Mechanisms and fitness of ceftazidime/avibactam-resistant Klebsiella pneumoniae clinical strains in Taiwan

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection is a global public health issue, and ceftazidime/avibactam is recommended by international guidelines as the preferred treatment for KPC- and OXA-48-producing CRKP. Since its introduction in Taiwan in 2019, ceftazidime/avibactam-resistant strains have emerged. Our aim is to investigate the mechanisms of ceftazidime/avibactam resistance in CRKP in Taiwan and study their associated fitness costs. Methods: Ceftazidime/avibactam-resistant CRKP strains with exposure to ceftazidime/avibactam isolated from clinical specimens were consecutively collected at Taipei Veterans General Hospital in 2020. The serial strains exhibiting ceftazidime/avibactam-susceptible and ceftazidime/avibactam-resistant phenotypes isolated from the same patient were characterized using whole-genome sequencing and tested for their growth rates and competitive abilities. Results: A total of 35 ceftazidime/avibactam-resistant CRKP strains were identified, with 20 being metallo-β-lactamase producers. Ten strains harboured KPC variants, exhibiting MIC for ceftazidime/avibactam ranging from 64 to ≥256 mg/L. The 10 strains demonstrating high-level ceftazidime/avibactam resistance possessed mutated KPC variants: KPC-33 (n = 3), KPC-31 (n = 1), KPC-39 (n = 1), KPC-44 (n = 1), KPC-58 (n = 1), KPC-90 (n = 1), and two novel KPC variants. Ceftazidime/avibactam-resistant strains with KPC-33 and KPC-39 showed a significant fitness cost and lower growth rate compared to their parental strains. In contrast, ceftazidime/avibactam-resistant strains with KPC-58 and KPC-58 plus D179Y showed similar growth rates and competitive abilities compared to their parental strains. Conclusions: Mutated KPC variants conferred high-level ceftazidime/avibactam resistance in Taiwan. Significant fitness costs were observed in both the ceftazidime/avibactam-resistant KPC-33 and KPC-39 strains. Despite conferring a similar level of ceftazidime/avibactam resistance, different KPC variants could entail varying degrees of fitness costs.