Within-host transition to GES-55 during a GES-6-producing Serratia marcescens outbreak: Emergence of ceftazidime-avibactam resistance and increased susceptibility to carbapenems

Int J Antimicrob Agents. 2024 Aug;64(2):107257. doi: 10.1016/j.ijantimicag.2024.107257. Epub 2024 Jun 23.

Abstract

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 blaGES-carrying plasmid was assessed by conjugation experiments.

Results: In December 2020, we identified a cluster of S. marcescens harbouring blaGES-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 blaGES-6 gene was located in an IncQ3-type plasmid. Triparental mating experiments using a helper plasmid demonstrated mobilization of the blaGES-6-carrying plasmid. Our results also demonstrate within-host evolution in S. marcescens isolates, leading to a transition from blaGES-6 to the new blaGES-55, caused by the P162S mutation, in a subsequent infection in one of the affected patients. In blaGES-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 blaGES-6 and blaGES-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.

Keywords: Ceftazidime-avibactam; GES carbapenemase; Serratia marcescens.

MeSH terms

  • Aged
  • Anti-Bacterial Agents* / pharmacology
  • Azabicyclo Compounds* / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • COVID-19 / epidemiology
  • Carbapenems* / pharmacology
  • Ceftazidime* / pharmacology
  • Disease Outbreaks*
  • Drug Combinations*
  • Drug Resistance, Multiple, Bacterial / genetics
  • Female
  • Humans
  • Male
  • Microbial Sensitivity Tests*
  • Middle Aged
  • Plasmids / genetics
  • Retrospective Studies
  • Serratia Infections* / epidemiology
  • Serratia Infections* / microbiology
  • Serratia marcescens* / drug effects
  • Serratia marcescens* / genetics
  • Serratia marcescens* / isolation & purification
  • Spain / epidemiology
  • Whole Genome Sequencing
  • beta-Lactamases* / genetics
  • beta-Lactamases* / metabolism

Substances

  • Ceftazidime
  • avibactam, ceftazidime drug combination
  • Azabicyclo Compounds
  • Drug Combinations
  • beta-Lactamases
  • Carbapenems
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • carbapenemase