Bakthavatchalam Yamuna Devi, Shankar Abirami, Abdullah Fiza, Srinivasan Devishree, Ragothaman Harathi, KrishnaMoorthy Soniya, Manokaran Yuvasri, Nambi Senthur, Ramasubramanian V, Nagvekar Vasanth, Manesh Abi, Karthik Rajiv, Varghese George M, Kumar Deepak, Deswal Vikas, Dwarakanathan Hariharan, Raj Santhosh, Rodrigues Camilla, Soman Rajeev, Todi Subash, Solaimalai Dhanalakshmi, Veeraraghavan Balaji
Department of Clinical Microbiology, Christian Medical College, Vellore 632004, India.
Department of Infectious Diseases, Apollo Hospitals, Chennai, India.
Diagn Microbiol Infect Dis. 2025 Jul 5;113(3):116993. doi: 10.1016/j.diagmicrobio.2025.116993.
Extended spectrum beta-lactamase producing Enterobacterales are classified as critical priority pathogens with limited therapeutic options. Enmetazobactam is a novel penicillanic sulfone beta-lactamase inhibitor with the spectrum of coverage against range of ESBLs. The combination of cefepime/enmetazobactam has been approved for the treatment of cUTI including acute pyelonephritis in United States and Europe, and additionally licensed for the treatment of hospital acquired pneumonia including ventilator associated pneumonia and their associated bacteremia in Europe. In this study, we determined the in-vitro activity of cefepime/enmetazobactam along with comparators against molecularly well characterised third generation cephalosporin resistant Enterobacterales and P. aeruginosa isolates METHODS: Non-duplicate third generation cephalosporin resistant Enterobacterales (E. coli, n = 262; K. pneumoniae, n = 250; Enterobacter sp., n = 32; Proteus spp., n = 22) and P. aeruginosa (n = 100) clinical isolates were included in this study. Presence of ESBLs, ampCs and OXA-1 encoding genes were detected by PCR. MICs of cefepime/enmetazobactam and comparators were determined by reference broth microdilution. Time kill assay was performed to assess the antibacterial activity of cefepime/enmetazobactam against ESBL and/or ampC producers.
Cefepime/enmetazobactam potently inhibited all CTX-M and/or OXA-1 producing E. coli isolates at MIC of ≤ 2 mg/L and ampC (CMY and/or DHA) producing isolates at MIC of ≤ 4 mg/L. Among CTX-M producing E. coli, susceptibility to TZP was significantly dropped from 78% to 58% in the presence of OXA-1. Further, cefepime/enmetazobactam continued to show potent activity against CTX-M producing K. pneumoniae and were inhibited at MIC of ≤ 1 mg/L. All the tested P. aeruginosa isolates were highly susceptible to cefepime/enmetazobactam with 100% inhibition. In time-kill assay, cefepime/enmetazobactam showed ≥ 3 log kill against CTX-M producingE. coli and CTX-M producingK. pneumoniae isolates, which is comparable to that of meropenem.
The findings of the present study retraites that the spectrum of coverage of cefepime/enmetazobactam is superior to that of TZP and similar to that of meropenem, emphasising the importance of cefepime/enmetazobactam as a carbapenem-sparing option.
产超广谱β-内酰胺酶的肠杆菌科细菌被列为关键优先病原体，治疗选择有限。恩美他唑巴坦是一种新型青霉烷砜β-内酰胺酶抑制剂，对多种超广谱β-内酰胺酶具有覆盖范围。头孢吡肟/恩美他唑巴坦联合制剂已在美国和欧洲获批用于治疗复杂性尿路感染，包括急性肾盂肾炎，在欧洲还额外获批用于治疗医院获得性肺炎，包括呼吸机相关性肺炎及其相关菌血症。在本研究中，我们测定了头孢吡肟/恩美他唑巴坦与对照药物对分子特征明确的第三代头孢菌素耐药肠杆菌科细菌和铜绿假单胞菌分离株的体外活性。
本研究纳入了非重复的第三代头孢菌素耐药肠杆菌科细菌（大肠杆菌，n = 262；肺炎克雷伯菌，n = 250；肠杆菌属，n = 32；变形杆菌属，n = 22）和铜绿假单胞菌（n = 100）临床分离株。通过聚合酶链反应检测超广谱β-内酰胺酶、AmpC酶和OXA-1编码基因的存在情况。采用参考肉汤微量稀释法测定头孢吡肟/恩美他唑巴坦及对照药物的最低抑菌浓度。进行时间杀菌试验以评估头孢吡肟/恩美他唑巴坦对产超广谱β-内酰胺酶和/或AmpC酶菌株的抗菌活性。
头孢吡肟/恩美他唑巴坦能有效抑制所有产CTX-M和/或OXA-1的大肠杆菌分离株，最低抑菌浓度≤2 mg/L，对产AmpC酶（CMY和/或DHA）的分离株最低抑菌浓度≤4 mg/L。在产CTX-M的大肠杆菌中，在有OXA-1存在的情况下，对哌拉西林/他唑巴坦的敏感性从78%显著降至58%。此外，头孢吡肟/恩美他唑巴坦对产CTX-M的肺炎克雷伯菌仍显示出强效活性，最低抑菌浓度≤1 mg/L时受到抑制。所有测试的铜绿假单胞菌分离株对头孢吡肟/恩美他唑巴坦高度敏感，抑制率达100%。在时间杀菌试验中，头孢吡肟/恩美他唑巴坦对产CTX-M的大肠杆菌和产CTX-M的肺炎克雷伯菌分离株显示出≥3个对数级的杀菌效果，与美罗培南相当。
本研究结果表明，头孢吡肟/恩美他唑巴坦的覆盖谱优于哌拉西林/他唑巴坦，与美罗培南相似，强调了头孢吡肟/恩美他唑巴坦作为一种碳青霉烯类药物替代选择的重要性。
