Overview

Inserm U1070 “Pharmacology of Antimicrobial Agents is oriented towards Europe!

 

The research unit affiliated to the University of Poitiers and INSERM has been created in 2012 and comprises 20 permanent staff members (clinicians, pharmacists and scientists) and 13 students (PhD and master students).

The INSERM U1070 unit aim to optimize the antibiotic usage with a triple target:

  • To increase their efficacy,
  • To control the toxicity and
  • To limit the emergence of antibiotic resistance.

In order to do so, we are developping innovative PK/PD modelling approaches to select the best dosing regimen of antibiotics administered alone or in combination as well as the best route of administration and best formulation.

Inserm U1070 conducts translational research, from cells culture models to patients, by integrating microbiology, analytical chemistry, drug formulation, and in vivo preclinical experiments.

To dateInserm U1070 received several grants from Region Nouvelle-Aquitaine, ANR, PHRC, JPIAMR, IMI and CPER-FEDER and has established collaborations with ANSES and several Universities in France (Paris Sud, Paris Diderot) and abroad (Dublin, Erasmus MC, Upssala, Hambourg, Catholic University of Louvain…), as well as leading pharmaceutical companies.

Current projects

Specific Targeting of Antimicrobial Resistant Strains in situ using Targeted Antibacterial Plasmid

Funded by :

In collaboration with :

CNRS UMR5086,  Lyon, France

Duration :

2022 – 2025

Summary :

One health research programs are needed to tackle the problem of Antimicrobial Resistance (AMR), which is a major concern worldwide. The STARS-TAP innovative strategy is based on Targeted-Antibacterial-Plasmids (TAPs) that use DNA conjugation to deliver CRISPR/Cas systems exerting an antibacterial activity on specifically targeted multidrug-resistant (MDR) strains. In vitro, we have shown that TAPs can selectively kill MDR strains by targeting the chromosome, or restore their susceptibility by targeting drug-resistance plasmids, without affecting non-targeted strains present in the bacterial population. Translating this in vitro proof of concept to various in situ settings would undoubtedly have a true impact by opening new intervention options to eliminate MDR strains from varied ecosystems. We will hence develop a library of TAPs directed against a range of clinically and environmentally relevant MDR strains or against specific genes conferring resistance to expanded-spectrum beta-lactams and carbapenems. We will evaluate TAPs ability to specifically eliminate MDR strains or plasmids from the microbiotas associated with the animal gut or from hospital wastewater. We will also address TAPs dissemination and ability to eliminate AMR strains or plasmids from environmental soil or the plant rhizosphere. This unexplored and versatile antibacterial strategy could be a promising approach for preventive treatment of human and animals gut colonized with MDR strains, or even to avoid AMR spread within anthropized environmental reservoirs such as agricultural soils and wastewater.

Pulmonary Administration of Antibiotic Nano-emulsion to treat gram-negative bacteria InfeCtions

Funded by :       

 

 

Whole genome sequencing and artificial intelligence to characterise and diagnose antibiotic resistance and capacity to escape treatment

Funded by :      

 

Duration :

June 2021 – Mai 2026

 

Apport de la modélisation PK/PD de données in vitro et in vivo pour lutter contre la résistance bactérienne aux antibiotiques utilisés seuls ou en combinaisons

Funded by :

In collaboration with :

Roche, Basel, Switzerland
Roche, Paris, France

Duration :

April 2020 – April 2023

Summary :

The Antibiotic resistance is a recurrent topic in the news due to the emergence of Multi-Drug Resistant bacteria (MDR) leading to therapeutic failures. The antibiotic efficacy is strongly correlated to the administration of the right dose at the right frequency for an appropriate treatment duration. The relationship between drug exposure and effects, the PK/PD relationship, is thus the key component determining the effect of antibiotic and is evaluated in in vitro systems and/or acute animal infection model.  Nevertheless, predictions based on preclinical data do not always match well the clinical reality. Preclinical in vitro and in vivo models are very specific and the outcome highly dependent on the exact testing conditions. The lack of data translatability between in vitro assays and in vivo animal studies may be correlated to the increasing emergence of therapeutic failures in the treatment of acute or chronic bacterial infection.

During this project, alternative in vivo relevant testing conditions will be investigated for their impact on antibiotic activity and bacteria susceptibility/resistance using in vitro static and dynamic systems (Time-kill and Hollow fiber) and results will be compared to in vivo animal infection model outcomesObtained data will be connected with modelling for a parallel improvement of semi-mechanistic PK/PD models as well as in vitro testing conditions. Further correlation will be done with available human data with the final goal of delivering in vitro PK/PD models that can be used in predicting safe and effective human dose and dosing regimens having the potential of overcoming resistance development in difficult to treat bacterial infections.

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)

Duration :

Janvier 2020 – Décembre 2022

Summary :

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. coliK. 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.

Population pharmacokinetic-pharmacodynamic stuudy of 7 broad-Spectrum anti-infective agents in the cerebro spinal fluid of brain injured patients with external ventricular drainage

Funded by :      

In collaboration with :

CHU de Poitiers, Poitiers, France

Duration :

2019 – 2022

Summary :

The aim of this study is to describe PK of 7 antibiotics (cefepime, ceftazidime, linezolid, meropenem, vancomycin, colistin and daptomycin) in cerebrospinal fluid (CSF) of patients with external ventricular drainage using PK/PD approaches. The study includes around 20 centers across France. The inclusions were started at the beginning of 2019, and will be extended in 2021 (inclusion deadline delayed in connection with the COVID-19 pandemic).

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.

Duration :

October 2019 – October 2022

Summary:

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 / pharmacodynamique de 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.

Development of a second generation of odilorhabdins

Funded by : 

More informations

Duration :

July 1st 2019 – June 30 2025

Summary :

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).

Antibiotic distribution and recovery in tissue

Funded by : 

In collaboration with :

GSK

CHU de Tours, CHU de Poitiers

Medizinische Universitaet Wien, Vienna, Austria

More Informations

Duration :

July 1st 2019 – June 30 2022

Summary :

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.

Past Projects

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

Duration :

April 2020 – January 2022

Summary :

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.

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)

Duration :

October 1st 2019 – March 31 2020

Summary :

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.

Developing combinations of CO-ACTIVE antimicrobials and non-antimicrobials

 

Funded by : 

In collaboration with :

Erasmus University, Rotterdam, Netherlands (J. Mouton)

Uppsala University (L. Friberg / T. Tangden)

Université catholique de Louvain (F. Van Bambeke)

Ecole Nationale Vétérinaire, INRA UMR 1331 (A. Bousquet-melou)

Duration :

January 2016 – January 2020

Summary :

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.

Combatting Bacterial Resistance in Europe – Carbapenem Resistance

 

Funded by : 

In collaboration with :

Basilea, GSK, Pfizer

CHU de Limoges (B. Francois)…

More informations

Duration :

September 2015 – September 2018

Summary :

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.

                 

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