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Abstract

Abstract
As antimicrobial resistance increases, it is crucial to develop new treatment strategies to counter the emerging threat. In this paper, we consider combination therapies involving conventional antibiotics and debridement, coupled with a novel anti-adhesion therapy, and their use in the treatment of antimicrobial resistant burn wound infections. Our models predict that anti-adhesion–antibiotic–debridement combination therapies can eliminate a bacterial infection in cases where each treatment in isolation would fail. Antibiotics are assumed to have a bactericidal mode of action, killing bacteria, while debridement involves physically cleaning a wound (e.g. with a cloth); removing free bacteria. Anti-adhesion therapy can take a number of forms. Here we consider adhesion inhibitors consisting of polystyrene microbeads chemically coupled to a protein known as multivalent adhesion molecule 7, an adhesin which mediates the initial stages of attachment of many bacterial species to host cells. Adhesion inhibitors competitively inhibit bacteria from binding to host cells, thus rendering them susceptible to removal through debridement. An ordinary differential equation model is developed and the antibiotic-related parameters are fitted against new in vitro data gathered for the present study. The model is used to predict treatment outcomes and to suggest optimal treatment strategies. Our model predicts that anti-adhesion and antibiotic therapies will combine synergistically, producing a combined effect which is often greater than the sum of their individual effects, and that anti-adhesion–antibiotic–debridement combination therapy will be more effective than any of the treatment strategies used in isolation. Further, the use of inhibitors significantly reduces the minimum dose of antibiotics required to eliminate an infection, reducing the chances that bacteria will develop increased resistance. Lastly, we use our model to suggest treatment regimens capable of eliminating bacterial infections within clinically relevant timescales.

Author summary
Since the development of the first antibiotics, bacteria have utilised and developed resistance mechanisms, helping them to avoid being eliminated and to survive within a host. Traditionally, the solution to this problem has been to treat with multiple antibiotics, switching to a new type when the one currently in use proves ineffective. However, the development of antibiotics has slowed significantly in the past two decades, while multi-drug resistant strains, otherwise known as ‘super bugs’, are on the rise. In answer to this challenge, alternative approaches, such as anti-adhesion therapy, are being developed as a complement or alternative to traditional antimicrobials. In this paper we formulate and analyse a mathematical model of a combination therapy, applied in the context of an infected burn wound, bringing together antibiotics, anti-adhesion therapy and debridement (the physical cleaning of a wound). We use our models to make sense of how these treatments interact to combat a bacterial infection, to predict treatment outcomes for a range of strategies and to suggest optimal treatment regimens. It is hoped that this study will guide future experimental and clinical research, helping biomedical researchers to identify the most promising approaches to treatment.

Publication Type:	Article
Additional Information:	© 2019 Roberts et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Subjects:	Q Science > QA Mathematics R Medicine > RC Internal medicine
Departments:	School of Health & Psychological Sciences School of Health & Psychological Sciences > Optometry & Visual Sciences
SWORD Depositor:	Symplectic Administrator

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