Leveraging the Dose-Dependent Kill of Metronidazole for Targeting Biofilms That Underpin Recalcitrant Infection
Abstract
Infection is the greatest mortality risk for Wounded Warriors who survive the first 3 hours from a point of injury. Due to the traumatic nature of battlefield-relevant injuries where bacterial contamination levels can be high, biofilm-related infection is a major concern for military healthcare. We found that the commonly used hypoxia-activated prodrugs metronidazole, has unreported activity against S. aureus bacteria in the biofilm phenotype, those underpinning disease. This discovery has likely been overlooked as metronidazole is ineffective against the planktonic phenotypes used in clinical assays. The killing-effect of metronidazole against biofilms is greatly enhanced when paired with certain clinical antibiotics including gentamicin and levofloxacin but not beta-lactam antibiotics, although the boundaries of this synergy phenomenon has not been fully elucidated. The rationale of this study is to leverage the dose-dependent biofilm killing-effect of this compound using an experimental drug delivery device under development in our lab. This device creates sustained high-concentration fields of therapeutics in a musculoskeletal site, and is used here as a research tool for studying the potential adjunctive utility of metronidazole for treating experimental S. aureus infections in an ovine trauma model of orthopedic infection. This report covers the project results form Year 1 comprising in vitro biofilm assays of combinations of metronidazole and clinical antibiotic compounds from the gamut of antibiotic classes against S. aureus (ATCC #6538), and P. aeruginosa (ATCC # 27853).
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1210810
Entities
People
- Dustin L Williams
- Nicholas Ashton
Organizations
- University of Utah