Dynamic evolution of ceftazidime-avibactam resistance due to interchanges between bla_KPC-2 and bla_KPC-145 during treatment of Klebsiella pneumoniae infection

Background: The emergence of ceftazidime-avibactam (CZA) resistance among carbapenem-resistant Klebsiella pneumoniae (CRKP) is of major concern due to limited therapeutic options. Methods: In this study, 10 CRKP strains were isolated from different samples of a patient with CRKP infection receiving CZA treatment. Whole-genome sequencing (WGS) and conjugation experiments were performed to determine the transferability of the carbapenem resistance gene. Results: This infection began with a KPC-2-producing K. pneumoniae (CZA MIC = 2 mu g/mL, imipenem MIC >= 16 mg/mL). After 20 days of CZA treatment, the strains switched to the amino acid substitution of T263A caused by a novel KPC-producing gene, bla(KPC-145), which restored carbapenem susceptibility but showed CZA resistance (CZA MIC >= 256 mu g/mL, imipenem MIC = 1 mu g/mL). The bla(KPC-145) gene was located on a 148,185-bp untransformable IncFII-type plasmid. The subsequent use of carbapenem against KPC-145-producing K. pneumoniae infection led to a reversion of KPC-2 production (CZA MIC = 2 mu g/mL, imipenem MIC >= 16 mu g/mL). WGS analysis showed that all isolates belonged to ST11-KL47, and the number of SNPs was 14. This implied that these bla(KPC)-positive K. pneumoniae isolates might originate from a single clone and have been colonized for a long time during the 120-day treatment period. Conclusion: This is the first report of CZA resistance caused by bla(KPC-145), which emerged during the treatment with CZA against bla(KPC-2)-positive K. pneumoniae- associated infection in China. These findings indicated that routine testing for antibiotic susceptibility and carbapenemase genotype is essential during CZA treatment.