Livermore David M, Mushtaq Shazad, Warner Marina, Vickers Anna, Woodford Neil
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England National Infection Service, 61 Colindale Avenue, London NW9 5EQ, UK.
Floor 2, Bob Champion Research & Educational Building, James Watson Road, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK.
J Antimicrob Chemother. 2017 May 1;72(5):1373-1385. doi: 10.1093/jac/dkw593.
Diazabicyclooctanes (DBOs) inhibit class A, class C and some class D β-lactamases. A few also bind PBP2, conferring direct antibacterial activity and a β-lactamase-independent 'enhancer' effect, potentiating β-lactams targeting PBP3. We tested a novel DBO, zidebactam, combined with cefepime.
CLSI agar dilution MICs were determined with cefepime/zidebactam in a chequerboard format. Bactericidal activity was also measured.
Zidebactam MICs were ≤2 mg/L (mostly 0.12-0.5 mg/L) for most Escherichia coli , Klebsiella , Citrobacter and Enterobacter spp., but were >32 mg/L for Proteeae, most Serratia and a few E. coli , Klebsiella and Enterobacter/Citrobacter . The antibacterial activity of zidebactam dominated chequerboard studies for Enterobacteriaceae, but potentiation of cefepime was apparent for zidebactam-resistant isolates with class A and C enzymes, illustrating β-lactamase inhibition. Overall, cefepime/zidebactam inhibited almost all Enterobacteriaceae with AmpC, ESBL, K1, KPC and OXA-48-like β-lactamases at 1 + 1 mg/L and also 29 of 35 isolates with metallo-carbapenemases, including several resistant to zidebactam alone. Zidebactam MICs for 36 of 50 Pseudomonas aeruginosa were 4-16 mg/L, and the majority of AmpC, metallo-β-lactamase-producing and cystic fibrosis isolates were susceptible to cefepime/zidebactam at 8 + 8 mg/L. Zidebactam MICs for Acinetobacter baumannii and Stenotrophomonas maltophilia were >32 mg/L; potentiation of cefepime was frequent for S. maltophilia , but minimal for A. baumannii . Kill curve results largely supported MICs.
Zidebactam represents a second triple-action DBO following RG6080, with lower MICs for Enterobacteriaceae and P. aeruginosa . Clinical evaluation of cefepime/zidebactam must critically evaluate the reliance that can be placed on this direct antibacterial activity and on the enhancer effect as well as β-lactamase inhibition.
二氮杂双环辛烷（DBOs）可抑制A类、C类以及部分D类β-内酰胺酶。少数DBOs还可结合青霉素结合蛋白2（PBP2），赋予直接抗菌活性以及不依赖β-内酰胺酶的“增强子”效应，增强靶向PBP3的β-内酰胺类药物的活性。我们对一种新型DBO——齐德巴坦与头孢吡肟联合用药进行了测试。
采用棋盘法以头孢吡肟/齐德巴坦测定美国临床和实验室标准协会（CLSI）琼脂稀释最低抑菌浓度（MIC）。同时也测定了杀菌活性。
对于大多数大肠埃希菌、克雷伯菌属、柠檬酸杆菌属和肠杆菌属细菌，齐德巴坦的MIC≤2mg/L（多数为0.12 - 0.5mg/L），但对于变形杆菌属、多数沙雷菌属以及少数大肠埃希菌、克雷伯菌属和肠杆菌属/柠檬酸杆菌属细菌，MIC>32mg/L。在针对肠杆菌科细菌的棋盘法研究中，齐德巴坦的抗菌活性占主导地位，但对于具有A类和C类酶的齐德巴坦耐药菌株，头孢吡肟的增效作用明显，表明存在β-内酰胺酶抑制作用。总体而言，头孢吡肟/齐德巴坦在1 + 1mg/L时可抑制几乎所有产AmpC、超广谱β-内酰胺酶（ESBL）、K1、KPC和OXA - 48样β-内酰胺酶的肠杆菌科细菌，以及35株产金属碳青霉烯酶菌株中的29株，包括几株单独对齐德巴坦耐药的菌株。50株铜绿假单胞菌中有36株的齐德巴坦MIC为4 - 16mg/L，大多数产AmpC、金属β-内酰胺酶的菌株以及囊性纤维化分离株在8 + 8mg/L时对头孢吡肟/齐德巴坦敏感。鲍曼不动杆菌和嗜麦芽窄食单胞菌的齐德巴坦MIC>32mg/L；嗜麦芽窄食单胞菌中头孢吡肟的增效作用常见，但鲍曼不动杆菌中则很微弱。杀菌曲线结果在很大程度上支持了MIC结果。
齐德巴坦是继RG6080之后的第二种具有三重作用的DBO，对肠杆菌科细菌和铜绿假单胞菌的MIC较低。头孢吡肟/齐德巴坦的临床评估必须严格评估对这种直接抗菌活性、增强子效应以及β-内酰胺酶抑制作用的依赖程度。
