Ceftazidime-avibactam based combinations against carbapenemase producing Klebsiella pneumoniae harboring hypervirulence plasmids.

The combination of carbapenem resistance and hypervirulence in is an emerging and urgent threat due to its potential to resist common antibiotics and cause life-threatening infections in healthy hosts. This study aimed to evaluate the activity of clinically relevant antibiotic regimens against carbapenem-resistant with hypervirulence plasmids and to identify pathways associated with antibiotic tolerance using transcriptomics. We studied two carbapenem-resistant isolates, CDI694 and CDI231, both harboring hypervirulence plasmids. Time-kill and dynamic one-compartment pharmacokinetic/pharmacodynamic assays were used to assess ceftazidime/avibactam-based therapies. RNAseq was performed following 48 h of antibiotic exposure. Closed genomes of CDI694 and CDI231 were obtained; each isolate harbored carbapenem-resistance and hypervirulence (containing and genes) plasmids. Ceftazidime/avibactam-based regimens were bactericidal, though both isolates continued to grow in the presence of antibiotics despite no shifts in MIC. Transcriptomic analyses suggested that perturbations to cell respiration, carbohydrate transport, and stress-response pathways contributed to the antibiotic tolerance in CDI231. Genes associated with hypervirulence and antibiotic resistance were not strongly impacted by drug exposure except for , which was significantly downregulated. Treatment of carbapenem-resistant harboring hypervirulence plasmids with ceftazidime/avibactam-based regimens may yield a tolerant population due to altered transcription of multiple key pathways.