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

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 blaKPC 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 blaKPC mutation, which changed from blaKPC2 to blaKPC33 and then back to blaKPC2. In addition, the blaKPC14 in the CZA-resistant K. pneumoniae strain reverted to blaKPC2 after treatment with carbapenem, confirming the reversibility of the blaKPC 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 blaKPC 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 blaKPC mutation was reversible. For such clinical isolates, the combination of IMP and CZA could delay or prevent mutations in blaKPC and have a synergistic effect.