PDF(Pubmed)
Abstract：
The siderophore-cephalosporin cefiderocol (FDC) presents a promising treatment option for carbapenem-resistant (CR) P. aeruginosa (PA). FDC circumvents traditional porin and efflux-mediated resistance by utilizing TonB-dependent receptors (TBDRs) to access the periplasmic space. Emerging FDC resistance has been associated with loss of function mutations within TBDR genes or the regulatory genes controlling TBDR expression. Further, difficulties with antimicrobial susceptibility testing (AST) and unexpected negative clinical treatment outcomes have prompted concerns for heteroresistance, where a single lineage isolate contains resistant subpopulations not detectable by standard AST. This study aimed to evaluate the prevalence of TBDR mutations among clinical isolates of P. aeruginosa and the phenotypic effect on FDC susceptibility and heteroresistance. We evaluated the sequence of pirR, pirS, pirA, piuA, or piuD from 498 unique isolates collected before the introduction of FDC from four clinical sites in Portland, OR (1), Houston, TX (2), and Santiago, Chile (1). At some clinical sites, TBDR mutations were seen in up to 25% of isolates, and insertion, deletion, or frameshift mutations were predicted to impair protein function were seen in 3% of all isolates (n = 15). Using population analysis profile testing, we found that P. aeruginosa with major TBDR mutations were enriched for a heteroresistant phenotype and undergo a shift in the susceptibility distribution of the population as compared to susceptible strains with wild-type TBDR genes. Our results indicate that mutations in TBDR genes predate the clinical introduction of FDC, and these mutations may predispose to the emergence of FDC resistance.
摘要：
铁载体-头孢菌素头孢地洛（FDC）为碳青霉烯耐药（CR）铜绿假单胞菌（PA）提供了一种有希望的治疗选择。FDC通过利用TonB依赖性受体（TBDR）进入周质空间来规避传统的孔蛋白和外排介导的抗性。新出现的FDC抗性与TBDR基因或控制TBDR表达的调节基因内的功能突变丧失有关。Further,抗菌药物敏感性试验(AST)的困难和意想不到的负面临床治疗结果促使人们对异质耐药的担忧，其中单谱系分离物含有标准AST不可检测的抗性亚群。本研究旨在评估TBDR突变在铜绿假单胞菌临床分离株中的患病率以及表型对FDC易感性和异质性耐药的影响。我们评估了pirR的序列，海盗,pira,Piua,或piuD从从波特兰的四个临床站点引入FDC之前收集的498个独特的分离株，OR（1），休斯顿,TX(2),还有圣地亚哥,智利（1）。在一些临床场所，在高达25%的分离株中观察到TBDR突变,和插入，删除,预测或移码突变会损害蛋白质功能，在所有分离株的3％（n=15）中可见。使用人口分析概况测试，我们发现,与具有野生型TBDR基因的易感菌株相比,具有主要TBDR突变的铜绿假单胞菌富集了异源耐药表型,并且群体的易感性分布发生了变化.我们的结果表明，TBDR基因的突变早于FDC的临床引入，这些突变可能导致FDC电阻的出现。
