Suboptimal ceftazidime-avibactam exposure drives sequential <i>bla</i> _KPC mutations and intra-host coexistence of <i>Klebsiella pneumoniae</i> harboring distinct variants leading to persistent infection

<i>Klebsiella pneumoniae</i>, especially those producing KPC or KPC variant enzymes, represent a growing threat to global health due to limited treatment options and frequent therapeutic failure. The emergence of <i>bla</i>_KPC mutations during treatment further complicates therapy, as these mutations can lead to shifts in resistance profiles. Understanding the patterns and driving factors behind <i>bla</i>_KPC mutations is crucial for developing more effective treatment strategies. This study shows that dose reduction of ceftazidime-avibactam during treatment for renal impairment can promote potential stepwise mutations in <i>bla</i>_KPC, leading to the emergence of multiple variants with corresponding resistance shifts. Moreover, insufficient ceftazidime-avibactam and carbapenems fail to eradicate the bacteria, allowing the coexistence of <i>K. pneumoniae</i> subpopulations carrying distinct <i>bla</i>_KPC variants within a single patient. The findings highlight the need for individualized treatment regimens and optimized dosing and combination strategies to limit the emergence and persistence of KPC variant-producing <i>K. pneumoniae</i> during therapy.