Antimicrobial Resistance and Healthcare-Associated Infections Reference Unit, Public Health England, 61 Colindale Avenue, London NW9 5EQ, UK.
Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK.
J Antimicrob Chemother. 2021 May 12;76(6):1511-1522. doi: 10.1093/jac/dkab067.
Triple-action diazabicyclooctanes, e.g. zidebactam, combine β-lactamase inhibition, antibacterial activity, and 'enhancement' of PBP3-targeted β-lactams.
To examine the activity of cefepime/zidebactam against consecutive 'problem' Gram-negative bacteria referred to the UK national reference laboratory.
MICs were determined by BSAC agar dilution for 1632 Enterobacterales, 745 Pseudomonas aeruginosa and 450 other non-fermenters, categorized by carbapenemase detection and interpretive reading.
Universal susceptibility to cefepime/zidebactam 8 + 8 mg/L was seen for otherwise multidrug-resistant Enterobacterales with AmpC, extended-spectrum, K1, KPC and OXA-48-like β-lactamases, or with impermeability and 'unassigned' mechanisms. Unlike ceftazidime/avibactam and all other comparators, cefepime/zidebactam 8 + 8 mg/L also inhibited most (190/210, 90.5%) Enterobacterales with MBLs. Resistance in the remaining minority of MBL producers, and in 13/24 with both NDM MBLs and OXA-48-like enzymes, was associated with Klebsiella pneumoniae ST14. For Pseudomonas aeruginosa, MICs of cefepime/zidebactam rose with efflux grade, but exceeded 8 + 8 mg/L for only 11/85 isolates even in the highly-raised efflux group. Among 103 P. aeruginosa with ESBLs or MBLs, 97 (94.5%) were inhibited by cefepime/zidebactam 8 + 8 mg/L whereas fewer than 15% were susceptible to any comparator. MICs for Acinetobacter baumannii with acquired OXA carbapenemases clustered around 8 + 8 to 32 + 32 mg/L, with higher values for MBL producers. A strong enhancer effect augmented activity against many isolates that were highly resistant to cefepime and zidebactam alone and which had mechanisms not inhibited by zidebactam.
Assuming successful clinical trials, cefepime/zidebactam has scope to widely overcome critical resistances in both Enterobacterales and non-fermenters.
三效作用的二氮杂二环辛烷，例如齐他培南，结合了β-内酰胺酶抑制、抗菌活性和针对 PBP3 的β-内酰胺类药物的“增强”作用。
检查头孢吡肟/齐他培南对英国国家参考实验室送检的连续“问题”革兰氏阴性菌的活性。
通过 BSAC 琼脂稀释法测定了 1632 株肠杆菌科、745 株铜绿假单胞菌和 450 株其他非发酵菌的 MICs，根据碳青霉烯酶检测和解释性读数进行了分类。
除了对头孢吡肟/齐他培南 8+8mg/L 具有多药耐药性的肠杆菌科，包括 AmpC、超广谱、K1、KPC 和 OXA-48 样β-内酰胺酶，或具有通透性和“未分类”机制的菌株外，其他菌株均对头孢吡肟/齐他培南 8+8mg/L 普遍敏感。与头孢他啶/阿维巴坦和所有其他对照药物不同，头孢吡肟/齐他培南 8+8mg/L 还抑制了大多数（190/210，90.5%）产金属β-内酰胺酶的肠杆菌科。少数产金属β-内酰胺酶的菌株以及 13/24 株同时产 NDM 金属β-内酰胺酶和 OXA-48 样酶的菌株存在耐药性，与肺炎克雷伯菌 ST14 有关。对于铜绿假单胞菌，头孢吡肟/齐他培南的 MICs 随着外排等级的升高而升高，但即使在外排等级较高的情况下，也只有 11/85 株分离株的 MICs 超过 8+8mg/L。在 103 株产 ESBLs 或金属β-内酰胺酶的铜绿假单胞菌中，97（94.5%）株对头孢吡肟/齐他培南 8+8mg/L 有抑制作用，而低于 15%的菌株对任何对照药物敏感。获得性 OXA 碳青霉烯酶的鲍曼不动杆菌的 MIC 聚集在 8+8 至 32+32mg/L 之间，产金属β-内酰胺酶的菌株的 MIC 值更高。强有力的增强剂作用增强了对许多单独使用头孢吡肟和齐他培南高度耐药且齐他培南不能抑制其机制的分离株的活性。
假设临床试验成功，头孢吡肟/齐他培南有望广泛克服肠杆菌科和非发酵菌的关键耐药性。
