Risk factors for in vivo emergence of ceftazidime-avibactam resistance in KPC-producing Klebsiella pneumoniae and the associated resistance mechanisms: a case-control study.

The emergence of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (CZA-R KPC-Kp), primarily due to KPC variants, poses a growing challenge to clinical practice. We aimed to investigate risk factors for in vivo development of CZA resistance in KPC-Kp and explore resistance mechanisms. A matched case-control study was conducted at Taipei Veterans General Hospital, including patients with sequential KPC-Kp isolates, between June 2019 and May 2025. Forty-five patients with CZA-R KPC-Kp and a prior CZA-susceptible KPC-Kp (i.e., cases) were matched 1:1 to controls with both the first and the second KPC-Kp isolates being CZA-susceptible, based on the interval between the first and second isolates. Logistic regression was used to determine risk factors for the emergence of CZA resistance. The median interval between the first and second isolates was 20 days. KPC variants accounted for 73.3% (33/45) of CZA-R KPC-Kp isolates, with 20 variant types identified. The most common KPC variant was KPC-33 (n = 11), followed by KPC-35 (n = 3). Most KPC variants-producing strains (81.8%, 27/33) exhibited restored imipenem susceptibility (minimum inhibitory concentration [MIC] ≤ 4 µg/mL). CZA use was an independent risk factor for the development of resistance (odds ratio [OR] = 9.47, P = 0.001), whereas carbapenem use was a protective factor (OR = 0.27, P = 0.015). In conclusion, CZA exposure was the only risk factor for CZA resistance development in KPC-Kp, whereas the use of carbapenem may reduce the risk, possibly due to restored imipenem susceptibility in most KPC variant-producing strains.IMPORTANCEThe emergence of ceftazidime-avibactam (CZA)-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae poses a new threat to public health. Our study found that 73.3% of CZA-resistant strains carried KPC variants, and KPC-33 was the most frequent. Most KPC variants (82%) regained imipenem susceptibility. Exposure to CZA independently predicted resistance in KPC-Kp, whereas carbapenem use was protective. These findings highlight the importance of antibiotic stewardship and warrant further comparative study of meropenem-vaborbactam or imipenem-cilastatin-relebactam versus CZA for KPC-producing K. pneumoniae infections.