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Objectives: To describe the in vivo emergence of ceftazidime-avibactam resistance in GES-type carbapenemases and to characterize an unusual outbreak of GES-6-producing Serratia marcescens during the COVID-19 pandemic in Spain., Methods: Retrospective study to describe a GES-CPSM outbreak based on whole genome sequencing and antimicrobial susceptibility testing (AST). Transferability of bla GES -carrying plasmid was assessed by conjugation experiments., Results: In December 2020, we identified a cluster of S. marcescens harbouring bla GES-6 involving 9 patients. Whole-genome sequence analysis revealed a clonal relationship (≤3 SNPs) between the first isolates identified in each of the evolved patients and environmental samples with GES-CPSM detection. Plasmid analysis showed that the bla GES-6 gene was located in an IncQ3-type plasmid. Triparental mating experiments using a helper plasmid demonstrated mobilization of the bla GES-6 -carrying plasmid. Our results also demonstrate within-host evolution in S. marcescens isolates, leading to a transition from bla GES-6 to the new bla GES-55 , caused by the P162S mutation, in a subsequent infection in one of the affected patients. In bla GES-55 we identified emergence of ceftazidime-avibactam resistance along with an increase of carbapenems susceptibility. This patient had been treated with a 14-day course of ceftazidime-avibactam. AST of the transformants bearing bla GES-6 and bla GES-55 plasmids, confirmed susceptibility variation affecting ceftazidime-avibactam and carbapenems., Conclusions: We report an unusual outbreak of GES-6 whose incidence is becoming increasing. Transition from GES-6 to GES-55 may readily occur in vivo leading to ceftazidime-avibactam resistance, which brings to the fore the critical need for developing more accurate diagnosis tools for detection of GES β-lactamases and optimise the use of antimicrobials., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)