头孢他啶/阿维巴坦治疗多重耐药铜绿假单胞菌感染后，对头孢菌素/β-内酰胺酶抑制剂组合和亚胺培南/雷巴他定的耐药性同时发生并出现分歧。
Simultaneous and divergent evolution of resistance to cephalosporin/β-lactamase inhibitor combinations and imipenem/relebactam following ceftazidime/avibactam treatment of MDR Pseudomonas aeruginosa infections.
机构信息
Servicio de Microbiología and Instituto de Investigación Biomédica A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña, Ciber de Enfermedades Infecciosas CIBERINFEC, A Coruña, Spain.
Servicio de Microbiología and Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain.
出版信息
J Antimicrob Chemother. 2023 May 3;78(5):1195-1200. doi: 10.1093/jac/dkad062.
OBJECTIVES
To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection.
METHODS
One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on β-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays.
RESULTS
Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC β-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility.
CONCLUSIONS
We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new β-lactam/β-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.
目的
描述并分析一名多重耐药铜绿假单胞菌中枢神经系统感染患者接受头孢他啶/阿维巴坦治疗时对头孢他啶/阿维巴坦、头孢唑肟/他唑巴坦和亚胺培南/雷巴坦产生耐药的情况。
方法
检测一名医院获得性铜绿假单胞菌脑膜炎患者在治疗前（PA1）和治疗期间（PA2 和 PA3）的 1 份基线（PA1）和 2 份暴露后（PA2 和 PA3）分离株。通过肉汤微量稀释法测定 MIC。通过 WGS 研究突变变化。通过克隆实验和互补测定确定 blaPDC 和 mexR 突变对β-内酰胺耐药性的影响。
结果
PA1 分离株显示 DacB（I354A）和 OprD（N142fs）的基线耐药突变，对传统抗假单胞菌药物具有耐药性，但对头孢他啶/阿维巴坦、头孢唑肟/他唑巴坦和亚胺培南/雷巴坦敏感。暴露后分离株显示出两种不同的头孢他啶/阿维巴坦耐药表型，与影响固有 P PDC β-内酰胺酶（S254Ins）（PA2：头孢唑肟/他唑巴坦和头孢他啶/阿维巴坦耐药）或 MexAB-OprM 负调节剂 MexR 的独特突变相关，同时修饰 PBP3（PA3：头孢他啶/阿维巴坦和亚胺培南/雷巴坦耐药）。克隆实验表明 PDC 修饰在头孢唑肟/他唑巴坦和头孢他啶/阿维巴坦耐药中的作用。在 PA3 中用功能完整的 mexR 基因互补恢复了对亚胺培南/雷巴坦的敏感性。
结论
我们证明了铜绿假单胞菌在接触头孢他啶/阿维巴坦时，通过导致 PDC 修饰和上调 MexAB-OprM 介导的外排的突变选择，如何同时产生耐药性并削弱新的β-内酰胺/β-内酰胺酶抑制剂组合的活性。
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