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Abstract：
New β-lactam-β-lactamase inhibitor combinations represent last-resort antibiotics to treat infections caused by multidrug-resistant Pseudomonas aeruginosa. Carbapenemase gene acquisition can limit their spectrum of activity, and reports of resistance toward these new molecules are increasing. In this multi-center study, we evaluated the prevalence of resistance to ceftazidime-avibactam (CZA) and comparators among P. aeruginosa clinical isolates from bloodstream infections, hospital-acquired or ventilator-associated pneumonia, and urinary tract infections, circulating in Southern Italy. We also investigated the clonality and content of relevant β-lactam resistance mechanisms of CZA-resistant (CZAR) isolates. A total of 120 P. aeruginosa isolates were collected. CZA was among the most active β-lactams, retaining susceptibility in the 81.7% of cases, preceded by cefiderocol (95.8%) and followed by ceftolozane-tazobactam (79.2%), meropenem-vaborbactam (76.1%), imipenem-relebactam (75%), and aztreonam (69.6%). Among non-β-lactams, colistin and amikacin were active against 100% and 85.8% of isolates respectively. In CZAR strains subjected to whole-genome sequencing (n = 18), resistance was mainly due to the expression of metallo-β-lactamases (66.6% VIM-type and 5.5% FIM-1), followed by PER-1 (16.6%) and GES-1 (5.5%) extended-spectrum β-lactamases, mostly carried by international high-risk clones (ST111 and ST235). Of note, two strains producing the PER-1 enzyme were resistant to all β-lactams, including cefiderocol. In conclusion, the CZA resistance rate among P. aeruginosa clinical isolates in Southern Italy remained low. CZAR isolates were mostly metallo-β-lactamases producers and belonging to ST111 and ST253 epidemic clones. It is important to implement robust surveillance systems to monitor emergence of new resistance mechanisms and to limit the spread of P. aeruginosa high-risk clones.
OBJECTIVE: Multidrug-resistant Pseudomonas aeruginosa infections are a growing threat due to the limited therapeutic options available. Ceftazidime-avibactam (CZA) is among the last-resort antibiotics for the treatment of difficult-to-treat P. aeruginosa infections, although resistance due to the acquisition of transferable β-lactamase genes is increasing. With this work, we report that CZA represents a highly active antipseudomonal β-lactam compound (after cefiderocol), and that metallo-β-lactamases (VIM-type) and extended-spectrum β-lactamases (GES and PER-type) production is the major factor underlying CZA resistance in isolates from Southern Italian hospitals. In addition, we reported that such resistance mechanisms were mainly carried by the international high-risk clones ST111 and ST235.
OBJECTIVE: Multidrug-resistant Pseudomonas aeruginosa infections are a growing threat due to the limited therapeutic options available. Ceftazidime-avibactam (CZA) is among the last-resort antibiotics for the treatment of difficult-to-treat P. aeruginosa infections, although resistance due to the acquisition of transferable β-lactamase genes is increasing. With this work, we report that CZA represents a highly active antipseudomonal β-lactam compound (after cefiderocol), and that metallo-β-lactamases (VIM-type) and extended-spectrum β-lactamases (GES and PER-type) production is the major factor underlying CZA resistance in isolates from Southern Italian hospitals. In addition, we reported that such resistance mechanisms were mainly carried by the international high-risk clones ST111 and ST235.
摘要：
新的β-内酰胺-β-内酰胺酶抑制剂组合代表了治疗由多重耐药铜绿假单胞菌引起的感染的最后手段抗生素。碳青霉烯酶基因的获取会限制其活性谱，对这些新分子的抗性的报道也在增加。在这项多中心研究中，我们评估了来自血流感染的铜绿假单胞菌临床分离株对头孢他啶-阿维巴坦（CZA）和比较物的耐药率，医院获得性肺炎或呼吸机相关性肺炎，尿路感染,在意大利南部流通。我们还研究了CZA抗性（CZAR）分离株的相关β-内酰胺抗性机制的克隆性和含量。收集总共120个铜绿假单胞菌分离物。CZA是最活跃的β-内酰胺类，在81.7%的病例中保留易感性，之前是头孢地洛洛尔（95.8％），其次是头孢洛赞-他唑巴坦（79.2％），美罗培南-伐巴坦（76.1%），亚胺培南-莱巴坦（75%），和氨曲南(69.6%)。在非β-内酰胺中，粘菌素和阿米卡星分别对100％和85.8％的分离株具有活性。在进行全基因组测序的CZAR菌株中（n=18），抗性主要是由于金属-β-内酰胺酶的表达（66.6%VIM型和5.5%FIM-1），其次是PER-1（16.6%）和GES-1（5.5%）超广谱β-内酰胺酶，主要由国际高风险克隆（ST111和ST235）携带。值得注意的是，两株产生PER-1酶的菌株对所有β-内酰胺都有抗性，包括头孢得洛.总之,意大利南部铜绿假单胞菌临床分离株的CZA耐药率仍然很低。CZAR分离株主要是金属β-内酰胺酶生产者，属于ST111和ST253流行病克隆。重要的是实施强大的监测系统以监测新的抗性机制的出现并限制铜绿假单胞菌高风险克隆的传播。
目的：多药耐药的铜绿假单胞菌感染是一个日益严重的威胁，由于有限的治疗选择。头孢他啶-阿维巴坦（CZA）是治疗难以治疗的铜绿假单胞菌感染的最后手段抗生素，尽管由于获得可转移的β-内酰胺酶基因而产生的抗性正在增加。有了这项工作,我们报告说，CZA代表一种高活性的反假子β-内酰胺化合物（头孢地洛之后），金属β-内酰胺酶（VIM型）和广谱β-内酰胺酶（GES和PER型）的产生是意大利南部医院分离株对CZA耐药的主要因素。此外,我们报道,此类抗性机制主要由国际高危克隆ST111和ST235携带.
目的：多药耐药的铜绿假单胞菌感染是一个日益严重的威胁，由于有限的治疗选择。头孢他啶-阿维巴坦（CZA）是治疗难以治疗的铜绿假单胞菌感染的最后手段抗生素，尽管由于获得可转移的β-内酰胺酶基因而产生的抗性正在增加。有了这项工作,我们报告说，CZA代表一种高活性的反假子β-内酰胺化合物（头孢地洛之后），金属β-内酰胺酶（VIM型）和广谱β-内酰胺酶（GES和PER型）的产生是意大利南部医院分离株对CZA耐药的主要因素。此外,我们报道,此类抗性机制主要由国际高危克隆ST111和ST235携带.
