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

Abstract

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 bla KPC−2 or bla KPC−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 bla KPC variants by selecting CAZ/AVI-sensitive and -resistant CRKP strains from a lung transplantation patient. Methods The bla KPC-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 bla KPC-variant changes during CAZ/AVI administration. qPCR primers/probes were designed to identify bla KPC−2 mutations. Results Among 104 lung transplant recipients infected by bla KPC-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 bla KPC−2 or bla KPC−33. The drop-plate experiment showed differing growth patterns on CAZ/AVI mediums. The in vitro induction experiment demonstrated shifting from bla KPC−2 to bla KPC−33. Conclusions The study identified a “transitional state” of the mixed CRKP strains carrying either bla KPC−2 or bla KPC−33 in CAZ/AVI-exposed patients. Molecular diagnostics are crucial for identifying mixed strains and the transitional state of bla KPC variants, guiding treatment decisions in this complex landscape.

Keywords

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