Mathematical model predicts anti-adhesion--antibiotic--debridement combination therapies can clear an antibiotic resistant infection

Roberts, Paul A, Huebinger, Ryan M, Keen, Emma, Krachler, Anne-Marie and Jabbari, Sara (2019) Mathematical model predicts anti-adhesion--antibiotic--debridement combination therapies can clear an antibiotic resistant infection. PLOS Computational Biology, 15 (7). e1007211 1-39. ISSN 1553-734X

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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.

Item Type: Article
Keywords: Ordinary differential equations; Competitive inhibition; Anti-virulence treatment; Multivalent adhesion molecule 7; anti-adhesion therapy; bacteria; burn wounds; Pseudomonas aeruginosa; antibiotic; debridement
Schools and Departments: School of Life Sciences > Neuroscience
Research Centres and Groups: Sussex Neuroscience
Subjects: Q Science > QA Mathematics
Q Science > QR Microbiology
Depositing User: Paul Roberts
Date Deposited: 06 Aug 2019 08:14
Last Modified: 06 Aug 2019 08:15
URI: http://sro.sussex.ac.uk/id/eprint/85321

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