Novel PiuC, PirA, and PiuA mutations leading to in vivo cefiderocol resistance progression in IMP-16- and KPC-2-producing Pseudomonas aeruginosa from a leukemic patient
Viñes, Joaquim (Universitat Autònoma de Barcelona. Servei Veterinari de Genètica Molecular (SVGM))
Herrera, Sabina (Hospital Clínic i Provincial de Barcelona)
Vergara, Andrea (Institut de Salut Global)
Roca, Ignasi (Institut de Salut Global)
Vila Estapé, Jordi (Universitat de Barcelona. Departament de Fonaments Clínics)
Aiello, Tommaso Francesco (Hospital Clínic i Provincial de Barcelona)
Martínez, José Antonio (Universitat de Barcelona. Departament de Fonaments Clínics)
del Río, Ana (Universitat de Barcelona. Departament de Fonaments Clínics)
Lopera, Carlos (Hospital Clínic i Provincial de Barcelona)
Garcia-Vidal, Carolina (Universitat de Barcelona. Departament de Fonaments Clínics)
Casals-Pascual, Climent (Hospital Clínic i Provincial de Barcelona)
Soriano Viladomiu, Alex (Universitat de Barcelona. Departament de Fonaments Clínics)
Pitart, Cristina (Institut de Salut Global)

Fecha:	2025
Resumen:	Pseudomonas aeruginosa is an opportunistic pathogen capable of causing severe infections in immunocompromised individuals, who often require prolonged antibiotic therapy. The emergence of carbapenemase-producing P. aeruginosa has further complicated the management of nosocomial infections, limiting therapeutic options. Cefiderocol has recently emerged as a promising antipseudomonal agent, using the bacterial iron transport system to gain entry into the cell; however, there have been reports of P. aeruginosa resistant to cefiderocol. We describe the in vivo cefiderocol resistance progression of four consecutive P. aeruginosa isolates from one patient with T-cell acute lymphoblastic leukemia. Analysis of potential genes involved in cefiderocol transport resulted in three genes mutated in two resistant isolates. One isolate presented a S116F substitution in PiuC, and the other presented a deletion of 29 amino acids in the signal peptide of PiuA and a STOP substitution in PirA, resulting in the deletion of a piece of the channel. These mutations increased 24- and 64-folds the cefiderocol minimum inhibitory concentration, respectively. The mutations in the aforementioned genes may directly impact siderophore internalization, thereby contributing to an elevation in the MIC of the antibiotic. IMPORTANCECarbapenem-resistant Pseudomonas aeruginosa poses a significant challenge due to its broad antibiotic resistance. Cefiderocol is a novel antibiotic aimed at combating infections caused by such organisms. However, if these pathogens develop resistance to this new drug, it hinders treatment efficacy and options. Therefore, it is crucial to identify and describe mutations in the genes involved in the uptake of cefiderocol to find better treatment strategies for patients infected with multidrug-resistant P. aeruginosa.
Ayudas:	Agencia Estatal de Investigación PID2021-127402OB-I00 Agencia Estatal de Investigación CEX2018-000806-S Govern de Catalunya 2017 SGR 0809 Ministerio de Ciencia e Innovación CM23/00277
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Pseudomonas aeruginosa ; Carbapenem-resistant ; Cefiderocol ; PiuA ; PiuC ; PirA ; Leukemia ; Oxford Nanopore
Publicado en:	Microbiology Spectrum, Vol. 13 (january 2025) , ISSN 2165-0497

DOI: 10.1128/spectrum.01928-24
PMID: 39873515

11 p, 626.0 KB

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