This study established the in vitro activity of ceftolozane/tazobactam (C/T) and its genotypic resistance mechanisms by whole-genome sequencing (WGS) in 195 carbapenem-nonsusceptible Pseudomonas aeruginosa (CNSPA) clinical isolates recovered from Singapore between 2009 and 2020. C/T susceptibility rates were low, at 37.9%. Cross-resistance to ceftazidime/avibactam was observed, although susceptibility to the agent was slightly higher, at 41.0%. Whole-genome sequencing revealed that C/T resistance was largely mediated by the presence of horizontally acquired β-lactamases, especially metallo-β-lactamases. These were primarily disseminated in well-recognized high-risk clones belonging to sequence types (ST) 235, 308, and 179. C/T resistance was also observed in several non-carbapenemase-producing isolates, in which resistance was likely mediated by β-lactamases and, to a smaller extent, mutations in AmpC-related genes. There was no obvious mechanism of resistance observed in five isolates. The high C/T resistance highlights the limited utility of the agent as an empirical agent in our setting. Knowledge of local molecular epidemiology is crucial in determining the potential of therapy with novel agents.

中文翻译：

---

碳青霉烯不敏感铜绿假单胞菌对头孢洛扎/他唑巴坦的耐药性及其机制

本研究通过全基因组测序 (WGS) 在2009 年至 2020 年间从新加坡回收的195株碳青霉烯不敏感铜绿假单胞菌(CNSPA) 临床分离株中建立了头孢洛扎/他唑巴坦 (C/T) 的体外活性及其基因型耐药机制。C /T 易感率很低，为 37.9%。观察到头孢他啶/阿维巴坦的交叉耐药性，尽管对该药物的敏感性略高，为 41.0%。全基因组测序显示，C/T 抗性主要由水平获得的β-内酰胺酶介导，尤其是金属β-内酰胺酶-内酰胺酶。这些主要在属于序列类型 (ST) 235、308 和 179 的公认高风险克隆中传播。在几个不产碳青霉烯酶的分离株中也观察到 C/T 抗性，其中抗性可能由β介导-内酰胺酶，以及在较小程度上，AmpC 相关基因的突变。在五个分离株中没有观察到明显的耐药机制。高 C/T 阻力突出了代理作为我们设置中的经验代理的有限效用。当地分子流行病学知识对于确定新型药物治疗的潜力至关重要。