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.

Automated summary

This study reports the first case of CZA resistance caused by bla(KPC-145) emerging during treatment of K. pneumoniae infection associated with bla(KPC-2) in China. Routine testing for antibiotic susceptibility and carbapenemase genotype is essential during CZA treatment.