Bonnin Rémy A, Jeannot Katy, Santerre Henriksen Anne, Quevedo Juan, Dortet Laurent
Team "Resist" UMR1184 "Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB)", INSERM, Université Paris-Saclay, CEA, LabEx LERMIT, Le Kremlin-Bicêtre, France; Bacteriology-Hygiene Unit, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France; Associated French National Reference Center for Antibiotic Resistance: Carbapenemase-Producing Enterobacteriaceae, Le Kremlin-Bicêtre, France.
Bacteriology Unit, University Hospital of Besançon, Besançon, France; Associated French National Reference Center for Antibiotic Resistance in Pseudomonas and Acinetobacter, Besançon, France.
Clin Microbiol Infect. 2025 Feb;31(2):240-249. doi: 10.1016/j.cmi.2024.09.031. Epub 2024 Oct 5.
Cefepime-enmetazobactam is a new β-lactam/βlactamase inhibitor combination with broad-spectrum activity against multidrug-resistant Enterobacterales, including extended-spectrum β-lactamase producers. This study evaluated the in vitro activity of cefepime-enmetazobactam towards a collection of carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa and Acinetobacter baumannii compared to the other β-lactam/β-lactamase inhibitor combinations.
The MIC of cefepime, cefepime-enmetazobactam, ceftazidime, ceftazidime-avibactam, meropenem, meropenem-vaborbactam, imipenem, imipenem-relebactam, and ertapenem were determined by broth microdilution on 2212 CRE, including 2089 carbapenemase producers (1000 OXA-48-like, 49 KPC, 697 NDM, 180 VIM, 1 IMP, 9 IMI, and 158 multiple carbapenemases) and 123 CRE that do not produce carbapenemase received at the French National Reference Centre (from March 1, 2023 to August 31, 2023), 50 P. aeruginosa, and 30 A. baumannii. All strains were fully sequenced.
We confirmed the absence of inhibitory activity of enmetazobactam towards metallo-β-lactamases. Cefepime-enmetazobactam and ceftazidime-avibactam exhibited a similar susceptibility (96.7% vs. 99.5%, respectively) on OXA-48-producers. Cefepime-enmetazobactam exhibited 66.9% and 63.3% susceptibility for CRE non-EPC and KPC, whereas those rates rose to 96.7%/95.9%, 93.4%/95.9%, and 95.9%/98.0% for ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam, respectively. Low MICs (≤0.25 mg/L) were obtained for ceftazidime-avibactam-resistant KPC variants. Cefepime-enmetazobactam did not display a significant added value when compared with cefepime alone on Pseudomonas aeruginosa and Acinetobacter baumannii.
OXA-48 producers displayed high susceptibility to cefepime-enmetazobactam, which is similar to ceftazidime-avibactam, including for OXA-48 producers that coproduce a ceftazidime hydrolyzing enzyme (extended-spectrum β-lactamases or AmpC). In vivo experiments have to be implemented to confirm if cefepime-enmetazobactam might be a relevant alternative to ceftazidime-avibactam for the treatment of infections caused by OXA-48 producers.
头孢吡肟-恩美他唑巴坦是一种新型β-内酰胺/β-内酰胺酶抑制剂组合，对包括产超广谱β-内酰胺酶菌株在内的多重耐药肠杆菌科细菌具有广谱活性。本研究评估了头孢吡肟-恩美他唑巴坦与其他β-内酰胺/β-内酰胺酶抑制剂组合相比，对一组耐碳青霉烯类肠杆菌科细菌（CRE）、铜绿假单胞菌和鲍曼不动杆菌的体外活性。
采用肉汤微量稀释法测定头孢吡肟、头孢吡肟-恩美他唑巴坦、头孢他啶、头孢他啶-阿维巴坦、美罗培南、美罗培南-法硼巴坦、亚胺培南、亚胺培南-瑞来巴坦和厄他培南对2212株CRE（包括2089株产碳青霉烯酶菌株，其中1000株为OXA-48样酶、49株为KPC、697株为NDM、180株为VIM、1株为IMP、9株为IMI和158株为多重碳青霉烯酶）以及法国国家参考中心在2023年3月1日至2023年8月31日期间收到的123株不产碳青霉烯酶的CRE、50株铜绿假单胞菌和30株鲍曼不动杆菌的最低抑菌浓度（MIC）。所有菌株均进行了全基因组测序。
我们证实恩美他唑巴坦对金属β-内酰胺酶无抑制活性。头孢吡肟-恩美他唑巴坦和头孢他啶-阿维巴坦对产OXA-48酶菌株的敏感性相似（分别为96.7%和99.5%）。头孢吡肟-恩美他唑巴坦对非EPC型和KPC型CRE的敏感性分别为66.9%和63.3%，而头孢他啶-阿维巴坦、亚胺培南-瑞来巴坦和美罗培南-法硼巴坦的相应比例分别升至96.7%/95.9%、93.4%/95.9%和95.9%/98.0%。对头孢他啶-阿维巴坦耐药的KPC变异株的MIC较低（≤0.25mg/L）。在铜绿假单胞菌和鲍曼不动杆菌方面，与单独使用头孢吡肟相比，头孢吡肟-恩美他唑巴坦未显示出显著的附加价值。
产OXA-48酶菌株对头孢吡肟-恩美他唑巴坦高度敏感，这与头孢他啶-阿维巴坦相似，包括对同时产生头孢他啶水解酶（超广谱β-内酰胺酶或AmpC）的产OXA-48酶菌株。必须进行体内实验，以确认头孢吡肟-恩美他唑巴坦是否可能成为治疗产OXA-48酶菌株引起感染的头孢他啶-阿维巴坦的相关替代药物。
