Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA.
J Antimicrob Chemother. 2023 Dec 1;78(12):2801-2809. doi: 10.1093/jac/dkad244.
Sulbactam-durlobactam is a potent combination active against Acinetobacter baumannii; however, it lacks activity against other nosocomial pathogens. Cefepime is a common first-line therapy for hospital/ventilator-associated pneumonia caused by Gram-negative pathogens including Pseudomonas aeruginosa and Enterobacterales. With increasing resistance to cefepime, and the significant proportion of polymicrobial nosocomial infections, effective therapy for infections caused by Acinetobacter baumannii, P. aeruginosa and Enterobacterales is needed. This study investigated the in vitro synergy of sulbactam-durlobactam plus cefepime against relevant pathogens.
Static time-kills assays were performed in duplicate against 14 cefepime-resistant isolates (A. baumannii, n = 4; P. aeruginosa, n = 4; Escherichia coli, n = 3; Klebsiella pneumoniae, n = 3). One WT K. pneumoniae isolate was included. Antibiotic concentrations simulated the free-steady state average concentration of clinically administered doses in patients.
Sulbactam-durlobactam alone showed significant activity against A. baumannii consistent with the MIC values. Sulbactam-durlobactam plus cefepime showed synergy against one A. baumannii isolate with an elevated MIC to sulbactam-durlobactam (32 mg/L). Against all P. aeruginosa isolates, synergy was observed with sulbactam-durlobactam plus cefepime. For the Enterobacterales, one E. coli isolate demonstrated synergy while the others were indifferent due to significant kill from sulbactam-durlobactam alone. The combination of sulbactam-durlobactam plus cefepime showed synergy against one of the K. pneumoniae and additive effects against the other two K. pneumoniae tested. No antagonism was observed in any isolates including the WT strain.
Synergy and no antagonism was observed with a combination of sulbactam-durlobactam and cefepime; further in vivo pharmacokinetic/pharmacodynamics data and clinical correlation are necessary to support our findings.
舒巴坦-多利布坦是一种针对鲍曼不动杆菌的强效联合制剂；然而，它对其他医院病原体没有活性。头孢吡肟是治疗革兰氏阴性病原体（包括铜绿假单胞菌和肠杆菌科）引起的医院/呼吸机相关性肺炎的常用一线治疗药物。随着对头孢吡肟的耐药性不断增加，以及多微生物医院感染的比例显著增加，需要有效的治疗药物来治疗由鲍曼不动杆菌、铜绿假单胞菌和肠杆菌科引起的感染。本研究调查了舒巴坦-多利布坦联合头孢吡肟对相关病原体的体外协同作用。
在 14 株头孢吡肟耐药株（鲍曼不动杆菌，n=4；铜绿假单胞菌，n=4；大肠埃希菌，n=3；肺炎克雷伯菌，n=3）中进行了两次重复的静态时间杀伤试验。包括一株 WT 肺炎克雷伯菌。抗生素浓度模拟了临床给予剂量的游离稳态平均浓度。
舒巴坦-多利布坦单独使用对鲍曼不动杆菌表现出显著的活性，与 MIC 值一致。舒巴坦-多利布坦联合头孢吡肟对 1 株 MIC 值升高至舒巴坦-多利布坦（32mg/L）的鲍曼不动杆菌分离株表现出协同作用。对于所有铜绿假单胞菌分离株，舒巴坦-多利布坦联合头孢吡肟观察到协同作用。对于肠杆菌科，1 株大肠埃希菌分离株表现出协同作用，而其他分离株则因舒巴坦-多利布坦单独的显著杀菌作用而无差异。舒巴坦-多利布坦联合头孢吡肟对 1 株肺炎克雷伯菌和另外 2 株测试的肺炎克雷伯菌表现出协同作用。在包括 WT 株在内的任何分离株中均未观察到拮抗作用。
舒巴坦-多利布坦和头孢吡肟联合使用观察到协同作用，无拮抗作用；需要进一步的体内药代动力学/药效学数据和临床相关性来支持我们的发现。
