Kocer Kaan, Boutin Sébastien, Moll Maximilian, Nurjadi Dennis
Medical Microbiology and Hygiene, Department of Infectious Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Institute of Medical Microbiology, University of Lübeck and University Medical Center of Schleswig-Holstein, Ratzeburger Allee 160, 23562 Lübeck, Germany.
JAC Antimicrob Resist. 2024 Nov 23;6(6):dlae183. doi: 10.1093/jacamr/dlae183. eCollection 2024 Dec.
Cefiderocol, a novel siderophore cephalosporin, is a promising therapeutic option for infections caused by multidrug-resistant . We evaluated the activity of cefiderocol against carbapenem-resistant (Cr-Pa) isolates and investigated the potential mechanisms involved in resistance.
108 CR-Pa isolates collected from patients without prior exposure to the substance were studied. MICs of cefiderocol were determined by broth microdilution using iron-depleted cation-adjusted Mueller-Hinton broth. Whole genome sequencing was performed to investigate the potential resistance mechanisms by comparing resistant and susceptible isolates and identifying unique mutations in the resistant group.
Of the 108 isolates, nine were resistant to cefiderocol with MIC values ranging from 4 to 32 mg/L. The genetic analysis revealed a broad spectrum of mutations in the resistant isolates associated with iron uptake systems, efflux pumps, AmpC β-lactamase and penicillin-binding proteins. The most frequently observed mutations among the resistant isolates were located in , and . Notably, the presence of carbapenemases did not correlate with cefiderocol resistance.
Our findings show the low prevalence of cefiderocol resistance among CR-Pa isolates, showing its potential as an effective treatment option. However, the complex genetic landscape of resistance mechanisms, particularly mutations affecting iron transport and other TonB-dependent receptors, requires continuous monitoring and functional analyses to identify and manage potential resistance mechanisms. This study provides a foundation for future research to improve antimicrobial resistance prediction and develop targeted therapies against CR-Pa.
头孢地尔是一种新型的铁载体头孢菌素，对于多重耐药菌引起的感染是一种有前景的治疗选择。我们评估了头孢地尔对耐碳青霉烯类鲍曼不动杆菌（Cr-Pa）分离株的活性，并研究了耐药相关的潜在机制。
研究了从未事先接触过该物质的患者中收集的108株Cr-Pa分离株。使用缺铁阳离子调整的 Mueller-Hinton 肉汤通过肉汤微量稀释法测定头孢地尔的最低抑菌浓度（MIC）。通过比较耐药和敏感鲍曼不动杆菌分离株并鉴定耐药组中的独特突变，进行全基因组测序以研究潜在的耐药机制。
在108株分离株中，9株对头孢地尔耐药，MIC值范围为4至32mg/L。遗传分析揭示了耐药分离株中与铁摄取系统、外排泵、AmpCβ-内酰胺酶和青霉素结合蛋白相关的广泛突变。耐药分离株中最常观察到的突变位于、和。值得注意的是，碳青霉烯酶的存在与头孢地尔耐药性无关。
我们的研究结果表明，Cr-Pa分离株中头孢地尔耐药性的发生率较低，显示出其作为有效治疗选择的潜力。然而，耐药机制的复杂遗传格局，特别是影响铁转运和其他TonB依赖性受体的突变，需要持续监测和功能分析，以识别和管理潜在的耐药机制。本研究为未来改善抗菌药物耐药性预测和开发针对Cr-Pa的靶向治疗的研究提供了基础。
