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In ongoing efforts to combat these \u201csuperbugs,\u201d we explored the clinical combination of aztreonam and ceftazidime\/avibactam together with varying dosages of polymyxin B and imipenem against\n              <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n              (\n              <jats:italic>Kp<\/jats:italic>\n              CDC Nevada) in a 9-day hollow fiber infection model (HFIM). As previously reported by our group, although the base of aztreonam and ceftazidime\/avibactam alone leads to 3.34 log\n              <jats:sub>10<\/jats:sub>\n              fold reductions within 72 hours, addition of polymyxin B or imipenem to the base regimen caused maximal killing of 7.55 log\n              <jats:sub>10<\/jats:sub>\n              and 7.4 log\n              <jats:sub>10<\/jats:sub>\n              fold reduction, respectively, by the 72-hour time point. Although low-dose polymyxin B and imipenem enhanced the bactericidal activity as an adjuvant to aztreonam +ceftazidime\/avibactam, regrowth to ~9 log\n              <jats:sub>10<\/jats:sub>\n              CFU\/mL by 216 hours rendered these combinations ineffective. When aztreonam +ceftazidime\/avibactam was supplemented with high-dose polymyxin B and or low-dose polymyxin B + imipenem, it resulted in effective long-term clearance of the bacterial population. Time lapse microscopy profiled the emergence of long filamentous cells in response to PBP3 binding due to aztreonam and ceftazidime. The emergence of spheroplasts via imipenem and damage to the outer membrane via polymyxin B was visualized as a mechanism of persister killing. Despite intrinsic\n              <jats:italic>mgrB<\/jats:italic>\n              and\n              <jats:italic>bla<\/jats:italic>\n              <jats:sub>NDM-1<\/jats:sub>\n              resistance, polymyxin B and \u03b2-lactam combinations represent a promising strategy. Future studies using an integrated molecularly precise pharmacodynamic approach are warranted to unravel the mechanistic details to propose optimal antibiotic combinations to combat untreatable, pan-drug-resistant Gram-negatives.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.00770-24","type":"journal-article","created":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T17:00:24Z","timestamp":1726592424000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Maximally precise combinations to overcome metallo-\u03b2-lactamase-producing\n            <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4808-3904","authenticated-orcid":false,"given":"Jan Naseer","family":"Kaur","sequence":"first","affiliation":[{"name":"Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, New York, USA"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack F.","family":"Klem","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, New York, USA"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, New York, USA"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie Rose","family":"Boissonneault","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia N.","family":"Holden","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, New York, USA"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0243-131X","authenticated-orcid":true,"given":"Barry","family":"Kreiswirth","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5845-2235","authenticated-orcid":true,"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, New York, USA"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0212-2787","authenticated-orcid":true,"given":"Nicholas M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, New York, USA"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2413-2118","authenticated-orcid":false,"given":"Brian T.","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, New York, USA"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, 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