25","author":"Giacobbe","year":"2021","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e0089021","DOI":"10.1128\/AAC.00890-21","article-title":"KPC-Mediated Resistance to Ceftazidime-Avibactam and Collateral Effects in Klebsiella pneumoniae","volume":"65","author":"Findlay","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jgar.2022.12.009","article-title":"In vitro-obtained meropenem-vaborbactam resistance mechanisms among clinical Klebsiella pneumoniae carbapenemase-producing K. pneumoniae isolates","volume":"32","author":"Findlay","year":"2023","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gaibani, P., Lombardo, D., Bussini, L., Bovo, F., Munari, B., Giannella, M., Bartoletti, M., Viale, P., Lazzarotto, T., and Ambretti, S. (2021). Epidemiology of Meropenem\/Vaborbactam Resistance in KPC-Producing Klebsiella pneumoniae Causing Bloodstream Infections in Northern Italy, 2018. Antibiotics, 10.","DOI":"10.21203\/rs.3.rs-237255\/v1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"106935","DOI":"10.1016\/j.ijantimicag.2023.106935","article-title":"In vitro development of imipenem\/relebactam resistance in KPC-producing Klebsiella pneumoniae involves multiple mutations including OmpK36 disruption and KPC modification","volume":"62","author":"Gato","year":"2023","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21746","DOI":"10.1038\/s41598-026-52233-z","article-title":"Ceftazidime\u2013Avibactam Drives Mutations, Insertion, or Overexpression in blaKPC-2 and Enhances Biofilm-Forming Ability of KPC-Producing Klebsiella Pneumoniae","volume":"16","author":"Li","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Xie, X., Chen, J., Qi, L., Yuan, Y., Long, J., Wu, X., Liu, Y., Guo, J., Wang, C., and Meng, X. (2025). Global Epidemiology and Resistance-Related Mutations of Ceftazidime-Avibactam-Resistant Klebsiella Pneumoniae Strains. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1645042"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sivori, F., Francalancia, M., Truglio, M., Cavallo, I., Pronesti, C., Fabrizio, G., Celesti, I., Cazzani, A., Furzi, L., and Pimpinelli, F. (2025). Meropenem\/vaborbactam activity against carbapenem-resistant Klebsiella pneumoniae from catheter-related bloodstream infections. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1616353"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s00284-026-04795-4","article-title":"In Vitro Antimicrobial Activities of Carbapenem-beta Lactamase Inhibitor Combinations Against Carbapenem-resistant Gram-negative Pathogens Isolated from T\u00fcrkiye","volume":"83","author":"Hacioglu","year":"2026","journal-title":"Curr. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.jgar.2020.07.028","article-title":"In vitro antibacterial activity of ceftazidime\/avibactam in combination against planktonic and biofilm carbapenemase-producing Klebsiella pneumoniae isolated from blood","volume":"23","author":"Papalini","year":"2020","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_17","unstructured":"The European Committee on Antimicrobial Susceptibility Testing (2025, September 05). Routine and Extended Internal Quality Control for MIC Determination and Disk Diffusion as Recommended by EUCAST, Available online: https:\/\/www.eucast.org\/news-detail\/the-130-versions-of-breakpoints-dosing-and-qc-2023-published\/."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kim, Y.C., Choi, H., Kim, Y.A., Park, Y.S., Seo, Y.H., Lee, H., and Lee, K. (2023). Risk factors and microbiological features of recurrent Escherichia coli bloodstream infections. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0280196"},{"key":"ref_19","unstructured":"Center for Genomic Epidemiology (2024, August 11). Available online: https:\/\/www.genomicepidemiology.org\/services\/."},{"key":"ref_20","unstructured":"BaseSpace Sequence Hub (2025, August 29). Available online: https:\/\/www.illumina.com\/products\/by-type\/informatics-products\/dragen-secondary-analysis\/pipelines-apps.html."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1089\/cmb.2012.0021","article-title":"SPAdes: A New Genome Assembly Algorithm and Its Applications to Single-Cell Sequencing","volume":"19","author":"Bankevich","year":"2012","journal-title":"J. Comput. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1093\/bioinformatics\/btu153","article-title":"Prokka: Rapid prokaryotic genome annotation","volume":"30","author":"Seemann","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"W78","DOI":"10.1093\/nar\/gkae268","article-title":"Interactive Tree of Life (iTOL) v6: Recent Updates to the Phylogenetic Tree Display and Annotation Tool","volume":"52","author":"Letunic","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/978-1-4939-9877-7_20","article-title":"PlasmidFinder and In Silico pMLST: Identification and Typing of Plasmid Replicons in Whole-Genome Sequencing (WGS)","volume":"Volume 2075","author":"Carattoli","year":"2020","journal-title":"Horizontal Gene Transfer"},{"key":"ref_25","first-page":"000748","article-title":"ResFinder\u2014An open online resource for identification of antimicrobial resistance genes in next-generation sequencing data and prediction of phenotypes from genotypes","volume":"8","author":"Florensa","year":"2022","journal-title":"Microb. Genom."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Devanga Ragupathi, N.K., Muthuirulandi Sethuvel, D.P., Triplicane Dwarakanathan, H., Murugan, D., Umashankar, Y., Monk, P.N., Karunakaran, E., and Veeraraghavan, B. (2020). The Influence of Biofilms on Carbapenem Susceptibility and Patient Outcome in Device Associated K. pneumoniae Infections: Insights Into Phenotype vs Genome-Wide Analysis and Correlation. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.591679"},{"key":"ref_27","unstructured":"European Committee on Antimicrobial Susceptibility Testing (2025, September 05). Clinical Breakpoints and Dosing of Antibiotics. Available online: https:\/\/www.eucast.org\/clinical_breakpoints."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W739","DOI":"10.1093\/nar\/gkac382","article-title":"SynergyFinder 3.0: An interactive analysis and consensus interpretation of multi-drug synergies across multiple samples","volume":"50","author":"Ianevski","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1089\/mdr.2018.0014","article-title":"Spread of Carbapenem and Colistin-Resistant Klebsiella Pneumoniae ST512 Clinical Isolates in Israel: A Cause for Vigilance","volume":"25","author":"Lalaoui","year":"2019","journal-title":"Microb. Drug Resist."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jgar.2025.01.009","article-title":"Clinical and molecular characteristics of KPC-producing Klebsiella pneumoniae bloodstream infections: Results of a multicentre study","volume":"41","author":"Brescini","year":"2025","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1128\/AAC.05308-11","article-title":"Klebsiella Pneumoniae ST258 Producing KPC-3 Identified in Italy Carries Novel Plasmids and OmpK36\/OmpK35 Porin Variants","volume":"56","author":"Villa","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"127896","DOI":"10.1016\/j.micres.2024.127896","article-title":"Conjugative Transmission of Virulence Plasmid in Klebsiella Pneumoniae Mediated by a Novel IncN-like Plasmid","volume":"289","author":"Xu","year":"2024","journal-title":"Microbiol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, Y., and Ni, M. (2023). Regulation of biofilm formation in Klebsiella pneumoniae. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1238482"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3454","DOI":"10.1038\/s41467-026-71505-w","article-title":"Rapid Evolution of Klebsiella Pneumoniae Biofilms in Vitro Delineates Adaptive Changes Selected during Infection","volume":"17","author":"Coelho","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_35","first-page":"e000110","article-title":"Diversity, Virulence, and Antimicrobial Resistance of the KPC-Producing Klebsiella Pneumoniae ST307 Clone","volume":"3","author":"Villa","year":"2017","journal-title":"Microb. Genom."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12941-025-00792-w","article-title":"Activity of imipenem\/relebactam against KPC-producing Klebsiella pneumoniae and the possible role of Ompk36 mutation in determining resistance: An Italian retrospective analysis","volume":"24","author":"Palomba","year":"2025","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e00891-25","DOI":"10.1128\/aac.00891-25","article-title":"Emergence of Co-Resistance to Imipenem\/Relebactam and Ceftazidime\/Avibactam in Clinical Klebsiella Pneumoniae ST11 Clone Due to KPC-2 N132S and CTX-M-65 S130G\/P167S Substitutions","volume":"69","author":"Fu","year":"2025","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.diagmicrobio.2017.06.022","article-title":"IncX3 Plasmid Harboring a Non-Tn 4401 Genetic Element (NTE KPC) in a Hospi-tal-Associated Clone of KPC-2-Producing Klebsiella Pneumoniae ST340\/CG258","volume":"89","author":"Cerdeira","year":"2017","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3581","DOI":"10.2147\/IDR.S324018","article-title":"Emergence of Klebsiella Pneumoniae ST307 Co-Producing CTX-M with SHV and KPC from Paediatric Patients at Shenzhen Children\u2019s Hospital, China","volume":"14","author":"Patil","year":"2021","journal-title":"IDR"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e0091822","DOI":"10.1128\/aac.00918-22","article-title":"In Vitro Mechanisms of Resistance Development to Imipenem-Relebactam in KPC-Producing Klebsiella pneumoniae","volume":"66","author":"Findlay","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Gaibani, P., Giani, T., Bovo, F., Lombardo, D., Amadesi, S., Lazzarotto, T., Coppi, M., Rossolini, G.M., and Ambretti, S. (2022). Resistance to Ceftazidime\/Avibactam, Meropenem\/Vaborbactam and Imipenem\/Relebactam in Gram-Negative MDR Bacilli: Molecular Mechanisms and Susceptibility Testing. Antibiotics, 11.","DOI":"10.3390\/antibiotics11050628"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e01443-17","DOI":"10.1128\/AAC.01443-17","article-title":"Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae","volume":"61","author":"Lomovskaya","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/s15010-025-02716-4","article-title":"Emergence of Resistance to Novel \u03b2-Lactam\/\u03b2-Lactamase Inhibitor Combinations in KPC-Producing Klebsiella Pneumoniae: Clinical and Genomic Insights from Consecutive Bloodstream Infections","volume":"54","author":"Boattini","year":"2026","journal-title":"Infection"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Tedeschi, S., Giannitsioti, E., and Mayer, C. (2025). Emerging Concepts for the Treatment of Biofilm-Associated Bone and Joint Infections with IV Fosfomycin: A Literature Review. Microorganisms, 13.","DOI":"10.3390\/microorganisms13050963"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e00282-18","DOI":"10.1128\/AAC.00282-18","article-title":"First Penicillin-Binding Protein Occupancy Patterns of \u03b2-Lactams and \u03b2-Lactamase Inhibitors in Klebsiella pneumoniae","volume":"62","author":"Sutaria","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1093\/jac\/dkae074","article-title":"Synergistic effects of ceftazidime\/avibactam combined with meropenem in a murine model of infection with KPC-producing Klebsiella pneumoniae","volume":"79","author":"Zheng","year":"2024","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"575082","DOI":"10.2147\/IDR.S575082","article-title":"Combination of Ceftazidime-Avibactam and Meropenem for the Treatment of Pneumonia and Bloodstream Infections Caused by Pan-Drug Resistant Pseudomonas aeruginosa ST244: A Case Report","volume":"19","author":"Kang","year":"2026","journal-title":"Infect. Drug Resist."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.2147\/IDR.S408228","article-title":"In vitro Synergistic Activity of Ceftazidime-Avibactam in Combination with Aztreonam or Meropenem Against Clinical Enterobacterales Producing blaKPC or blaNDM","volume":"16","author":"Kuai","year":"2023","journal-title":"Infect. Drug Resist."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Li, Y.Y., Wang, J., Wang, R., and Cai, Y. (2020). Double-carbapenem therapy in the treatment of multidrug resistant Gram-negative bacterial infections: A systematic review and meta-analysis. BMC Infect. Dis., 20.","DOI":"10.1186\/s12879-020-05133-0"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.cmi.2015.09.014","article-title":"Bactericidal and synergistic activity of double-carbapenem regimen for infections caused by carbapenemase-producing Klebsiella pneumoniae","volume":"22","author":"Oliva","year":"2016","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_51","first-page":"e52023","article-title":"The Effect of Double Carbapenem Regimen in the Management of Carbapenem-Resistant Klebsiella pneumoniae Infections: A Report of Five Cases","volume":"16","author":"Soanker","year":"2024","journal-title":"Cureus"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s13054-017-1769-z","article-title":"Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: A two-center, matched case-control study","volume":"21","author":"Martucci","year":"2017","journal-title":"Crit. Care"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e000243","DOI":"10.32892\/jmri.243","article-title":"The effect of double-carbapenem therapy on mortality rates and microbiological cure rates in patients diagnosed with carbapenem-resistant Klebsiella pneumoniae infections in comparison to monotherapy and currently used combinations of antibiotics","volume":"5","author":"Moody","year":"2021","journal-title":"J. Med. Res. Innov."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Comini, S., Boattini, M., Gaibani, P., and Bianco, G. (2026). Cefepime combined with late-generation \u03b2-lactamase inhibitors: Mechanisms of action, in vitro activity, PK\/PD characteristics, clinical evidence and resistance mechanisms. Antibiotics, 15.","DOI":"10.3390\/antibiotics15030263"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"107552","DOI":"10.1016\/j.ijantimicag.2025.107552","article-title":"In vitro activity of cefepime\/enmetazobactam against Klebsiella pneumoniae carrying blaKPC allelic variants conferring resistance to ceftazidime\/avibactam","volume":"66","author":"Caiazzo","year":"2025","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"dkaf440","DOI":"10.1093\/jac\/dkaf440","article-title":"In vitro susceptibility of cefepime-enmetazobactam, cefepime-taniborbactam and cefepime-zidebactam towards carbapenemase-producing Enterobacterales","volume":"81","author":"Dutkiewicz","year":"2026","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1080\/17460913.2025.2468112","article-title":"Cefepime-enmetazobactam: First approved cefepime-\u03b2- lactamase inhibitor combination for multi-drug resistant Enterobacterales","volume":"20","author":"Bhowmick","year":"2025","journal-title":"Future Microbiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"dkag141","DOI":"10.1093\/jac\/dkag141","article-title":"Synergistic activity of cefepime\/enmetazobactam with meropenem, piperacillin, piperacillin\/tazobactam, cefiderocol and fosfomycin against Klebsiella pneumoniae carrying blaKPC allelic variants","volume":"81","author":"Crema","year":"2026","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Zhang, S., Yang, J., Yang, Q., Li, Q., Zhong, Z., Wang, M., Jia, R., Chen, S., Liu, M., and Zhu, D. (2025). High Prevalence of Plas-mid-Mediated Fosfomycin Resistance in Waterfowl-Derived Escherichia Coli Strains: Insights into Genetic Context and Transmission Dynamics in China. Front. Vet. Sci., 12.","DOI":"10.3389\/fvets.2025.1481822"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1790\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:29:17Z","timestamp":1786696157000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1790"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":59,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["microorganisms14081790"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms14081790","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]}}}