Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada.
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.
Antimicrob Agents Chemother. 2020 Feb 21;64(3). doi: 10.1128/AAC.02055-19.
Ceftolozane-tazobactam is a potent β-lactam/β-lactamase inhibitor combination approved for the treatment of complicated intraabdominal and complicated urinary tract infections and, more recently, the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. Although the activities of ceftolozane are not enhanced by tazobactam against , it remains the most potent antipseudomonal agent approved to date. Emerging data worldwide has included reports of microbiological failure in patients with serious bacterial infections caused by multidrug-resistant (MDR) as a result of ceftolozane resistance developed within therapy. The objective of this study is to compare the efficacy of a tobramycin homodimer plus ceftolozane versus ceftolozane-tazobactam alone against MDR and extensively drug-resistant (XDR) Tobramycin homodimer, a synthetic dimer of two monomeric units of tobramycin, was developed to abrogate the ribosomal properties of tobramycin with a view to mitigating aminoglycoside-related toxicity and resistance. Herein, we report that tobramycin homodimer, a nonribosomal aminoglycoside derivative, potentiates the activities of ceftolozane versus MDR/XDR and delays the emergence of resistance to ceftolozane-tazobactam in the wild-type PAO1 strain. This combination is also more potent than a standard ceftazidime-avibactam combination against these isolates. Conversely, a tobramycin monomer with intrinsic ribosomal properties does not potentiate ceftolozane under similar conditions. Susceptibility and checkerboard studies were assessed using serial 2-fold dilution assays, following the Clinical and Laboratory Standards Institute (CLSI) guidelines. This strategy provides an avenue to further preserve the clinical utility of ceftolozane and enhances its spectrum of activity against one of the most difficult-to-treat pathogens in hospitals.
头孢洛扎他唑巴坦是一种强效的β-内酰胺/β-内酰胺酶抑制剂组合，已获批准用于治疗复杂性腹腔内和复杂性尿路感染，以及最近用于治疗医院获得性和呼吸机相关性细菌性肺炎。虽然替唑巴坦对头孢洛扎他唑巴坦没有增强作用，但它仍然是迄今为止批准的最有效的抗假单胞菌药物。世界各地的新出现的数据包括由于治疗过程中头孢洛扎他唑巴坦耐药性的发展，导致多药耐药（MDR）和广泛耐药（XDR） 引起的严重细菌感染患者的微生物学失败的报告。本研究的目的是比较妥布霉素同型二聚体加头孢洛扎他唑巴坦与单独使用头孢洛扎他唑巴坦治疗 MDR 和 XDR 的疗效。妥布霉素同型二聚体是妥布霉素两个单体制剂的合成二聚体，旨在通过消除妥布霉素的核糖体性质来减轻氨基糖苷类相关毒性和耐药性。在此，我们报告说，妥布霉素同型二聚体，一种非核糖体氨基糖苷类衍生物，增强了头孢洛扎他唑巴坦对 MDR/XDR 的活性，并延迟了野生型 PAO1 菌株对头孢洛扎他唑巴坦耐药性的出现。这种组合对这些分离株也比标准的头孢他啶-阿维巴坦组合更有效。相反，具有内在核糖体性质的妥布霉素单体在类似条件下不能增强头孢洛扎他唑巴坦的活性。采用连续 2 倍稀释法评估药敏试验和棋盘试验，遵循临床和实验室标准协会（CLSI）指南。这种策略为进一步保留头孢洛扎他唑巴坦的临床应用提供了途径，并增强了其对医院中最难治疗的病原体之一的活性谱。
