Temple University School of Podiatric Medicine Journal Review Club

Editor's note: This post is part of the Temple University School of Podiatric Medicine (TUSPM) journal review club blog series. In each blog post, a TUSPM student will review a journal article relevant to wound management and related topics and provide their evaluation of the clinical research therein.

Article Title: Stability, Activity, and Application of Topical Doxycycline Formulations in a Diabetic Wound Case Study

Authors: Gabriele, S; Buchanan, B; Kundu, A; Dwyer, HC; Gabriele, JP; Mayer, P; Baranowski, DC

Journal: Wounds. 2019;31(2):49-54

Reviewed by: Garrett Biela, Class of 2020, Temple University School of Podiatric Medicine

Introduction

The purpose of this study was to determine that doxycycline is capable of being effective in topical form to aid in healing of diabetic foot ulcers (DFUs). This issue was studied by using various tests to develop a stable doxycycline hyclate topical cream and determine its effect on matrix metalloproteinases (MMPs). These formulations were used on patients with DFUs at Mayer Institute in Hamilton, Ontario, Canada, and the results were presented. It is well documented that doxycycline has broad-spectrum antimicrobial properties and that oral doxycycline is a mainstay in the treatment of infections. However, doxycycline is also found to inhibit MMP-9 in vitro, which has many functions in healing and is beneficial at certain levels. In DFUs, MMPs have a tendency to be increased during the inflammatory stage of healing and do not allow the body to produce new, healthy granulation tissue. A topical vehicle is necessary for these beneficial effects to be produced because the oral formulations do not have high enough levels at the wound site to allow this inhibitory activity.

Methods

To test the MMP inhibitory action of doxycycline further via activity assays, two stable topical vehicles were produced and tested using high-performance liquid chromatography and mass spectrometry. Two formulations were deemed reproducible, and a constant concentration of 2% (by weight [w/w]) doxycycline-d3 hyclate (DOXY) matrix effects was compared with a blank topical vehicle control showing a 30% decrease in MMP-9 inhibitory action. However, the most beneficial results occurred when the topical vehicles were preserved at 4°C for up to 70 days, a finding that suggests further need for patient compliance when this agent is prescribed for in-home application.

Results

The MMP-9 inhibitory assay results showed that the pure doxycycline control half-maximal inhibitory concentration (IC50) was consistent with previous results reported by Bannikov et al. The IC50 of 2% DOXY was slightly higher than the control, showing positive results. The study investigators believe this was possible via the 2% DOXY formulation chelating zinc, which prevents MMP activation.

Discussion

The DOXY formulation was tested on an undisclosed number of patients at Mayer Institute, and one chronic ulceration was published in the study. The female subject, who had a history of diabetes, hypertension, obesity, and an International Working Group on the Diabetic Foot Risk Classification of 3 as a result of recent digital amputation, presented with an infected 0.9cm² University of Texas Diabetic Wound Classification A2 pressure-induced ulceration of the left lateral ankle. Previous treatment included debridement, cleansing, offloading, and use of Inadine (KCl Medical Canada, Mississauga, Ontario, Canada) dressing (standard of care). The ulcer increased to 1.3cm² over the next 54 days before 2% DOXY was included in the treatment regimen. The wound reduced in size by 23% in two weeks and closed within 98 days of starting DOXY application. A concern is patient compliance if at-home application is necessary for treatment, given that the formulation is stable at 4°C. The prescribing clinician needs to take time to explain to the patient that for 2% DOXY to have a beneficial effect, it must be stored in the patient's freezer. In a busy clinic, simple details can be forgotten, and it would be upsetting to the patient if they were not aware of this instruction and treatment remained ineffective after a period of use. However, the standard of care is still necessary, and 2% DOXY is an adjunct to this practice.

Conclusion

This study shows considerable promise of topical doxycycline in treating DFUs. More studies need to be done to prove the benefits of its application further. Hopefully, this study will increase the number of institutions applying topical doxycycline, and more independent research will be subsequently published. With further investigation, topical doxycycline may be an effective adjunctive treatment for DFUs across North America.

About the Author

Garrett Biela is currently a third-year student at Temple University School of Podiatric Medicine (TUSPM) in Philadelphia. He completed his bachelor’s degree in biology at the University of Tampa, Florida in 2015, with experience in Cuban tree frog research. He is the proud recipient of a Temple University Merit Scholarship when entering school, as well as Lynn Catapano, DPM Memorial, J. David Derr, DPM Memorial, and Terleckyi Scholarships in his subsequent years. He also participated in a work-study program at the Temple Foot and Ankle Institute Ambulatory Surgical Center and was captain of the TUSPM men’s basketball team. He has a profound interest in reconstructive surgery, wound care, and microbiology. Dr. James McGuire is the director of the Leonard S. Abrams Center for Advanced Wound Healing and an associate professor of the Department of Podiatric Medicine and Orthopedics at the Temple University School of Podiatric Medicine in Philadelphia.