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.
Highlights
Antimicrobial resistance (AMR) is on the rise [1,2,3] and with it the need to develop and apply novel treatment strategies [4, 5]
The mathematical model developed in the present study extends our earlier model in Roberts et al [26], which considered the response of a purely susceptible bacterial infection to treatment with inhibitors and debridement
The environment-dependent parameters used in this paper were fitted to an in vivo rat model with the bacterial species P. aeruginosa in [26]; this model is of relevance to burn wounds in humans and for any bacterial species for which host cell attachment is partly mediated by MAM7
Summary
Antimicrobial resistance (AMR) is on the rise [1,2,3] and with it the need to develop and apply novel treatment strategies [4, 5]. Resistance spreads through the bacterial population via vertical (parent to daughter) and/ or horizontal (cell to cell) gene transfer, until the resistant phenotype comes to dominate [7,8,9] One solution to this problem is to use multiple antibiotics; this runs the risk of selecting for multi-drug resistant bacteria, or ‘super bugs’ [10]. Anti-virulence therapies are diverse [11,12,13]; they have the common aim of preventing or limiting disease in the host [6] By using these therapies in combination with more traditional treatments, such as antibiotics and debridement (physical clearance of a wound e.g. with a cloth), it is hoped that bacteria can be cleared from a host more rapidly, while reducing the risk of resistant phenotypes emerging [14, 15]
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