{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T18:21:10Z","timestamp":1778782870375,"version":"3.51.4"},"reference-count":20,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo-Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF16OC0023482"],"award-info":[{"award-number":["NNF16OC0023482"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Danish Innovationsfonden","award":["NNF16OC0023482"],"award-info":[{"award-number":["NNF16OC0023482"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: Carbapenemase-producing Klebsiella pneumoniae and Escherichia coli have become a significant global health challenge. This has created an urgent need for new treatment modalities. We evaluated the efficacy of mecillinam in combination with either avibactam or ceftazidime\/avibactam against carbapenemase-producing clinical isolates. Materials and methods: Nineteen MDR clinical isolates of K. pneumoniae and E. coli were selected for the presence of blaKPC, blaNDM, blaOXA or blaIMP based on whole-genome sequencing and phenotypic susceptibility testing. We tested the synergy between mecillinam and avibactam or ceftazidime\/avibactam. We used time\u2013kill studies in vitro and a mouse peritonitis\/sepsis model to confirm the synergistic effect. We investigated avibactam\u2019s impact on mecillinam\u00b4s affinity for penicillin-binding proteins with a Bocillin assay, and cell changes with phase-contrast and confocal laser scanning microscopy. Results: Mecillinam combined with ceftazidime\/avibactam or avibactam substantially reduced MICs (from up to &gt;256 \u00b5g\/mL to &lt;0.0016 \u00b5g\/mL) for 17\/18 strains. Significant log-CFU reductions were confirmed in time\u2013kill and in vivo experiments. The Bocillin assay did not reveal changes. Conclusion: Mecillinam in combination with avibactam or ceftazidime\/avibactam has a notable effect on most types of CPEs, both in vitro and in vivo. The mecillinam\/avibactam combination treatment could be a new efficient antibiotic treatment against multi-drug-resistant carbapenemase-producing Gram-negative pathogens.<\/jats:p>","DOI":"10.3390\/antibiotics11101280","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T21:12:53Z","timestamp":1663708373000},"page":"1280","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Synergy between Mecillinam and Ceftazidime\/Avibactam or Avibactam against Multi-Drug-Resistant Carbapenemase-Producing Escherichia coli and Klebsiella pneumoniae"],"prefix":"10.3390","volume":"11","author":[{"given":"Karoline Knudsen","family":"List","sequence":"first","affiliation":[{"name":"Department of Clinical Microbiology, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5575-0384","authenticated-orcid":false,"given":"Mette","family":"Kolpen","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7662-9118","authenticated-orcid":false,"given":"Kasper N\u00f8rskov","family":"Kragh","sequence":"additional","affiliation":[{"name":"Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4792-1889","authenticated-orcid":false,"given":"Godefroid","family":"Charbon","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Rigshospitalet, DK-2100 Copenhagen, Denmark"},{"name":"Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stine","family":"Radmer","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Hansen","sequence":"additional","affiliation":[{"name":"Statens Serum Institut, DK-2300 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0344-6417","authenticated-orcid":false,"given":"Anders","family":"L\u00f8bner-Olesen","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1966-8302","authenticated-orcid":false,"given":"Niels","family":"Frimodt-M\u00f8ller","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0888-4616","authenticated-orcid":false,"given":"Frederik Boetius","family":"Hertz","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"dlab023","DOI":"10.1093\/jacamr\/dlab023","article-title":"ICMR\u2019s Antimicrobial Resistance Surveillance system (i -AMRSS): A promising tool for global antimicrobial resistance surveillance","volume":"3","author":"Kaur","year":"2021","journal-title":"JAC-Antimicrob. 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