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Deciphering mechanisms affecting cefepime-taniborbactam in vitro activity in carbapenemase-producing Enterobacterales and carbapenem-resistant Pseudomonas spp. isolates recovered during a surveillance study in Spain

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Abstract

Purpose

To characterize the resistance mechanisms affecting the cefepime-taniborbactam combination in a collection of carbapenemase-producing Enterobacterales (CPE) and carbapenem-resistant Pseudomonas spp. (predominantly P. aeruginosa; CRPA) clinical isolates.

Methods

CPE (n = 247) and CRPA (n = 170) isolates were prospectively collected from patients admitted to 8 Spanish hospitals. Susceptibility to cefepime-taniborbactam and comparators was determined by broth microdilution. Cefepime-taniborbactam was the most active agent, inhibiting 97.6% of CPE and 67.1% of CRPA (MICs ≤ 8/4 mg/L). All isolates with cefepime-taniborbactam MIC > 8/4 mg/L (5 CPE and 52 CRPA) and a subset with MIC ≤ 8/4 mg/L (23 CPE and 24 CRPA) were characterized by whole genome sequencing.

Results

A reduced cefepime-taniborbactam activity was found in two KPC-ST307-Klebsiella pneumoniae isolates with altered porins [KPC-62-K. pneumoniae (OmpA, OmpR/EnvZ), KPC-150-K. pneumoniae (OmpK35, OmpK36)] and one each ST133-VIM-1-Enterobacter hormaechei with altered OmpD, OmpR, and OmpC; IMP-8-ST24-Enterobacter asburiae; and NDM-5-Escherichia coli with an YRIN-inserted PBP3 and a mutated PBP2. Among the P. aeruginosa (68/76), elevated cefepime-taniborbactam MICs were mostly associated with GES-5-ST235, OXA-2+VIM-2-ST235, and OXA-2+VIM-20-ST175 isolates also carrying mutations in PBP3, efflux pump (mexR, mexZ) and AmpC (mpl) regulators, and non-carbapenemase-ST175 isolates with AmpD-T139M and PBP3-R504C mutations. Overall, accumulation of these mutations was frequently detected among non-carbapenemase producers.

Conclusions

The reduced cefepime-taniborbactam activity among the minority of isolates with elevated cefepime-taniborbactam MICs is not only due to IMP carbapenemases but also to the accumulation of multiple resistance mechanisms, including PBP and porin mutations in CPE and chromosomal mutations leading to efflux pumps up-regulation, AmpC overexpression, and PBP modifications in P. aeruginosa.

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Data Availability

The sequences generated in this project were submitted to the European Nucleotide Archive under the study accession number PRJNA985214.

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Acknowledgements

The study group includes the following members: Germán Bou and M. Carmen Fernández, Hospital Universitario A Coruña, A Coruña, Spain; Jorge Calvo, Jesús Rodríguez-Lozano, and María Siller-Ruiz, Hospital Universitario Marqués de Valdecilla, Santander, Spain; Jordi Vila and Cristina Pitart, Hospital Clínic i Provincial, Barcelona, Spain; Luis Martínez-Martínez and Irene Gracia-Ahufinger, Hospital Universitario Reina Sofía, Córdoba, Spain; Antonio Oliver and Xavier Mulet, Hospital Universitario Son Espases, Palma de Mallorca, Spain; Álvaro Pascual and Elena Marín-Martínez, Hospital Universitario Virgen Macarena, Sevilla, Spain; Concepción Gimeno and Nuria Tormo, Consorcio Hospital General Universitario de Valencia, Valencia, Spain; Marta Hernández-García, María García del Castillo, Patricia Ruiz-Garbajosa, Marta Nieto-Torres, and Rafael Cantón, Hospital Ramón y Cajal, Madrid, Spain.

Funding

This study was also supported by Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases [RD16/0016/0001, RD16/0016/0004, RD16/0016/0006, RD16/0016/0007, RD16/0016/0008, RD16/0016/0010, and REIPI RD16/0016/0011], CIBER de Enfermedades Infecciosas (CIBERINFEC) (CB21/13/00084), and co-financed by the European Development Regional Fund “A way to achieve Europe” (ERDF), Operative program Intelligent Growth 2014–2020. MH-G is supported by a postdoctoral contract by CIBERINFEC (CB21/13/00084).

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Authors and Affiliations

  1. Servicio de Microbiología, Hospital Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

    Marta Hernández-García, María García-Castillo, Marta Nieto-Torres, Patricia Ruiz-Garbajosa & Rafael Cantón

  2. CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain

    Marta Hernández-García, María García-Castillo, Germán Bou, Alain Ocampo-Sosa, Irene Gracia-Ahufinger, Xavier Mulet, Álvaro Pascual, Antonio Oliver, Patricia Ruiz-Garbajosa & Rafael Cantón

  3. Servicio de Microbiología, Hospital Universitario A Coruña and Instituto de Investigación Biomédica A Coruña (INIBIC), A Coruña, Spain

    Germán Bou

  4. Servicio de Microbiología, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Santander, Spain

    Alain Ocampo-Sosa

  5. Laboratorio de Microbiología, Hospital Clínic i Provincial, Barcelona, Spain

    Cristina Pitart

  6. UGC de Microbiología, Hospital Universitario Reina Sofía-Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain

    Irene Gracia-Ahufinger

  7. Servicio de Microbiología, Hospital Universitario Son Espases and Instituto de investigación Sanitaria Illes Balears (idISBa), Palma de Mallorca, Spain

    Xavier Mulet & Antonio Oliver

  8. Unidad de Enfermedades Infecciosas y Microbiología Clínica, Hospital Universitario Virgen Macarena, Departamento de Microbiología, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS) (Hospital Universitario Virgen Macarena/CSIC/Universidad de Sevilla), Sevilla, Spain

    Álvaro Pascual

  9. Servicio de Microbiología, Consorcio Hospital General Universitario de Valencia, Valencia, Spain

    Nuria Tormo

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  1. Marta Hernández-García
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  2. María García-Castillo
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  3. Marta Nieto-Torres
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Corresponding authors

Correspondence to Marta Hernández-García or Rafael Cantón.

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The ethics committees of Ramón y Cajal University hospital approved the study (Ref. 038-20).

Conflict of interest

RC has participated in educational programs organized by MSD, Pfizer, and Shionogi, and has received research support from MSD and Venatorx Pharmaceuticals, Inc. Other authors do not declare conflict of interest.

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Hernández-García, M., García-Castillo, M., Nieto-Torres, M. et al. Deciphering mechanisms affecting cefepime-taniborbactam in vitro activity in carbapenemase-producing Enterobacterales and carbapenem-resistant Pseudomonas spp. isolates recovered during a surveillance study in Spain. Eur J Clin Microbiol Infect Dis 43, 279–296 (2024). https://doi.org/10.1007/s10096-023-04697-4

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