Evaluation of ebselen in resolving a methicillin-resistant Staphylococcus aureus infection of pressure ulcers in obese and diabetic mice.

Haroon Mohammad,Alexandra M Dieterly,L Tiffany Lyle,Mohamed N Seleem,Nader S Abutaleb,Rita G Sobral

doi:10.1371/journal.pone.0247508

Haroon Mohammad, Alexandra M Dieterly + Show 4 more

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https://doi.org/10.1371/journal.pone.0247508

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Abstract

Pressure ulcers (PUs) are a source of morbidity in individuals with restricted mobility including individuals that are obese or diabetic. Infection of PUs with pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), impairs ulcers from healing. The present study evaluated ebselen as a topical antibacterial to treat MRSA-infected PUs. Against two different S. aureus strains, including MRSA USA300, resistance to ebselen did not emerge after 14 consecutive passages. Resistance to mupirocin emerged after only five passages. Additionally, ebselen was found to exert a modest postantibiotic effect of five hours against two MRSA strains. Ebselen was subsequently evaluated in MRSA-infected PUs in two models using obese and diabetic mice. In obese mice, topical ebselen (89.2% reduction) and oral linezolid (84.5% reduction) similarly reduced the burden of MRSA in infected PUs. However, in diabetic mice, topical ebselen (45.8% reduction in MRSA burden) was less effective. Histopathological evaluation of ulcers in diabetic mice determined that ebselen treatment resulted in fewer bacterial colonies deep within the dermis and that the treatment exhibited evidence of epithelial regeneration. Topical mupirocin was superior to ebselen in reducing MRSA burden in infected PUs both in obese (98.7% reduction) and diabetic (99.3% reduction) mice. Ebselen’s antibacterial activity was negatively impacted as the bacterial inoculum was increased from 105 CFU/mL to 107 CFU/mL. These results suggest that a higher dose of ebselen, or a longer course of treatment, may be needed to achieve a similar effect as mupirocin in topically treating MRSA-infected pressure ulcers.

Highlights

Each year, over 2.5 million individuals develop pressure ulcers (PUs) in the U.S alone resulting in total treatment costs estimated to range from $9 to $11 billion USD [1]
A one-fold increase in the minimum inhibitory concentration (MIC) of ebselen was observed after passage 10 against S. aureus ATCC 6538
Bacterial infected-pressure ulcers are a source of morbidity in individuals with limited mobility including individuals that are obese and diabetic

Summary

Introduction

Over 2.5 million individuals develop pressure ulcers (PUs) in the U.S alone resulting in total treatment costs estimated to range from $9 to $11 billion USD [1]. Ranging from mild to severe, PUs often develop in individuals with limited mobility including those who are obese, hospitalized, or residents in long-term care facilities. It is estimated that up to 12.1% of adult patients in hospital intensive care units (ICU) in the U.S develop a PU annually; hospital-acquired PUs alone can result in total treatment costs that exceed $3 billion USD [2, 3]. Individuals that are obese and/or diabetic are at greater risk for developing PUs, in lower extremities, due to pathophysiological changes that occur that include vascular insufficiency, peripheral neuropathy, and breakdown of skin tissue [6, 7]. It is estimated that up to 34% of people with diabetes will develop a foot ulcer at least once in their lifetime [8]

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