The synergistic effect of imipenem combined with ceftazidime-avibactam against Klebsiella pneumoniae with alternating resistance to CZA and carbapenem.

Abstract

Purposes: The purpose of this study was to explore the mechanisms of resistance of clinically isolated K. pneumoniae, which is alternately resistant to carbapenems and ceftazidime/avibactam (CZA), and therapeutic strategies.

Methods: Whole-genome sequencing was used to determine the resistance mechanisms of K. pneumoniae. In vitro antibiotic induction experiments were used to verify the reversibility of bla_KPC mutations in these strains. Checkerboard analysis and growth curve analysis were used to evaluate the efficacy of imipenem (IMP) combined with CZA.

Results: The clinical strains exhibited alternating resistance and susceptibility to IMP and CZA during clinical treatment, namely, resistance-susceptibility-resistance to IMP and susceptibility-resistance-susceptibility to CZA. The resistance mechanism involved bla_KPC mutation, which changed from bla_KPC2 to bla_KPC33 and then back to bla_KPC2. In addition, the bla_KPC14 in the CZA-resistant K. pneumoniae strain reverted to bla_KPC2 after treatment with carbapenem, confirming the reversibility of the bla_KPC mutations under the selective pressure of antibiotics. For KPC-producing K. pneumoniae (KPC-Kp) with the above drug-resistant phenotype, the combination of IMP and CZA had synergistic effects, indicating better bactericidal efficacy than IMP, MER, or CZA alone.

Conclusion: This study revealed that CRKP developed CZA resistance due to bla_KPC mutation, and carbapenem susceptibility was restored. After retreatment with carbapenem, the strains showed carbapenem resistance, and they regained susceptibility to CZA. For the first time, we showed that the bla_KPC mutation was reversible. For such clinical isolates, the combination of IMP and CZA could delay or prevent mutations in bla_KPC and have a synergistic effect.