In vitro activity of cefepime/zidebactam against Klebsiella pneumoniae carrying bla KPC variants conferring resistance to ceftazidime/avibactam

Objectives: Resistance to ceftazidime/avibactam among KPC-producing Klebsiella pneumoniae (KPC-Kp) is often due to mutations within the bla KPC gene, determining a widespread occurrence of novel variants. Against KPC-Kp carrying novel bla KPC variants, further therapeutic agents are needed. Methods: We evaluated the in vitro activity of cefepime/zidebactam against 21 KPC-Kp clinical isolates carrying different bla KPC variants showing different antimicrobial susceptibility patterns to ceftazidime/avibactam, and compared it with the in vitro activity of cefepime/enmetazobactam. WGS was performed to identify antimicrobial resistance genes associated with ceftazidime/avibactam resistance. Analysis of porins and PBP-2 sequences was performed by manual alignment. Antimicrobial susceptibility testing to cefepime, cefepime/enmetazobactam and cefepime/zidebactam was performed by MIC test strips. Results: We selected a total of 21 ceftazidime/avibactam susceptible (n = 9) or resistant (n = 12) strains. Genomic analysis revealed that all ceftazidime/avibactam-resistant KPC-Kp carried mutations within bla KPC variants (bla KPC-31, bla KPC-14, bla KPC-33, bla KPC-93, bla KPC-203, bla KPC-205, bla KPC-49 and bla KPC-167), whereas susceptible strains carried bla KPC-3 and bla KPC-2 alleles. Overall, 42.85% (9/21) and 4.76% (1/21) of KPC-Kp harboured, respectively, a truncated OmpK35 or OmpK36 porin. PBP-2 analysis showed that all KPC-Kp carried WT enzymes, whereas one isolate carried a V521M substitution (valine→methionine). Cefepime/zidebactam (median 0.38 mg/L, IQR 0.222–0.5 mg/L) exhibited greater antibacterial activity (P < 0.0001) than cefepime alone and cefepime/enmetazobactam against ceftazidime/avibactam-susceptible KPC-Kp, whereas it exhibited no statistically significant difference (P = 0.4621) in antibacterial activity compared with cefepime/enmetazobactam against ceftazidime/avibactam-resistant strains carrying bla KPC variants. Also, we observed that cefepime/zidebactam exhibited greater antibacterial activity (P < 0.001) against KPC-Kp strains carrying the mutated bla KPC gene than against isolates harbouring the WT bla KPC gene. Conclusions: Cefepime/zidebactam provided potent in vitro results against KPC-Kp due to bla KPC variants, supporting its clinical utility for the treatment of infections due to ceftazidime/avibactam-resistant strains. Also, we demonstrated that zidebactam was not influenced by different bla KPC variants.