In vivo selection of KPC-94 and KPC-95 in Klebsiella pneumoniae isolates from patients treated with ceftazidime/avibactam

J Guzmán-Puche; E Pérez-Nadales; M Pérez-Vázquez; M Causse; I Gracia-Ahufinger; A Mendez-Natera; Y Allalou-Ruiz; C Elías; J Oteo-Iglesias; J Torre-Cisneros; L Martínez-Martínez

doi:10.1016/j.ijantimicag.2022.106524

In vivo selection of KPC-94 and KPC-95 in Klebsiella pneumoniae isolates from patients treated with ceftazidime/avibactam

Int J Antimicrob Agents. 2022 Feb;59(2):106524. doi: 10.1016/j.ijantimicag.2022.106524. Epub 2022 Jan 14.

Authors

Affiliations

¹ Microbiology Unit, Reina Sofía University Hospital, Cordoba, Spain; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Cordoba, Spain; Spanish Network for Research in Infectious Diseases, Carlos III Research Institute, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Carlos III Research Institute, Majadahonda, Madrid, Spain. Electronic address: juliam.guzman.sspa@juntadeandalucia.es.
² Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Cordoba, Spain; Spanish Network for Research in Infectious Diseases, Carlos III Research Institute, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Carlos III Research Institute, Majadahonda, Madrid, Spain.
³ Spanish Network for Research in Infectious Diseases, Carlos III Research Institute, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Carlos III Research Institute, Majadahonda, Madrid, Spain; Reference Laboratory and Research on Resistance to Antibiotics and Infections Related to Healthcare, National Centre for Microbiology, Carlos III Health Institute, Majadahonda, Madrid, Spain.
⁴ Microbiology Unit, Reina Sofía University Hospital, Cordoba, Spain; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Cordoba, Spain; Spanish Network for Research in Infectious Diseases, Carlos III Research Institute, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Carlos III Research Institute, Majadahonda, Madrid, Spain.
⁵ Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Cordoba, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Carlos III Research Institute, Majadahonda, Madrid, Spain.
⁶ Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Cordoba, Spain.
⁷ Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Cordoba, Spain; Spanish Network for Research in Infectious Diseases, Carlos III Research Institute, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Carlos III Research Institute, Majadahonda, Madrid, Spain; Department of Medical and Surgical Sciences, University Hospital, Córdoba, Spain; Infectious Diseases Unit, Reina Sofía University Hospital, Cordoba, Spain.
⁸ Microbiology Unit, Reina Sofía University Hospital, Cordoba, Spain; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Cordoba, Spain; Spanish Network for Research in Infectious Diseases, Carlos III Research Institute, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Carlos III Research Institute, Majadahonda, Madrid, Spain; Department of Agricultural Chemistry, Soil Science and Microbiology, University of Cordoba, Cordoba, Spain.

PMID: 35038557
DOI: 10.1016/j.ijantimicag.2022.106524

Abstract

Ceftazidime/avibactam (CZA) is used to treat infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp). Resistance to CZA is commonly related to point mutations in the bla_KPC gene. Here we describe the in vivo emergence of CZA resistance in clinical isolates of KPC-Kp from four patients treated with this combination therapy. Four pre-therapy and five post-therapy KPC-Kp isolates were examined. Antibiogram (microdilution and gradient strips) and whole-genome sequencing were performed. The role of KPC mutations was validated by cloning bla_KPC genes into competent Escherichia coli. All KPC-Kp isolates recovered before treatment with CZA were susceptible to CZA and produced KPC-3. Five KPC-Kp isolates recovered after treatment were resistant to this combination. Three post-therapy isolates from two patients produced KPC-31 (D179Y mutation). Additionally, we identified the novel substitution LN169-170H (KPC-94) in one isolate, and the combination of two independently described mutations, D179Y and A172T (KPC-95), in another isolate. All KPC-Kp isolates belonged to sequence type 512 (ST512). All CZA-resistant isolates with bla_KPC variants had restoration of carbapenem susceptibility. In conclusion, resistance to CZA was related to bla_KPC mutations, including the new KPC-94 and KPC-95 alleles, which do not cause carbapenem resistance.

Keywords: Ceftazidime/avibactam; KPC-94; KPC-95; Klebsiella pneumoniae; Resistance.

MeSH terms

Anti-Bacterial Agents / pharmacology
Anti-Bacterial Agents / therapeutic use
Azabicyclo Compounds / pharmacology
Azabicyclo Compounds / therapeutic use
Bacterial Proteins / genetics
Ceftazidime / pharmacology
Ceftazidime / therapeutic use
Drug Combinations
Drug Resistance, Bacterial*
Humans
Klebsiella Infections* / drug therapy
Klebsiella Infections* / microbiology
Klebsiella pneumoniae* / drug effects
Klebsiella pneumoniae* / genetics
Microbial Sensitivity Tests
beta-Lactamases / genetics

Substances

Anti-Bacterial Agents
Azabicyclo Compounds
Bacterial Proteins
Drug Combinations
avibactam
Ceftazidime
beta-Lactamases