Servicio de Microbiología-Instituto de Investigación Biomédica, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain.
Servicio de Microbiología, Hospital Universitario Puerta del Mar, Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain.
Antimicrob Agents Chemother. 2019 Sep 23;63(10). doi: 10.1128/AAC.01110-19. Print 2019 Oct.
Selection of extended-spectrum mutations in narrow-spectrum oxacillinases (e.g., OXA-2 and OXA-10) is an emerging mechanism for development of resistance to ceftolozane-tazobactam and ceftazidime-avibactam in Detection of these challenging enzymes therefore seems essential to prevent clinical failure, but the complex phenotypic plasticity exhibited by this species may often lead to their underestimation. The underlying resistance mechanisms of two sequence type 175 (ST175) isolates showing multidrug-resistant phenotypes and recovered at early and late stages of a long-term nosocomial infection were evaluated. Whole-genome sequencing (WGS) was used to investigate resistance genomics, whereas molecular and biochemical methods were used for characterization of a novel extended-spectrum OXA-2 variant selected during therapy. The metallo-β-lactamase and the narrow-spectrum oxacillinase were present in both isolates, although they differed by an inactivating mutation in the subunit, present only in the early isolate, and in a mutation in the β-lactamase, present only in the final isolate. The new OXA-2 variant, designated OXA-681, conferred elevated MICs of the novel cephalosporin-β-lactamase inhibitor combinations in a PAO1 background. Compared to OXA-2, kinetic parameters of the OXA-681 enzyme revealed a substantial increase in the hydrolysis of cephalosporins, including ceftolozane. We describe the emergence of the novel variant OXA-681 during treatment of a nosocomial infection caused by a ST175 high-risk clone. The ability of OXA-681 to confer cross-resistance to ceftolozane-tazobactam and ceftazidime-avibactam together with the complex antimicrobial resistance profiles exhibited by the clinical strains harboring this new enzyme argue for maintaining active surveillance on emerging broad-spectrum resistance in .
选择窄谱苯唑西林酶(如 OXA-2 和 OXA-10)的扩展谱突变是对头孢洛扎坦他唑巴坦和头孢他啶-阿维巴坦产生耐药性的新兴机制。因此,检测这些具有挑战性的酶似乎是预防临床失败的关键,但该物种表现出的复杂表型可塑性常常导致它们被低估。评估了两个序列类型 175(ST175)分离株的多药耐药表型,这些分离株是在长期医院感染的早期和晚期恢复的。使用全基因组测序(WGS)来研究耐药性基因组学,而分子和生化方法则用于在治疗过程中选择的新型扩展谱 OXA-2 变体的表征。两种分离株均存在金属β-内酰胺酶和窄谱苯唑西林酶,尽管它们在β-内酰胺酶的一个亚单位中存在失活突变,仅存在于早期分离株中,而在最终分离株中存在一个突变。新型 OXA-681 被指定为 OXA-681,在 PAO1 背景下赋予新型头孢菌素-β-内酰胺酶抑制剂组合升高的 MIC。与 OXA-2 相比,OXA-681 酶的动力学参数显示出对头孢菌素(包括头孢洛扎坦)的水解有实质性增加。我们描述了新型 OXA-681 变体在由 ST175 高风险克隆引起的医院感染治疗期间的出现。OXA-681 能够赋予头孢洛扎坦他唑巴坦和头孢他啶-阿维巴坦的交叉耐药性,以及携带这种新酶的临床菌株表现出复杂的抗菌药物耐药谱,这表明需要对新兴的广谱耐药性进行积极监测。