Clonal transmission of a ceftazidime–avibactam-resistant hypervirulent Klebsiella pneumoniae KL64-ST11 strains harboring bla NDM-1 , bla KPC-2 , and ompk36 deletion

Ceftazidime–avibactam (CZA) exhibits promising activity against carbapenem-resistant Klebsiella pneumoniae (CRKP). However, CZA-resistant CRKP (CRKP ^CZA−R ) strains have been emerging. This study explored the mechanism underlying CZA resistance in these strains. CRKP ^CZA−R was screened from non-repetitive CRKP at our hospital from January 1, 2018 to October 30, 2021. The drug resistance mechanism and homology were analyzed through carbapenemase phenotype detection and next-generation sequencing. In total, 67 of 623 isolates (10.8%) were CRKP ^CZA−R . The most prevalent resistant genes were bla _NDM−1 (44.8%, 30/67), followed by bla _IMP−4 (9.0%, 6/67), bla _NDM−5 (7.5%, 5/67), and bla _NDM−4 (1.5%, 1/67). Furthermore, 37.3% (25/67) of CRKP ^CZA−R simultaneously harbored more than two carbapenemase-encoding genes. The enzyme inhibitor enhancement method detected the carbapenemase with high sensitivity (82.1%), particularly for strains harboring a single carbapenemase (100%). However, the presence of two or more carbapenemase limited its detection ability. Notably, 21 ST11-KL64 CRKP ^CZA−R exhibiting bla _NDM−1 , bla _KPC−2 , and also with ompk36 deletion, and 17 co-carried two or more high virulence gene markers, suggesting clonal transmission. Patients infected with these 21 strains were older and more serious than other drug-resistant strains, which were higher with MIC ₅₀ of fosfomycin than other drug-resistant strains. In conclusion, the detection rate of CRKP ^CZA−R was relatively high, which could be attributed to the transmission of MBL genes. Although enzyme inhibitor enhancement method can detect carbapenemases with high sensitivity and specificity, it might have limited detection ability for strains that simultaneously produce more than two carbapenemases. Patients infected with CRKP ^CZA−R harboring both bla _KPC−2 and bla _NDM−1 should be closely monitored.