The additive effect of ꞵ-lactamases in cefiderocol non-susceptibility in carbapenem-resistant klebsiella pneumoniae

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dc.contributor.advisorMunita, José Manuel
dc.contributor.authorSolar Zamora, Camila Verónica
dc.coverage.spatialSantiago
dc.date.accessioned2026-11-03T12:40:03Z
dc.date.available2026-11-03T12:40:03Z
dc.date.issued2026
dc.descriptionTesis presentada a la Facultad de Medicina de la Universidad del Desarrollo para optar al grado de Doctor en Ciencias e Innovación en Medicina
dc.description.abstractAntimicrobial resistance among carbapenem-resistant Enterobacterales (CRE) has created an urgent need for therapeutic options active against highly resistant Gram-negative pathogens. Cefiderocol (FDC), a siderophore cephalosporin with stability against a broad range of β-lactamases, including metallo-β-lactamases (MBLs), represents an important treatment option for these infections. However, reduced susceptibility and heteroresistance to FDC have increasingly been reported, and the contribution of the β-lactamase background to these phenotypes remains incompletely understood. This doctoral thesis investigated how β-lactamase identity and co-production influence FDC susceptibility and heteroresistance in CRE. First, FDC activity and heteroresistance were evaluated in a longitudinal collection of 128 carbapenem-resistant Klebsiella pneumoniae (CR-Kpn) isolates recovered from invasive infections in Chile before the clinical introduction of FDC. Although all isolates were susceptible according to CLSI criteria, approximately 70% exhibited FDC heteroresistance by population analysis profiling. Heteroresistance was particularly associated with NDM-7 production and with higher FDC MICs. Studies of additional highly resistant Enterobacterales further showed reduced FDC activity among isolates co-producing multiple carbapenemases and suggested that additional β-lactamases may contribute to variability in susceptibility. To directly evaluate this hypothesis, representative carbapenemases, extended-spectrum β-lactamases, and narrow-spectrum β-lactamases were expressed individually and in defined combinations in an isogenic Escherichia coli background. Individual β-lactamases produced variable effects on FDC MICs, whereas co-expression frequently resulted in cumulative reductions in susceptibility. Notably, enzymes with no detectable effect individually, such as OXA-1 and OXA-10, increased the FDC MIC when co-expressed, while the combination of NDM-7 and OXA-1 increased the MIC from 1 μg/mL with NDM-7 alone to 8 μg/mL. Finally, β-lactamase inhibition markedly reduced or eliminated FDC-resistant subpopulations in representative heteroresistant CR-Kpn isolates, supporting a direct contribution of both serine- and metallo-β-lactamases to the phenotype. Together, these findings demonstrate that FDC susceptibility and heteroresistance are shaped by the combined β-lactamase background rather than by carbapenemase identity alone. Increasing β-lactamase complexity may therefore progressively compromise FDC activity and facilitate the survival of resistant subpopulations, with important implications for susceptibility testing and the future clinical use of FDC against CRE infections.
dc.format.extent35 p.
dc.identifier.urihttps://hdl.handle.net/11447/11308
dc.language.isoen
dc.publisherUniversidad del Desarrollo. Facultad de Medicina
dc.subject090036S
dc.subjectAntimicrobial resistance
dc.subjectβ-lactamase
dc.titleThe additive effect of ꞵ-lactamases in cefiderocol non-susceptibility in carbapenem-resistant klebsiella pneumoniae
dc.typeThesis
dcterms.accessRightsEmbargo

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