Editor’s Note: With the escalating issue of antimicrobial resistance globally, newly emerged resistant strains pose a serious threat to public health. At the 34th European Congress of Clinical Microbiology and Infectious Diseases (ESCMID Global 2024), a study by Professor Ning Shen 's team from Peking University Third Hospital (Abstract No.: E0451) focused on the resistance issues of cefiderocol, a drug not yet marketed in China. The study discovered that cefiderocol can induce resistance in vitro and amplify the blaSHV-12 gene. Long-read sequencing technology demonstrated its potential in the rapid and accurate detection of resistance gene amplification, offering a new tool for future resistance research.Dynamic In-host Cefiderocol Heteroresistance in Pan-drug Resistant ST11 Klebsiella pneumoniae Due to blaSHV-12 Gene Amplification (Abstract No.: E0451)
Objective:
Despite cefiderocol (FDC) not yet being marketed in China, pan-drug resistant, highly virulent Klebsiella pneumoniae (PDR-hvKp) resistant to FDC has emerged. This study conducted susceptibility testing on clinical Kp isolates to investigate the prevalence and mechanisms of FDC resistance.
Methods:
The study retrospectively included 151 carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates to assess FDC sensitivity. Seven blaSHV-12 containing isolates from two patients were subjected to whole-genome sequencing to determine their drug susceptibility, virulence, blaSHV-12 expression, and fitness cost phenotypes. qPCR and long-read sequencing further explored blaSHV-12 amplification.
Results:
The 151 CRKP isolates exhibited low FDC resistance (MIC50/MIC90 = 1/4 mg/L). Among the 7 PDR-hvKP, two isolates showed FDC resistance (MIC = 32 mg/L). The two FDC-resistant isolates had IncR/IncFII plasmids carrying 6 or 15 copies of blaSHV-12, respectively, whereas four FDC-sensitive isolates only had one copy, and one sensitive isolate had three copies. These blaSHV-12 genes were located within the same 7.3 kb fragment flanked by IS26, which increased blaSHV-12 expression and led to FDC resistance, without any fitness cost.
Furthermore, the study found that FDC could induce resistance in vitro and the amplification of blaSHV-12, which could be reversed over successive passages.
Conclusion:
The amplification of blaSHV-12 and its resultant in-host heteroresistance is a significant issue for the rational use of antimicrobials. Long-read sequencing may be the preferred method for rapidly and accurately detecting resistance gene amplification.
