TY - JOUR
T1 - Ceftazidime-avibactam based combinations against carbapenemase producing Klebsiella pneumoniae harboring hypervirulence plasmids
AU - Bulman, Zackery P.
AU - Tan, Xing
AU - Chu, Ting Yu
AU - Huang, Yanqin
AU - Rana, Amisha P.
AU - Singh, Nidhi
AU - Flowers, Stephanie A.
AU - Kyono, Yasuhiro
AU - Kreiswirth, Barry N.
AU - Chen, Liang
N1 - Funding Information:
This work was in part supported by grants from the National Institutes of Health (NIH) to BK and LC (R01AI090155) and to ZB, BK, and LC (R01AI148560). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/1
Y1 - 2022/1
N2 - The combination of carbapenem resistance and hypervirulence in Klebsiella pneumoniae 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 K. pneumoniae with hypervirulence plasmids and to identify pathways associated with antibiotic tolerance using transcriptomics. We studied two carbapenem-resistant K. pneumoniae 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 rmpA/rmpA2 and iut 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 ompW, which was significantly downregulated. Treatment of carbapenem-resistant K. pneumoniae harboring hypervirulence plasmids with ceftazidime/avibactam-based regimens may yield a tolerant population due to altered transcription of multiple key pathways.
AB - The combination of carbapenem resistance and hypervirulence in Klebsiella pneumoniae 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 K. pneumoniae with hypervirulence plasmids and to identify pathways associated with antibiotic tolerance using transcriptomics. We studied two carbapenem-resistant K. pneumoniae 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 rmpA/rmpA2 and iut 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 ompW, which was significantly downregulated. Treatment of carbapenem-resistant K. pneumoniae harboring hypervirulence plasmids with ceftazidime/avibactam-based regimens may yield a tolerant population due to altered transcription of multiple key pathways.
KW - Antibiotic tolerance
KW - Carbapenem-resistant
KW - Hypervirulent
KW - Klebsiella pneumoniae
KW - Transcriptomic
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U2 - 10.1016/j.csbj.2022.07.017
DO - 10.1016/j.csbj.2022.07.017
M3 - Article
AN - SCOPUS:85134888076
SN - 2001-0370
VL - 20
SP - 3946
EP - 3954
JO - Computational and Structural Biotechnology Journal
JF - Computational and Structural Biotechnology Journal
ER -