新型β-内酰胺-β-内酰胺酶抑制剂组合(BLBLIs)正在临床开发中,用于治疗由碳青霉烯耐药和难以治疗的耐药(DTR)(定义为对所有测试的β-内酰胺和氟喹诺酮类药物的耐药性)引起的感染。本研究评估了头孢吡肟-齐巴坦的体外活性,头孢他啶-阿维巴坦,头孢吡肟-他唑巴坦,头孢洛赞-他唑巴坦,和其他比较者对2019年从中国不同地区(46家医院)收集的4042株非重复革兰氏阴性临床分离株。基于药代动力学-药效学(PK-PD)断点,头孢吡肟-齐巴坦抑制98.5%的肠杆菌和98.9%的铜绿假单胞菌,分别。针对耐碳青霉烯和难以治疗的耐药革兰氏阴性杆菌,头孢吡肟-齐达巴坦对肠杆菌表现出更好的活性(96%和97.2%,分别)和铜绿假单胞菌(98.2%和96.9%,分别)。在379株碳青霉烯类耐药肠杆菌中,最常见的碳青霉烯酶基因是blaKPC-2(64.1%)和blaNDM(30.9%)。头孢吡肟-齐巴坦对98.8%的blaKPC阳性分离株和89.7%的blaNDM阳性分离株显示MIC90≤2mg/L。头孢他啶-阿维巴坦还显示了针对肠杆菌(93.6%)和铜绿假单胞菌(87.7%)的有效体外活性。头孢他啶-阿维巴坦对97.5%的blaKPC阳性分离株和100%的blaOXA-232阳性分离株具有活性。头孢吡肟-齐巴坦抑制97.3%的鲍曼不动杆菌分离株,MIC50/90为16/32mg/L。我们的研究系统地评估了这些新型BLBLIs对多种革兰氏阴性杆菌的体外活性,为在中国批准这些BLBLIs提供了临床前数据,并支持头孢吡肟-齐达巴坦和头孢他啶-阿维巴坦作为碳青霉烯耐药肠杆菌(CRE)引起的感染的潜在有效疗法,耐碳青霉烯铜绿假单胞菌(CRPA),和DTR分离株。重要性肠杆菌,铜绿假单胞菌,鲍曼不动杆菌和鲍曼不动杆菌是世界上最常见的引起医院感染的革兰氏阴性杆菌。由于其巨大的公共卫生和社会影响,耐碳青霉烯类鲍曼不动杆菌(CRAB),耐碳青霉烯铜绿假单胞菌(CRPA),碳青霉烯耐药和第三代头孢菌素耐药肠杆菌科被世界卫生组织(WHO)视为2017年新药投资的全球优先事项。本研究表明,这些新型BLBLIs和其他比较物对革兰氏阴性杆菌分离株具有强大的体外活性,包括碳青霉烯类耐药或难以治疗的耐药表型。多粘菌素,替加环素,头孢他啶-阿维巴坦(blaNDM阳性分离株除外)可用于治疗CRE分离株引起的感染。目前,头孢吡肟-齐达巴坦和其他BLBLIs尚未在中国批准使用。这里,我们的研究旨在评估BLBLIs对革兰氏阴性杆菌分离株的体外活性,尤其是CRE,在临床使用前。
Novel β-lactam-β-lactamase inhibitor combinations (BLBLIs) are in clinical development for the treatment of infections caused by carbapenem-resistant and difficult-to-treat resistant (DTR) (defined as resistance to all tested β-lactams and fluoroquinolones) Gram-negative bacilli. This study evaluated the in vitro activities of cefepime-zidebactam, ceftazidime-avibactam, cefepime-tazobactam, ceftolozane-tazobactam, and other comparators against 4,042 nonduplicate Gram-negative clinical isolates collected from different regions of China (46 hospitals) in 2019. Based on the pharmacokinetic-pharmacodynamic (PK-PD) breakpoints, cefepime-zidebactam inhibited 98.5% of Enterobacterales and 98.9% of Pseudomonas aeruginosa isolates, respectively. Against carbapenem-resistant and difficult-to-treat resistant Gram-negative bacilli, cefepime-zidebactam demonstrated better activity against Enterobacterales (96% and 97.2%, respectively) and P. aeruginosa (98.2% and 96.9%, respectively). Among the 379 carbapenem-resistant Enterobacterales isolates, the most common carbapenemase genes detected were blaKPC-2 (64.1%) and blaNDM (30.9%). Cefepime-zidebactam showed an MIC90 of ≤2 mg/L for 98.8% of blaKPC-positive isolates and 89.7% of blaNDM-positive isolates. Ceftazidime-avibactam also showed efficient in vitro activity against Enterobacterales (93.6%) and P. aeruginosa (87.7%). Ceftazidime-avibactam was active against 97.5% of blaKPC-positive isolates and 100% of blaOXA-232-positive isolates. Cefepime-zidebactam inhibited 97.3% of Acinetobacter baumannii isolates with an MIC50/90 of 16/32 mg/L. Our study systematically evaluated the in vitro activities of these new BLBLIs against a variety of Gram-negative bacilli, provided preclinical data for the approval of these BLBLIs in China, and supported cefepime-zidebactam and ceftazidime-avibactam as potential efficient therapies for infections caused by carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant P. aeruginosa (CRPA), and DTR isolates. IMPORTANCE Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii are the most common Gram-negative bacilli to cause nosocomial infections throughout the world. Due to their large public health and societal implications, carbapenem-resistant A. baumannii (CRAB), carbapenem-resistant P. aeruginosa (CRPA), and carbapenem-resistant and third-generation-cephalosporin-resistant Enterobacteriaceae were regarded by the World Health Organization (WHO) as a global priority for investment in new drugs in 2017. The present study showed the potent in vitro activity of these novel BLBLIs and other comparators against Gram-negative bacillus isolates, including carbapenem-resistant or difficult-to-treat resistant phenotypes. Polymyxins, tigecycline, and ceftazidime-avibactam (except for blaNDM-positive isolates) were available for the treatment of infections caused by CRE isolates. Currently, cefepime-zidebactam and other BLBLIs have not yet been approved for use in China. Here, our study aimed to evaluate the in vitro activities of BLBLIs against Gram-negative bacillus isolates, especially CRE, before clinical use.