ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Infectious Diseases
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1570278
This article is part of the Research TopicMultidrug Resistant Bacteria: New Therapeutic Approaches for a Challenging ProblemView all 5 articles
From Genomics to Treatment: Overcoming Pan-Drug-Resistant Klebsiella pneumoniae in Clinical Settings
Provisionally accepted
Fernando Pasteran1*
Juan Manuel De Mendieta1Natalia Pujato2Gina Dotta3Lisandro J González3Mabel Rizzo4Alejandra Fernández5Paola Ceriana1Lucia Maccari1Melina Rapoport1
Sonia Alejandra Gomez1Celeste Lucero1María Alejandra Menocal1Ezequiel Albornoz1Denise De Belder1Marcelo Radisic2
Alejandro J Vila3Alejandra Corso1- 1Instituto Nacional de Enfermedades Infecciosas Dr. Carlos G. Malbrán (INEI), Buenos Aires, Argentina
- 2Instituto de Trasplantes y Alta Complejidad (ITAC), Buenos Aires, Buenos Aires, Argentina
- 3CONICET Instituto de Biología Molecular y Celular de Rosario (IBR), Rosario, Santa Fe, Argentina
- 4Hospital Interzonal General de Agudos Dr. José Penna, BAHIA BLANCA, Argentina
- 5Laboratorio Dr. Rapela, Buenos Aires, Buenos Aires, Argentina
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The spread pan-drug resistant pathogens pose a critical challenge to current therapies, resulting in high mortality and necessitating alternative approaches. We report pan-drug resistant Klebsiella pneumoniae isolates from five patients in a single hospital, including resistance to cefiderocol and cefepime-zidebactam in one isolate. Whole-genome sequencing identified blaNDM-5 and blaCTX-M-15 genes in all isolates, explaining carbapenemase and extended-spectrum β-lactamase phenotypes, with blaKPC-2 in one isolate. A novel sulfhydryl variable β-lactamase (SHV) variant, blaSHV-231, was present in all isolates under a strong promoter. Two isolates exhibited a non-synonymous mutation in fstI encoding PBP3, the primary target of aztreonam in Gram-negative bacteria. Genomic and phenotypic characterization guided successful compassionate treatment using aztreonam, ceftazidime-avibactam, and amoxicillin-clavulanate at maximum doses. Dissection of the roles of the substitutions present in blaSHV-231 revealed that this variant was responsible for the reduced susceptibility to aztreonam-avibactam, at the expense of a higher susceptibility to clavulanate. Targeted therapy can be successful upon dissection of unexpected mechanisms of resistance that enhance the contribution of endemic β-lactamase.
Keywords: multi-drug resistance, emerging pathogens, Klebsiella pneumoniae, Pan-drug resistance, Aztreonam-avibactam, NDM carbapenemase, cefiderocol, Cefepime-zidebactam
Received: 03 Feb 2025; Accepted: 15 May 2025.
Copyright: © 2025 Pasteran, Manuel De Mendieta, Pujato, Dotta, González, Rizzo, Fernández, Ceriana, Maccari, Rapoport, Gomez, Lucero, Menocal, Albornoz, De Belder, Radisic, Vila and Corso. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Fernando Pasteran, Instituto Nacional de Enfermedades Infecciosas Dr. Carlos G. Malbrán (INEI), Buenos Aires, Argentina
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