In vivo emergence of cross-resistance to ceftazidime/avibactam and cefiderocol through selection of KPC variants in Klebsiella pneumoniae clinical isolates
Abstract
OBJECTIVES: To investigate the clinical and molecular drivers of in-vivo cross-resistance to ceftazidime/avibactam (CZA) and cefiderocol (FDC) in infections caused by KPC-producing Klebsiella pneumoniae (KPC-Kp).
MATERIAL AND METHODS: We conducted a retrospective case series of patients initially infected or colonized by CZA- and FDC-susceptible KPC-Kp who subsequently developed infections due to strains co-resistant to both agents. Whole-genome sequencing (WGS) and cloning of blaKPC alleles into E. coli were performed to elucidate resistance mechanisms.
RESULTS: Three patients developed bloodstream infections with KPC-Kp resistant to both CZA and FDC following CZA exposure. WGS identified blaKPC variants featuring substitutions within or adjacent to the Ω-loop: KPC-31 (D179Y), KPC-49 (R164S), and KPC-167 (D179Y with a DDKYSE 270-loop duplication). All resistant isolates belonged to ST512 and exhibited porin alterations (OmpK35 truncation and OmpK36 GD insertion). Cloning experiments demonstrated that these KPC variants markedly increased CZA MICs and modestly elevated FDC MICs, confirming their functional contribution to the resistance phenotype.
CONCLUSIONS: These findings demonstrate the in-vivo emergence of cross-resistance to CZA and FDC driven by stepwise selection of KPC Ω-loop and 270-loop variants combined with permeability defects.
How strong is the evidence?
Evidence Hub reads this as a case series, done in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
Read the paper
Related studies
- eggNOG 5.0: a hierarchical, functionally and phylogenetically annotated orthology resource based on 5090 organisms and 2502 viruses
- Online Survival Analysis Software to Assess the Prognostic Value of Biomarkers Using Transcriptomic Data in Non-Small-Cell Lung Cancer
- OptiType: precision HLA typing from next-generation sequencing data
- Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications
- Saccharomyces cerevisiae cells have three Omega class glutathione S-transferases acting as 1-Cys thiol transferases
- Hemolysis at low blood flow rates: in-vitro and in-silico evaluation of a centrifugal blood pump
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.