Developing combinations of CO-ACTIVE antimicrobials and non-antimicrobials (CO-ACTION )

Therapeutics

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The CO-ACTION project aims to develop and provide a framework for evaluating and validating the effectiveness of antibiotic- and non-antibiotic combinations (COMs) in the preclinical setting based on pharmacokinetic/pharmacodynamic (PK/PD) principles, with a specific emphasis on Neglected and Disused AntiBiotics (ND-AB) as well as COMs with non-antibiotics (NA) both for human and veterinary medicine.

Completed project

To fulfill this ambitious goal, 6 work-packages with 6 interacting partners were developed involving several steps in the development of useful COMs and are executed partly sequential, partly in parallel: screening for CO-ACTION between ND-AB and NA in a collection of strains with well described resistance mechanisms, selecting potential synergistic COMs, subsequent validation using PK/PD experiments and modelling and finally testing COMs in animal models. A full PK/PD work-up and analyses form an important part of the process. The interaction between ND-AB from at least 6 different classes, including Polymyxin B will be determined using checkerboard experiments in 10 well characterized Gram-negative (e.g. P. aeruginosa, K. pneumoniae) multidrug resistant strains and analysed by surface response modelling. In parallel, a high throughput system (the oCelloscope) will be applied to allow efficient screening for large numbers of COMs.

The CO-ACTION of clearly synergistic COMs will be quantified using kill-curves both in medium as well as intracellulary and PK/PD modelling will be used to predict effective dosing regimens vivo. Effectiveness of the most promising 3-6 COMs will be determined in up to 4 different available animal model systems : a neutropenic mouse thigh and lung model, a rat model and effectiveness in a pig model to evaluate emergence of resistance in the gut of different COMs. A full PK/PD evaluation, including in vivo checkerboards will be performed and assessment of concentrations in ELF and microdialysis.

The potential of the COMs in patients will be evaluated by Monte Carlo Simulations of the COMs both using plasma as well as ELF concentrations and derived PK/PD relationships and PD targets. The development of useful COMs requires a high level of interaction between specialized partners. This international collaboration of six partners in CO-ACTION will lead to synergistic antibiotic COMs useful in patient care by bringing together specialists that each have significant expertise in their own field.

Project partners

  • Joseph Meletiadis, Erasmus MC University Medical Center, Netherlands (Coordinator)
  • Lena Friberg, Uppsala University, Sweden
  • Francoise Van Bambeke, Université Catholique de Louvain, Belgium
  • Thomas Tängdén, Uppsala University, Sweden
  • William Couet, Université de Poitiers, France
  • Alain Bousquet-Melou, National Veterinary School/INRA, France

Increasingly, patients with infections are difficult to treat because the bacteria that cause the infection have become resistant to antibiotics. There is therefore an increasing demand for new antimicrobials to overcome resistance. However, there are few new antibiotics in development. An alternative strategy to overcome resistance that has been insufficiently explored is a more efficient use of existing antibiotics (AB) by combining them, in particular Neglected and Disused AB (ND-AB). Also, the combination of antibiotics and other drugs -non-antibiotics (NA) might be efficacious but has not been well explored.

CO-ACTION project identified several AB+ND-AB combinations with increased activity against multidrug resistant gram negative bacteria Acinetobacter baumannii, Klebsiella pneuoniae and Pseudomonas aeruginosa. Polymyxin B with rifampicin and minocycline was the most promising combinations in in vitro extracellular and intracellular studies verified in several animal models (murine thigh and lung infection models, pig model) where pharmacokinetics, pharmacodynamics and resistance development was studied. Furthermore, in search of effective ND-AB+NA combinations, synergism was found between polymyxin B and some NA with spironolactone identified as a potential candidate for further studies. In addition, a high throughput model for screening multiple ND-AB+AB combinations against large set of isolates was developed whereas a method for testing AB+NA combinations was assessed. Finally, PK-PD models were developed by associating drug concentrations with antimicrobial activity and clinical doses for the combined drugs were proposed.

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