The AB-DIRECT project aims to explore the potential of gepotidacin as a treatment for infections caused by N. gonorrhoeae or E. coli elsewhere in the body. Their starting point for this will be tissue samples taken from patients who have received a single dose of gepotidacin before surgery to remove their tonsils or prostate. This will allow the scientists to assess the extent to which the antibiotic gets into these tissues and to evaluate different dosing levels. They will also carry out studies of the drug in animals. Ultimately, the data generated by AB-DIRECT will contribute to a decision on whether or not to run clinical trials of gepotidacin as a treatment for throat infections caused by N. gonorrhoeae or prostate infections caused by E. coli.
This project is coordinated by W. Couet, the director of our team.
Rational beta-lactam/beta-lactamase-inhibitor-based combination therapies of last-resort antibiotics to maximise efficacy and protect against emergence of resistance.
Funded by :
In collaboration with :
University of Hamburg, Institute of Pharmacy (Pr. S. Wicha)
EA7380 Dynamyc, Université Paris-Est, France (Dr J-W Decousser)
European Molecular Biology Laboratory Heidelberg, Germany (PR. T. Alexandrov)
October 2019 – October 2021
Novel and structurally diverse beta-lactam – beta-lactamase inhibitor (BL-BLI) combinations displaying activity against multi-drug resistant (MDR) Gram-negative bacteria have recently become available including ceftazidime-avibactam, ceftolozane-tazobactam and meropenem-vaborbactam. Despite their limited use, resistance to the BL-BLI has already been described. The CO-PROTECT project aims to (i) systematically evaluate the epidemiology of resistance development against BL-BLI in MDR E. coli, K. pneumoniae and P. aeruginosa and dissect their mechanisms incl. genome sequencing and –omics approaches; (ii) investigate addition of several combination partner antibiotics active against MDR in order to protect BL-BLI against resistance development exploiting synergy, evolutionary selective disadvantage and collateral sensitivity incl. the dissection of the combined mode of action; and (iii) establish a translational framework comprising state-of-the-art hollow-fiber experiments, innovatively designed in vivo animal studies and pharmacokinetic-pharmacodynamic modelling and simulations. Hence, CO-PROTECT will identify favorable combination regimens (high efficacy, low selection of resistance) that are implementable off the shelve in the clinical setting. Moreover, CO-PROTECT will deliver an innovative research platform that can be applied to further research investigating combination therapies.
This project is coordinated by W. Couet, the director of our team and S. Wicha from Hamburg university.
Développement de nanoparticules de polymère chargées en colistine pour traiter les infections pulmonaires à bactéries multirésistantes : validations précliniques
Funded by :
In collaboration with :
University of Zaragoza, Aragon, Spain (Manuel Arruebo)
October 1st 2019 – March 31 2020
Pseudomonas aeruginosa (PA) is a bacterium responsible for chronic pneumonia in patients with cystic fibrosis. These infections are impossible to treat due to the presence of multidrug-resistant bacteria (MR), and the presence of biofilms and viscous mucus protecting PA from the action of antibiotics (ATB). Colistin (COLI) is used by inhalation as a last resort ATB against these infections. However, resistance against COLI appears. To avoid this, the effectiveness of COLI could be improved by increasing its diffusion through the mucus and biofilms of the respiratory tract, where PA is protected from its action. Thus, the aim of the study is to develop inhalable nanoparticles (NP) of poly (lactic – co-glycolic acid), capable of diffusing and releasing COLI within these viscous media. The NPs containing the COLI will be produced in Zaragoza by electrospray. The most promising formulations will be selected on the basis of various criteria, including their ability to improve the diffusion of COLI and their aerosolization performance. This stage will be carried out jointly in Zaragoza and Poitiers. The best formulation will then be chosen for a pharmacokinetic study in rats after pulmonary administration. This project should make it possible to obtain a set of chemical, biological and pharmaceutical data necessary to consider or not a demonstration of the concept in humans.
Development of a second generation of odilorhabdins
During the 5 years of the project, GNA-NOW aims to exploit a consortium of experts, representing all the skills and experience necessary to advance potential Gram (-) antibiotics towards phase I clinical trials. In this project, we take part in development of a second generation of odilorhabdins (NOSO-2G) covering a wider spectrum of enterobacteria, and which can be active on P. aeruginosa and on A. baumanii, thus widening the spectrum of urinary indications (UTI) and intra -abdominal (ATI) to pneumonia acquired in hospital (PAH) and / or associated with ventilation (VAP). In this project, we are evaluating the tolerance of new odilorhabdin molecules, as well as their efficacy at single dose and at repeated doses in a murine model of infectious E. coli peritonitis (3-4 molecules / month).
Evaluation sur un modèle d’infection chronique murin (rat) de l’efficacité d’une nouvelle formulation de nanoparticules chargée en tobramycine (KuDa-tob)
Funded by :
In collaboration with :
Kusudama Therapeutics, Euskadi, Spain
Pharmamodelling, Navarra, Spain
April 2020 – February 2021
This trilateral project consisting of KUSUDAMA THERAPEUTICS SL (Euskadi), PHARMAMODELLING SL (Navarra), and the INSERM unit U1070 pharmacology of Antimicrobial Agents from the University of Poitiers (Nouvelle-Aquitaine) aims to validate on animal models the competitive advantage of a new formulation of nanoparticles loaded with tobramycin, called KuDa-tob. This formulation has an extended-release profile and is designed to reduce the frequency of administration of tobramycin in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. KUSUDAMA THERAPEUTICS will synthesize and characterize independent batches of kuDa-tob in order to carry out preclinical tests on animals. To validate the concept of sustained release, pharmacokinetic studies in the lungs and plasma of healthy animals (mice, rats, and pigs) will be performed, comparing the administration of KuDa-tob with tobramycin solution used in the clinic. PHARMAMODELLING will be responsible for the interpretation and modeling of the results of this study. Subsequently, an efficacy and pharmacokinetics study will be carried out on a model of chronic Pseudomonas aeruginosa infection in rats developed by INSERM U1070 of the University of Poitiers. The results obtained through this collaboration should make it possible to advance the development of KuDa-tob towards preclinical regulation and, possibly, towards phase I clinical trial. This project will also allow the creation of an international, but close, network, which will serve as a platform to develop the activities of the entities participating in the project.
Pharmacologie des nouveaux antibiotiques dans les PAVM à bactéries multirésistantes
Funded by :
In collaboration with : Inserm U1092 Limoges (O. Barraud), and CIC-1435 Limoges (B. François) and EMF Poitiers.
October 2019 – October 2021
La résistance aux antibiotiques est devenue un problème de santé publique majeur faisant l’objet de mesures prises tant au niveau national qu’européen. La problématique actuelle concerne surtout les bactéries à Gram négatif (BGN) multirésistantes, notamment les entérobactéries et Pseudomonas aeruginosa pour lesquels l’arsenal thérapeutique devient limité. Ces BGN multirésistants sont principalement rencontrés à l’hôpital chez des patients hospitalisés dans des unités de soins intensifs. De nouveaux antibiotiques associant une bêta-lactamine et un inhibiteur de bêta-lactamases sont désormais utilisés pour le traitement d’infections médiées par ces BGN. Ils sont notamment utilisés dans le domaine de la réanimation pour traiter des infections respiratoires survenant chez des patients intubés-ventilés (PAVM : pneumopathie acquise sous ventilation mécanique). Cependant, au cours du traitement, des résistances à ces antibiotiques (ceftazidime / avibactam et ceftolozane / tazobactam) ont déjà été observées en clinique en particulier chez P. aeruginosa.
Nous proposons de réaliser un projet de recherche translationelle (du laboratoire au patient) permettant de comprendre les mécanismes mis en jeu, couplé à une description pharmacocinétique / pharmacodynamiquede ces associations qui permettra d’optimiser les doses et donc l’efficacité de ces molécules mais aussi de les préserver en évitant l’émergence des résistances.
Combatting Bacterial Resistance in Europe – Carbapenem Resistance
The COMBACTE-CARE project aims to shed new light on the best ways to understand and treat ‘carbapenem-resistant enterobacteriaceae’ CRE infections. It will also run clinical trials of a novel antibiotic combination (Aztreonam/Avibactam) designed to tackle a sub-type of CRE infections for which there are limited or no treatment options.
CO-ACTION (JPIAMR: Joint Programming Initiative on Antimicrobial Resistance)
Developing combinations of CO-ACTIVE antimicrobials and non-antimicrobials
Ecole Nationale Vétérinaire, INRA UMR 1331 (A. Bousquet-melou)
January 2016 – January 2020
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. 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.