Sastre-Femenia Miquel Àngel, Fernández-Muñoz Almudena, Gomis-Font María Antonia, Taltavull Biel, López-Causapé Carla, Arca-Suárez Jorge, Martínez-Martínez Luis, Cantón Rafael, Larrosa Nieves, Oteo-Iglesias Jesús, Oliver Antonio
Servicio de Microbiología, Hospital Son Espases, Instituto de Investigación Sanitaria Illes Balears (IdISBa), Palma de Mallorca, Spain; Ciber de Enfermedades Infecciosa (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain.
Ciber de Enfermedades Infecciosa (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Servicio de Microbiología, Complexo Hospitalario Universitario A Coruña, Instituto Investigación Biomédica A Coruña (INIBIC), A Coruña, Spain.
Int J Antimicrob Agents. 2025 Jul 1;66(4):107563. doi: 10.1016/j.ijantimicag.2025.107563.
Cefiderocol is a new siderophore-cephalosporin showing potent activity against Pseudomonas aeruginosa, including isolates showing extensively drug-resistant (XDR) or difficult-to-treat resistant (DTR) phenotypes. However, there is still a limited understanding of the potential resistance mechanisms. The objective of this study was to analyse the activity of cefiderocol in a nationwide Spanish survey, determine its stability against most relevant resistance mechanisms, and analyse potential drivers of resistance through whole-genome sequencing.
Cefiderocol MICs were determined by broth microdilution in cation-adjusted iron-depleted Müller-Hinton broth for 1735 isolates from 66 Spanish hospitals and compared with those of a panel of 13 antipseudomonal agents. All XDR/DTR strains and those resistant to ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam or cefiderocol were subjected to whole-genome sequencing (NovaSeq, Illumina, San Diego, California, US) and bioinformatic analysis, including specific pipelines developed for the assessment of acquired resistance determinants, the mutational resistome and iron-uptake genes.
Cefiderocol showed the highest percentage of susceptibility (99.7%) and conserved activity (<5-10% resistance) against XDR/DTR strains and those producing carbapenemases. Only five resistant isolates were detected and the complex resistome included acquired β-lactamases or AmpC mutations along with mutations in iron-uptake systems and AmpC and/or efflux pump regulators. Novel drivers of resistance such as piuE were identified. Moreover, the production of acquired oxacillinases and mutations in ampC, mexR or piuA were statistically associated with increased MICs, whereas mutations in gyrA, parC or pvdS were associated with increased susceptibility.
While cefiderocol shows potent activity against P. aeruginosa, active surveillance at the phenotypic and genomic level for the emergence of resistant strains should be implemented.
头孢地尔是一种新型的铁载体头孢菌素，对铜绿假单胞菌具有强大的活性，包括表现出广泛耐药（XDR）或难治性耐药（DTR）表型的菌株。然而，对其潜在耐药机制的了解仍然有限。本研究的目的是在一项全国性的西班牙调查中分析头孢地尔的活性，确定其对最相关耐药机制的稳定性，并通过全基因组测序分析耐药的潜在驱动因素。
采用肉汤微量稀释法，在阳离子调整的缺铁Müller-Hinton肉汤中测定来自西班牙６６家医院的1735株菌株的头孢地尔最低抑菌浓度（MIC），并与一组13种抗假单胞菌药物的MIC进行比较。所有XDR/DTR菌株以及对头孢洛扎/他唑巴坦、头孢他啶/阿维巴坦、亚胺培南/瑞来巴坦或头孢地尔耐药的菌株均进行全基因组测序（美国加利福尼亚州圣地亚哥Illumina公司的NovaSeq平台）和生物信息学分析，包括为评估获得性耐药决定因素、突变耐药组和铁摄取基因而开发的特定流程。
头孢地尔对XDR/DTR菌株和产碳青霉烯酶菌株的敏感性百分比最高（99.7%），且活性保持稳定（耐药率<5-10%）。仅检测到5株耐药菌株，复杂的耐药组包括获得性β-内酰胺酶或AmpC突变，以及铁摄取系统、AmpC和/或外排泵调节因子的突变。鉴定出了如piuE等新的耐药驱动因素。此外，获得性苯唑西林酶的产生以及ampC、mexR或piuA的突变与MIC升高在统计学上相关，而gyrA、parC或pvdS的突变与敏感性增加相关。
虽然头孢地尔对铜绿假单胞菌显示出强大的活性，但应在表型和基因组水平上对耐药菌株的出现进行主动监测。
