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Resistance may emerge during therapy, but knowledge on mutant prevention and collateral effects remains limited. Killing kinetics assays of ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and the combination of ceftazidime-avibactam with meropenem (CZA + MER) were performed against clinical KPC-3-ST307-Kp isolates and ceftazidime-avibactam-resistant KPC-ST307-Kp mutants (KPC-31\/KPC-46\/KPC-53\/KPC-61\/KPC-62\/KPC-66\/KPC-92\/KPC-150-Kp) with different genetic backgrounds. Single-step mutant frequencies and resistance trajectories were established. WGS was used to identify resistance mechanisms, and collateral resistance to other last-line agents was assessed. In time-kill assays, meropenem and ceftazidime-avibactam showed bactericidal activity at high concentrations (2\u00d7 MIC and 4\u00d7 MIC). Meropenem-vaborbactam was bactericidal only at high exposures (2\u00d7 MIC and 4\u00d7 MIC) and with reduced activity in porin-deficient strains, whereas imipenem-relebactam was bactericidal in half of the strains at 4\u00d7 MIC. CZA + MER showed synergistic bactericidal activity across all KPC-Kp isolates, even at subinhibitory concentrations. CZA + MER completely suppressed the emergence of resistant mutants (mutation rate &lt;10\u207b\u00b9\u2070), while stepwise selection with ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam rapidly led to resistance. Meropenem-vaborbactam and imipenem-relebactam selected mutants at lower concentrations and higher frequencies than ceftazidime-avibactam. Ceftazidime-avibactam resistance was mainly driven by\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>KPC<\/jats:sub>\n                      diversification, whereas meropenem-vaborbactam and imipenem-relebactam selected truncating mutations in OmpK36. Imipenem-relebactam exerted stronger collateral effects than meropenem-vaborbactam, extending cross-resistance to aztreonam-avibactam and cefepime-taniborbactam, while cefiderocol activity remained largely preserved. Plasmid copy number contributed minimally to resistance phenotypes. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam impose distinct evolutionary pressures on KPC-ST307-Kp, resulting in divergent resistance pathways and collateral resistance profiles. CZA + MER may offer a more sustainable strategy by preventing resistance emergence and limiting cross-resistance to last-line agents.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00488-26","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T14:26:46Z","timestamp":1782916006000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Addressing therapeutic options for KPC-3-producing ST307-\n                    <i>Klebsiella pneumoniae<\/i>\n                    : insights from\n                    <i>in vitro<\/i>\n                    evolution and mutant prevention strategies"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2857-2572","authenticated-orcid":true,"given":"Marta","family":"Hern\u00e1ndez-Garc\u00eda","sequence":"first","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Hospital 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