Combination Therapy Development Toolbox against Antimicrobial Resistance
( COMBAT-AMR )

Therapeutics

Research Project: 2025-04-01 - 2028-03-31
Total sum awarded: €1 092 712

Antimicrobial combinations are an essential therapeutic strategy to combat antimicrobial resistance (AMR) and treat complex infections. So far, combinations have generally been derived empirically using sub-optimal drug choices and dosing ratios, including beta-lactam/beta-lactamase inhibitor combination treatments. Defining the optimal drug combination of antibiotics and the associated dosing schedules to maximise efficacy and minimise the risk for AMR selection is complex and requires extensive preclinical development. To advance development and optimization of combination treatments, and exploit their currently underused potential, there is an urgent need for alignment and integration of the assays to evaluate combination therapy novel suitable experimental and computational methodologies. This project aims to develop a standardised toolbox of connected experimental and computational approaches tailored to the pre-clinical design of antibiotic combination treatments, which addresses current hurdles in the design and evaluation of antibacterial combinations, which are optimized towards treatment of AMR-associated pathogens and preventing AMR emergence. The tools and workflows will be applied to exemplar combinations to further evaluate their potential, and to demonstrate the application of the developed toolbox. The results will be used to seek regulatory qualification for the developed workflows and to guide the development of combination clinical breakpoints.

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  • Coen van Hasselt, Universiteit Leiden, Netherlands (Coordinator)
  • Sebastian Wicha, University of Hamburg, Germany (Partner)
  • Joseph Standing, University College London, United Kingdom (Partner)
  • Sandrine Marchand, University of Poitiers, France (Partner)
  • Oana Ciofu, University of Copenhagen, Denmark (Observer)

Antibiotic combinations have a large but underused potential to overcome or prevent infections associated with AMR. Although antibiotic treatments are commonly used, they have generally not been sufficiently optimised. Antibiotic combination treatments often involve one antibiotic and one agent limiting resistance to the antibiotic (“resistance breaker”). Some “resistance breakers” also have good antibiotic activity, but this is often not accounted for, possibly leading to sub-optimal dose ratios or choice of agents to combine. One major challenge in developing combination treatments is the limited range of tools and methods available to identify and optimise combinations before they are studied in patients. This project aims to address this challenge by creating a standardised toolbox of experimental and computational methods specifically for designing antibiotic combinations. These methods will include advanced experimental models that simulate human dosing schedules, as well as computer simulations to predict the effect of combination treatments on pathogens. This toolbox will enable the rational design of combination treatments resensitising resistant pathogens and supressing resistance development. The developed approach will be tested in clinically relevant scenarios to demonstrate their potential. The results of this project will be used to formulate a guidance document for drug developers and will furthermore be used to establish guidelines for the use of combination treatments in clinical practice.

Call

2024 - Interventions moving forward to promote action to counteract the emergence and spread of bacterial and fungal resistance and to improve treatments