Emergence of Ceftazidime‐Avibactam‐Induced KPC Variants (KPC‐25/127) in Intracranial Infection and Implications for Clinical Management

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ABSTRACT The emergence of novel Klebsiella pneumoniae carbapenemase (KPC) variants contributing to clinical treatment failure poses a substantial threat to public health. To inform the clinical management of infections caused by KPC‐variant‐harboring K. pneumoniae , this study reports the complex evolutionary trajectory of ceftazidime‐avibactam (CAZ‐AVI)‐resistant KPC‐variant‐harboring K. pneumoniae in a single patient during CAZ‐AVI treatment. Three KPC‐producing K. pneumoniae (KPC‐KP) isolates were obtained from a patient with K. pneumoniae infection who received sequential treatment with imipenem followed by CAZ‐AVI. Isolate K2, harboring bla KPC‐2 , exhibited carbapenem resistance. After 12 days of CAZ‐AVI administration, isolate K25 (carrying bla KPC‐25 ) showed CAZ‐AVI resistance but remained susceptible to imipenem. In contrast, isolate K127 (harboring bla KPC‐127 firstly identified by our group), recovered after combined CAZ‐AVI and imipenem therapy, displayed dual resistance to both CAZ‐AVI and carbapenems; this carbapenem resistance was attributed to outer membrane protein mutations combined with bla KPC‐127 overexpression. Analysis of the genetic regions revealed that all subtypes were located within a conserved genetic background: IS 26 ‐IS Kpn8 ‐ bla KPC ‐ΔIS Kpn6 ‐Δ tnpR ‐Tn 1721 . Cloning and heterologous expression of the KPC variants, followed by enzymatic kinetic analyses and minimum inhibitory concentration (MIC) determinations, confirmed that the variants altered the MICs of CAZ‐AVI and carbapenems. Compared with the KPC‐2 protein, both variant proteins exhibited reduced hydrolytic activity against ceftazidime. Additionally, the half‐maximal inhibitory concentration (IC 50 ) of avibactam against the KPC variants was significantly higher than that of the wild‐type KPC‐2 protein. These results indicate that the KPC variant proteins have low affinity for avibactam, thereby reducing susceptibility to this inhibitor.

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