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Article

Emerging Cross-Resistance to Cefiderocol and Ceftazidime-Avibactam in KPC-Producing Klebsiella pneumoniae During Ceftazidime-Avibactam Therapy

by
Cristina Riazzo
1,2,†,
Cristina Elías-López
1,3,*,†,
Montserrat Muñoz-Rosa
1,2,
Cristina Arjona-Torres
1,
Tania Blanco-Martín
3,4,
Isabel Machuca
1,3,5,
Julian Torre-Cisneros
1,3,5,
Irene Gracia-Ahufinger
1,2,3,6,
Nicolas Kieffer
1,
Jorge Arca-Suárez
3,4 and
Luis Martínez-Martínez
1,2,3,6
1
Maimonides Biomedical Research Institute of Cordoba, Reina Sofía University Hospital, University of Cordoba (IMIBIC/HURS/UCO), 14004 Cordoba, Spain
2
Unit of Microbiology, Reina Sofía University Hospital, 14004 Cordoba, Spain
3
CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain
4
Servicio de Microbiología Clínica and Grupo de Investigación en Microbiología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), SERGAS, Universidade da Coruña (UDC), 15006 A Coruña, Spain
5
Infectious Diseases Service, Reina Sofía University Hospital, 14004 Cordoba, Spain
6
Department of Agricultural Chemistry, Soil Sciences and Microbiology, University of Cordoba, 14071 Cordoba, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Antibiotics 2026, 15(7), 701; https://doi.org/10.3390/antibiotics15070701
Submission received: 11 June 2026 / Revised: 2 July 2026 / Accepted: 7 July 2026 / Published: 17 July 2026
(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria, 3rd Edition)
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Abstract

Background/Objectives: Ceftazidime-avibactam (CAZ/AVI) and cefiderocol (FDC) retain activity against most clinical isolates of KPC-producing Klebsiella pneumoniae (KPC-Kp). Nevertheless, the emergence of cross-resistance between both agents has become an increasing clinical concern. In this study, the development of resistance to both CAZ/AVI and FDC was retrospectively investigated in KPC-Kp isolates recovered from patients treated with CAZ/AVI between 2014 and 2023. Methods: Twenty-two isolates (pre- and post-therapy) obtained from nine patients were included. Demographic and clinical data were collected. FDC susceptibility testing was determined for both clinical isolates and E. coli TOP10 transformants by reference broth microdilution using iron-depleted medium, and MICs were interpreted according to EUCAST breakpoints. Resistance mechanisms were characterized using whole genome sequencing. Results: Cross-resistance to both CAZ/AVI and FDC emerged in six patients (66.7%) during CAZ/AVI therapy, after a median treatment duration of 12.8 ± 7.6 days. The presence of different KPC-3 variants in the CAZ/AVI-FDC resistant isolates was revealed by genomic analysis. Furthermore, the role of KPC-28, KPC-31, KPC-47, KPC-94, KPC-95, and KPC-148 in mediating reduced susceptibility to CAZ/AVI and FDC was confirmed by AST of transformants carrying blaKPC variants. However, differences in MIC values compared with those obtained for the corresponding clinical isolates supported the relevance of additional mechanisms of co-resistance. The presence of ferric citrate transport (FEC) system was also associated with higher FDC MICs. Mutations in genes coding siderophore-iron transporter, PBPs, sensor histidine kinase or Tol-Pal system were also found in some of the isolates. Conclusions: These findings highlight the ability of KPC-Kp to develop co-resistance to both CAZ/AVI and FDC during CAZ/AVI therapy.
Keywords: Klebsiella pneumoniae; KPC; ceftazidime/avibactam; cefiderocol Klebsiella pneumoniae; KPC; ceftazidime/avibactam; cefiderocol

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MDPI and ACS Style

Riazzo, C.; Elías-López, C.; Muñoz-Rosa, M.; Arjona-Torres, C.; Blanco-Martín, T.; Machuca, I.; Torre-Cisneros, J.; Gracia-Ahufinger, I.; Kieffer, N.; Arca-Suárez, J.; et al. Emerging Cross-Resistance to Cefiderocol and Ceftazidime-Avibactam in KPC-Producing Klebsiella pneumoniae During Ceftazidime-Avibactam Therapy. Antibiotics 2026, 15, 701. https://doi.org/10.3390/antibiotics15070701

AMA Style

Riazzo C, Elías-López C, Muñoz-Rosa M, Arjona-Torres C, Blanco-Martín T, Machuca I, Torre-Cisneros J, Gracia-Ahufinger I, Kieffer N, Arca-Suárez J, et al. Emerging Cross-Resistance to Cefiderocol and Ceftazidime-Avibactam in KPC-Producing Klebsiella pneumoniae During Ceftazidime-Avibactam Therapy. Antibiotics. 2026; 15(7):701. https://doi.org/10.3390/antibiotics15070701

Chicago/Turabian Style

Riazzo, Cristina, Cristina Elías-López, Montserrat Muñoz-Rosa, Cristina Arjona-Torres, Tania Blanco-Martín, Isabel Machuca, Julian Torre-Cisneros, Irene Gracia-Ahufinger, Nicolas Kieffer, Jorge Arca-Suárez, and et al. 2026. "Emerging Cross-Resistance to Cefiderocol and Ceftazidime-Avibactam in KPC-Producing Klebsiella pneumoniae During Ceftazidime-Avibactam Therapy" Antibiotics 15, no. 7: 701. https://doi.org/10.3390/antibiotics15070701

APA Style

Riazzo, C., Elías-López, C., Muñoz-Rosa, M., Arjona-Torres, C., Blanco-Martín, T., Machuca, I., Torre-Cisneros, J., Gracia-Ahufinger, I., Kieffer, N., Arca-Suárez, J., & Martínez-Martínez, L. (2026). Emerging Cross-Resistance to Cefiderocol and Ceftazidime-Avibactam in KPC-Producing Klebsiella pneumoniae During Ceftazidime-Avibactam Therapy. Antibiotics, 15(7), 701. https://doi.org/10.3390/antibiotics15070701

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