Adaptive evolution of extensive drug resistance and persistence in epidemic ST11 KPC-producing Klebsiella pneumoniae during antimicrobial chemotherapy.

IF 4.1 2区 医学 Q2 MICROBIOLOGY
Tinghua Li, Yiwei Zhu, Guoxiu Xiang, Ziyang Xu, Haihui Yang, Min Li, Zhen Shen
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引用次数: 0

Abstract

The global rise of carbapenem-resistant Klebsiella pneumoniae, including strains producing K. pneumoniae carbapenemase (KPC) types, poses a significant public health challenge due to their resistance to critical antibiotics. Treatment options for infections caused by KPC-producing K. pneumoniae (KPC-KP) are increasingly limited, particularly as these strains develop resistance to last-line antibiotics such as ceftazidime/avibactam and colistin. This study investigates the evolution of antibiotic resistance and persistence in a series of clonally related ST11 KPC-KP strains isolated from a single patient undergoing extended antimicrobial treatment. The patient, a 47-year-old male with a history of kidney transplantation, developed multiple KPC-KP lung infections during his hospital stay. Resistance to colistin and ceftazidime/avibactam emerged during treatment with these antibiotics. Key resistance mechanisms identified included the integration of ISKpn26 into mgrB gene, leading to mgrB inactivation and colistin resistance, and the emergence of novel blaKPC-2 variants (blaKPC-71 and blaKPC-179) that confer resistance to ceftazidime/avibactam. Despite the development of colistin resistance in a ceftazidime/avibactam-resistant KPC-KP strain following combination therapy, the patient's clinical condition significantly improved. Phenotypic assays showed that mgrB disruption in KPC-KP resulted in increased biofilm formation and higher susceptibility to phagocytosis. In mouse models, KPC-KP strains with mgrB disruption showed reduced virulence, increased lung colonization and persistence, and a lower inflammatory response, suggesting that mgrB disruption facilitates the transition from acute infection to colonization. This study highlights the complex interplay between antibiotic resistance and bacterial fitness, offering insights into why some patients experience clinical improvement despite severe drug resistance and incomplete bacterial clearance.

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来源期刊
CiteScore
10.00
自引率
8.20%
发文量
762
审稿时长
3 months
期刊介绍: Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
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