The resistance mechanisms and risk factors of carbapenem-resistant Klebsiella pneumoniae to ceftazidime-avibactam.

OBJECTIVE

This study aimed to investigate the molecular epidemiological characteristics of carbapenem-resistant Klebsiella pneumoniae (CRKP), elucidate the mechanisms underlying ceftazidime-avibactam (CZA) resistance and identify the risk factors associated with the emergence of CZA resistance. Clinical and microbiological data from 292 hospitalized patients with CRKP infections were retrospectively collected at the First Affiliated Hospital of Xi'an Jiaotong University from January 2024 to March 2025. Ptients were categorized into CZA-susceptible (n=228) and CZA-resistant (n=64) CRKP groups based on the findings of CZA susceptibility testing. A total of five carbapenemase genes (blaKPC, blaNDM, blaVIM, blaIMP and blaOXA) were identified by the lateral flow assay and their respective subtypes of the genes was identified by PCR amplification followed by sanger sequencing. The relative expression of blaKPC was quantified using real-time quantitative PCR (RT-qPCR). Independent risk factors for CZA-resistant CRKP infections were identified using multivariate logistic regression analysis.

RESULTS

Among the 292 CRKP isolates, a total of 64 were CZA-resistant CRKP strains. Among these, isolates co-producing KPC and NDM accounted for 42.18%; those producing NDM alone accounted for 35.94%, those producing KPC alone accounted for 15.63%, isolates co-expressing NDM and IMP accounted for 1.56%, and carbapenemase-negative isolates accounted for 4.69%. Among the 10 KPC-only producing isolates, 8 were KPC mutants, including five harboring blaKPC-33, two harboring blaKPC-90 and one harboring blaKPC-78. Additionally, the relative gene expression levels of two blaKPC-2 isolates increased by 2.80- and 3.07-fold, respectively. This study demonstrates that, alongside MBLs, mutated KPC variants serve as the predominant mechanism underlying high-level CZA resistance. The multivariate logistic regression analysis showed that the patients receiving renal replacement therapy (OR = 2.611, 95 % CI: 1.192 - 5.721) and those with previous exposure to CZA (OR = 2.749, 95 % CI: 1.269 5.953) were independent risk factors for CZA-resistant CRKP infections.