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Klebsiella pneumoniae  can cause both hospital- and community-acquired clinical infections. Last-line antibiotics against carbapenem-resistant  K. pneumoniae  (CRKP), such as ceftazidime/avibactam (CZA) and tigecycline (TGC), remain limited as treatment choices. This study aimed to investigate the mechanisms by which CRKP acquires CZA and TGC resistance  in vivo  under β-lactam antibiotic and TGC exposure. Three CRKP strains (XDX16, XDX31 and XDX51) were consecutively isolated from an inpatient with a urinary tract infection in two months. PFGE and MLST showed that these strains were closely related and belonged to sequence type (ST) 4496, which is a novel ST closely related to ST11. Compared to XDX16 and XDX31, XDX51 developed CZA and TGC resistance. Sequencing showed that double copies of  bla   KPC-2  were located on a 108 kb IncFII plasmid, increasing  bla   KPC-2  expression in XDX51. In addition,  ramR  was interrupted by Insertion sequence (IS) Kpn14 in XDX51, with this strain exhibiting upregulation of  ramA ,  acrA  and  acrB  expression compared with XDX16 and XDX31. Furthermore, LPS analysis suggested that the O-antigen in XDX51 was defective due to IS Kpn26  insertion in the rhamnosyl transferase gene  wbbL , which slightly reduced TGC susceptibility. In brief, CZA resistance was caused mainly by  bla   KPC-2  duplication, and TGC resistance was caused by  ramR  inactivation with additional LPS changes due to IS element insertion in  wbbL . Notably, CRKP developed TGC and CZA resistance within one month under TGC and β-lactam treatment without exposure to CZA. The CRKP clone ST4496 has the ability to evolve CZA and TGC resistance rapidly, posing a potential threat to inpatients during antibiotic treatment.

Emergence of Ceftazidime/Avibactam and Tigecycline Resistance in Carbapenem-Resistant Klebsiella pneumoniae Due to In-Host Microevolution