Ceftazidime-avibactam treatment dilemma of blaKPC-2-containing Klebsiella pneumoniae due to the development of co-existence of mixed strains carrying blaKPC-2 or blaKPC-33 in lung transplant recipients

Ann Clin Microbiol Antimicrob. 2024 Nov 8;23(1):99. doi: 10.1186/s12941-024-00743-x.

Abstract

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant threat to immunocompromised populations, including lung transplant recipients. This study investigates mixed CRKP strains carrying either blaKPC-2 or blaKPC-33 following ceftazidime-avibactam (CAZ/AVI) exposure, particularly in the context of lung transplantation. Mixed CRKP strains with shifting resistance phenotypes were frequently identified in patients exposed to CAZ/AVI. We aimed to elucidate the transitional state of blaKPC variants by selecting CAZ/AVI-sensitive and -resistant CRKP strains from a lung transplantation patient.

Methods: The blaKPC-variant-carrying CRKP strains were collected from lung transplant recipients exposed to CAZ/AVI in less than two years. Antibiotic susceptibility testing (AST) was conducted using microbroth dilution, and whole-genome sequencing (WGS) was used to identify genotypes and resistance mechanisms. Limiting dilution, drop-plate, and in vitro induction experiments determined blaKPC-variant changes during CAZ/AVI administration. qPCR primers/probes were designed to identify blaKPC-2 mutations.

Results: Among 104 lung transplant recipients infected by blaKPC-harboring CRKP strains and receiving CAZ/AVI, 10 (9.6%) experienced changing resistance phenotypes. The limiting dilution method found that Patient 10's CRKP strains carried either blaKPC-2 or blaKPC-33. The drop-plate experiment showed differing growth patterns on CAZ/AVI mediums. The in vitro induction experiment demonstrated shifting from blaKPC-2 to blaKPC-33.

Conclusions: The study identified a "transitional state" of the mixed CRKP strains carrying either blaKPC-2 or blaKPC-33 in CAZ/AVI-exposed patients. Molecular diagnostics are crucial for identifying mixed strains and the transitional state of blaKPC variants, guiding treatment decisions in this complex landscape.

Keywords: bla KPC−2; bla KPC−33; Carbapenem-resistant Klebsiella pneumoniae; Ceftazidime/Avibactam; Lung transplant recipients; Mixed strains carrying different bla KPC variants.

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*
  • Female
  • Humans
  • Klebsiella Infections* / drug therapy
  • Klebsiella Infections* / microbiology
  • Klebsiella pneumoniae* / drug effects
  • Klebsiella pneumoniae* / genetics
  • Lung Transplantation*
  • Male
  • Microbial Sensitivity Tests*
  • Middle Aged
  • Transplant Recipients*
  • Whole Genome Sequencing
  • beta-Lactamases* / genetics

Substances

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