Ceftolozane/Tazobactam Resistance and Mechanisms in Carbapenem-Nonsusceptible Pseudomonas aeruginosa.
Ceftolozane/Tazobactam Resistance and Mechanisms in Carbapenem-Nonsusceptible Pseudomonas aeruginosa.
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DOI：
10.1128/msphere.01026-20
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发表时间：
2021-01-27
期刊：
影响因子：
4.8
通讯作者：
Kwa AL
中科院分区：
文献类型：
--
作者：
Teo JQ;Lim JC;Tang CY;Lee SJ;Tan SH;Sim JH;Ong RT;Kwa AL
铜绿假单胞菌感染是最难治疗的医疗保健相关感染之一，因为该生物体能够获得多种耐药机制并表达多药耐药表型。 Ceftolozane/他唑巴坦 (C/T) 是一种新型 β-内酰胺/β-内酰胺酶抑制剂组合，可解决多重耐药铜绿假单胞菌感染患者未满足的医疗需求。本研究通过全基因组测序（WGS）建立了 2009 年至 2020 年间从新加坡回收的 195 株碳青霉烯类不敏感铜绿假单胞菌（CNSPA）临床分离株中头孢特咯嗪/他唑巴坦（C/T）的体外活性及其基因型耐药机制。C/T 敏感性较低，为 37.9%。观察到对头孢他啶/阿维巴坦的交叉耐药性，但对该药物的敏感性略高，为 41.0%。全基因组测序表明，C/T 耐药性很大程度上是由水平获得的 β-内酰胺酶，尤其是金属-β-内酰胺酶的存在介导的。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。在一些不产生碳青霉烯酶的分离株中也观察到了 C/T 抗性，其中抗性可能是由 β-内酰胺酶介导的，并且在较小程度上是由 AmpC 相关基因的突变介导的。在五个分离株中没有观察到明显的耐药机制。高 C/T 阻力凸显了在我们的环境中该智能体作为经验智能体的效用有限。了解当地分子流行病学对于确定新药治疗的潜力至关重要。重要性 铜绿假单胞菌感染是最难治疗的医疗保健相关感染之一，因为该生物体能够获得多种耐药机制并表达多药耐药表型。 Ceftolozane/他唑巴坦 (C/T) 是一种新型 β-内酰胺/β-内酰胺酶抑制剂组合，可解决多重耐药铜绿假单胞菌感染患者未满足的医疗需求。我们的研究结果表明，由于当地不同的分子流行病学，C/T 易感性存在地理差异。这项研究丰富了人们对 C/T 耐药性，特别是突变耐药性的认识，并将有助于设计未来的 β-内酰胺和 β-内酰胺酶抑制剂。事实证明，全基因组测序是了解铜绿假单胞菌耐药性及其对新型抗菌药物耐药性的贡献的有用工具。
Pseudomonas aeruginosa infection is one of the most difficult health care-associated infections to treat due to the ability of the organism to acquire a multitude of resistance mechanisms and express the multidrug resistance phenotype. Ceftolozane/tazobactam (C/T), a novel β-lactam/β-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa infections. 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. IMPORTANCE Pseudomonas aeruginosa infection is one of the most difficult health care-associated infections to treat due to the ability of the organism to acquire a multitude of resistance mechanisms and express the multidrug resistance phenotype. Ceftolozane/tazobactam (C/T), a novel β-lactam/β-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa infections. Our findings demonstrate geographical variation in C/T susceptibility owing to the distinct local molecular epidemiology. This study adds on to the growing knowledge of C/T resistance, particularly mutational resistance, and will aid in the design of future β-lactams and β-lactamase inhibitors. WGS proved to be a useful tool to understand the P. aeruginosa resistome and its contribution to emerging resistance in novel antimicrobial agents.