期刊
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
卷 75, 期 6, 页码 1474-1478出版社
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkaa036
关键词
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资金
- Wockhardt Bio AG, Switzerland
- Ministerio de Economia y Competitividad of Spain
- Instituto de Salud Carlos III
- European Regional Development Fund 'A way to achieve Europe' ERDF, through the Spanish Network for Research in Infectious Diseases [RD12/0015, RD16/0016]
Objectives: The combination of cefepime and the novel beta-lactamenhancer zidebactam(WCK 5222) is under development for the treatment of difficult-to-treat Gram-negative infections. Against MBL-producing pathogens, cefepime and zidebactam induce cell elongation and spheroplast formation, indicating PBP3 and PBP2 dysfunction, respectively, having a potent bactericidal effect as a combination. The objective of the present study was to determine the mechanistic basis of the bactericidal effect of cefepime/zidebactam on MBL-expressing pathogens. Methods: Pseudomonal PBP-binding affinities of cefepime, zidebactam and imipenem were assessed at different timepoints and also in the presence of purified VIM-1 using a Bocillin FL competition assay. The antibacterial activity of cefepime/zidebactam against three VIM-expressing Pseudomonas aeruginosa isolates was assessed by time-kill and neutropenic mouse lung/thigh infection studies. Results: Amidst cefepime-hydrolysing concentrations of VIM-1, substantial cefepime binding to target PBPs was observed. High-affinity binding of zidebactam to PBP2 remained unaltered in the presence of VIM-1; however, MBL addition significantly affected imipenem PBP2 binding. Furthermore, the rate of cefepime binding to the primary target PBP3 was found to be higher compared with the imipenem PBP2 binding rate. Finally, complementary PBP inhibition by cefepime/zidebactam resulted in enhanced bactericidal activity in time-kill and neutropenic mouse lung/thigh infection studies against VIM-6-, VIM-10- and VIM-11-expressing P. aeruginosa, thus revealing the mechanistic basis of beta-lactamenhancer action. Conclusions: For the first time ever (to the best of our knowledge), this study demonstrates that in the presence of VIM-1 MBL, beta-lactamase-labile cefepime and beta-lactamase-stable zidebactam produce effective inhibition of respective target PBPs. For cefepime, this seems to be a result of a faster rate of PBP binding, which helps it overcome beta-lactamase-mediated hydrolysis.
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