Objectives: To investigate mechanisms for the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae (KPC-KP).
Methods: A total of 24 isolates, 8 each with ceftazidime/avibactam MICs of 4-8, 1-2 and 0.5 mg/L, were randomly selected from 214 clinical isolates of KPC-KP, and the beta-lactamase hydrolysis activity and porin expression profiles were determined. Plasmid profile and relative expression and copy number of the bla(KPC) gene were also analysed.
Results: Ceftazidime/avibactam MIC50 and MIC90 were 2 and 4 mg/L, respectively, for the 214 KPC-KP isolates. The hydrolysis activities of nitrocefin and ceftazidime in both of the ceftazidime/avibactam MIC 4-8 and 1-2 mg/L groups were significantly higher than those of the MIC 0.5 mg/L group, while the hydrolysis activities were 4-4.6-fold higher in the MIC 4-8 mg/L group than in the other two groups when 4 mg/L avibactam was added. The relative expression and copy number of the bla(KPC) gene in the MIC 4-8 mg/L group were 4.2-4.8-fold higher than in the other two groups. Meanwhile, SDS-PAGE showed that all isolates in the two groups with MIC 1 mg/L lacked OmpK35, which had either an early frameshift with a premature stop codon (n = 15, ST11) or overexpression of the negative regulation genes, micF and ompR (n = 1, ST15), whereas OmpK35 and OmpK36 could both be observed in all isolates with MIC 0.5 mg/L.
Conclusions: Decreased ceftazidime/avibactam susceptibility in KPC-KP clinical isolates is caused by high ceftazidime hydrolysis activity and OmpK35 porin deficiency and the majority of isolates belong to ST11.
[1]Fudan Univ, Huashan Hosp, Inst Antibiot, 12 M Wulumuqi Rd, Shanghai 200040, Peoples R China.
[2]Natl Hlth & Family Planning Commiss Peoples Repub, Key Lab Clin Pharmacol Antibiot, Shanghai, Peoples R China.
[3]Shanghai Jiao Tong Univ, Affiliated Hosp 6, Dept Infect Dis, Shanghai, Peoples R China.
(8.0+极速模式)