Document Detail


Imaging the distribution of polymyxins in the kidney.
MedLine Citation:
PMID:  25377569     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
OBJECTIVES: Dose-limiting nephrotoxicity remains the Achilles' heel of polymyxin B and polymyxin E (also known as colistin), which are important last-line antibiotics used against infections caused by MDR Gram-negative 'superbugs'. An understanding of the mechanisms of nephrotoxicity, including renal tissue distribution, is crucial for the development of safer polymyxin lipopeptide antibiotics. This is the first study to visualize the kidney distribution of polymyxin B using a mouse nephrotoxicity model and in situ immunostaining of kidney sections.
METHODS: Polymyxin B nephrotoxicity in mice was induced over the course of 3 days (accumulated intravenous dose 175 mg/kg) and kidneys were harvested and frozen sectioned. The sections were fixed in cold acetone, dried and treated with 1% hydrogen peroxide. Endogenous mouse immunoglobulins were blocked and the tissue sections were treated with anti-polymyxin B mouse IgM antibody. The sections were incubated with a biotinylated anti-mouse secondary antibody conjugate followed by an Alexa Fluor 647-streptavidin conjugate. Polymyxin B distribution in the kidney sections was then visualized using a fluorescence scanning microscope. Kidney sections were also subjected to haematoxylin and eosin staining to assess pathological damage from the polymyxin-induced nephrotoxicity.
RESULTS: Immunostaining of kidney sections from a mouse with polymyxin B-induced nephrotoxicity revealed that polymyxin B distributed predominantly within the renal cortex. More specifically, polymyxin B accumulated within the proximal tubular cells.
CONCLUSIONS: The observed accumulation of polymyxin B within proximal tubular cells is consistent with the extensive renal reabsorption of polymyxins and the likely cause of the associated nephrotoxicity.
Authors:
Bo Yun; Mohammad A K Azad; Jiping Wang; Roger L Nation; Philip E Thompson; Kade D Roberts; Tony Velkov; Jian Li
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-5
Journal Detail:
Title:  The Journal of antimicrobial chemotherapy     Volume:  -     ISSN:  1460-2091     ISO Abbreviation:  J. Antimicrob. Chemother.     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-7     Completed Date:  -     Revised Date:  2014-11-8    
Medline Journal Info:
Nlm Unique ID:  7513617     Medline TA:  J Antimicrob Chemother     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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