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Teaching an Old Drug to Maintain its Tricks

Wayne State to lead $4.8 million study that will help treat superbugs.

by Wayne State University
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B. Keith Kaye, MDB. Keith Kaye, MDPhoto courtesy of Wayne State UniversityDETROIT – With the decline of the development of new antibiotics due to the complexity and expense of discovering them, there has been a rapid growth of antibiotic resistant pathogens that is one of the leading causes of death. With the help of a nearly $4.9 million, 5-year grant from the National Institute for Allergy and Infectious Diseases of the National Institutes of Health, Wayne State University School of Medicine researchers are leading a landmark multi-center, international study that will provide essential information to clinicians for use of polymoxin B in critically ill patients where no other treatments will work.

The study, “Optimizing clinical use of polymyxin B: teaching an old drug to treat superbugs,” will focus on Gram-negative bacteria resistant to all other antibiotics except polymyxin B. Keith Kaye, M.D., professor of infectious diseases will lead the study that includes collaborators from Australia and Singapore.

“Our study will provide urgently needed information to guide clinicians in the proper intravenous dosing of polymyxin B in critically-ill patients,” said Kaye. “It is critical to have these dosing guides to assure that this agent of last resort is preserved and that these superbugs do not become resistant to it.  These guides will aid in minimizing unnecessary toxic side effects of the drug.”

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Since its release in the 1950s, there has been no clear definition of how to dose polymyxin B optimially, and how to minimize the emergence of resistance to this drug. Recent studies on polymyxins have focused on colistin methanesulfonate (CMS). These studies have demonstrated that CMS has significant limitations, and therefore dosage recommendations for CMS should not be applied to polymyxin B.  Polymyxin B has fewer limitations than does CMS.

The team will focus on defining the optimal dosage regimens by determining the association between dose and the timing of nephrotoxicity and use of next-generation proteomics to identify the most predictive biomarkers of polymyxin B associated nephrotoxicity.  One of the most exciting components of the study is to develop therapeutic drug monitoring systems to assist physicians in optimizing polymyxin B dose and minimizing toxicity. 

“Patients being treated with intravenous polymyxin B will be identified, and will have blood collected at various times surrounding a dose of polymyxin B between days 1 and 5 of therapy,” said Kaye. “Development of nephrotoxicity, clinical response and bacteriological response will be examined. Total and free plasma concentrations of polymyxin B will be determined, and bacterial isolates will be examined for the emergence of polymyxin resistance.”

Life-threatening infections caused by the Gram-negative superbugs that become resistant to polymyxin B are practically untreatable.  The results from this study will provide critical information that will guide clinicians in the proper intravenous dosing of polymyxin B in critically ill patients, ultimately preserving the usefulness of the drug and maintaining its stature as an essential agent of last resort.

Collaborators on the grant include Jason Pogue, PharmD of Sinai Grace Hospital, DMC; Jian Li, Ph.D. of Monash University, Australia; and Alan Forrest, PharmD of the University of North Carolina.

The grant number for this National Institutes of Health award is AI119446.