Within-host evolution of tandemly duplicated blaKPC-14 conferring cross-resistance to ceftazidime-avibactam, cefiderocol and aztreonam-avibactam in hypervirulent ST11 Klebsiella pneumoniae.

OBJECTIVES

Hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) exhibiting cross-resistance to multiple antimicrobial agents represents a formidable therapeutic challenge. Therefore, elucidating the mechanisms driving antimicrobial resistance is crucial.

METHODS

A ceftazidime-avibactam-resistant K. pneumoniae isolate was recovered and subjected to antimicrobial susceptibility testing and whole-genome sequencing. Resistance mechanisms were investigated through gene cloning and enzymatic kinetic assays. Public NCBI databases were interrogated to determine the prevalence of multicopy blaKPC genes. Growth curves and plasmid stability assays were performed to evaluate the fitness costs.

RESULTS

An hv-CRKP isolate harboring two IS26-mediated copies of blaKPC-14 was identified following prolonged ceftazidime-avibactam therapy. The strain displayed high-level resistance to ceftazidime-avibactam, cefiderocol, and aztreonam-avibactam without appreciable fitness cost. Throughout treatment, the critically ill patient exhibited a persistently elevated estimated glomerular filtration rate. Comparative plasmid analysis demonstrated that IS26-mediated tandem duplication was widespread among plasmids carrying multiple copies of blaKPC.

CONCLUSIONS

Selective pressure from prolonged ceftazidime-avibactam therapy, with potential contributions from host-related factors affecting antimicrobial exposure, could facilitate the emergence of blaKPC variants and consequently promote cross-resistance. Dual-copy blaKPC substantially increased resistance levels without imposing a significant fitness burden. These findings underscore the value of timely genomic surveillance and antimicrobial susceptibility testing for optimizing antimicrobial therapy.