Bacterial infections caused by carbapenemase-producing Enterobacterales are a major health problem. One of the few treatment options is the new antibiotic ceftazidime/avibactam. However, relapse of infection may occur with associated resistance development.
Use of continuous infusion and combination therapies, in particular the addition of an old antibiotic, fosfomycin, to ceftazidime/avibactam, seem to be associated with improved outcomes. Indeed, in laboratory models, adding fosfomycin can lead to synergistic bacterial killing and less development of resistance to ceftazidime/avibactam. Yet, the dosing rationale is unclear; currently, massive doses of up to 24 g of fosfomycin are used, frequently leading to sodium overload.
The aim of the present project is to define and implement a rational dosing regimen for the combination of ceftazidime or ceftazidime-avibactam with fosfomycin against Enterobacterales. We will use state-of-the-art preclinical pharmacokinetic/pharmacodynamic (PK/PD) models (hollow-fiber, humanized-PK mouse model) with patient-derived bacterial isolates and PK to define optimised dosing regimens. Using whole genome sequencing/artificial intelligence, we will define the link between genetics and phenotypic bacterial susceptibility as well as synergistic effects, which could be developed into a rapid test to quickly identify patients who will benefit most from optimised combination therapy. Lastly, we will implement the optimised, pharmacometrics-guided dosing approach in a proof-of-concept controlled trial.
- Sandrine Marchand, Inserm U1070, France (Coordinator)
- Sebastian WICHA, University of Hamburg, Germany
- Jacob Moran-Gilad, Ben Gurion University of the Negev, Israel
- Angela Huttner, University of Geneva / Geneva University Hospitals, Switzerland
- Fernando Docobo-Perez, University of Sevilla / Hospital Virgen Macarena, Spain
- Maddalena Giannella, IRCCS Azienda Ospedaliero/University Alma Mater Studiorum of Bologna, Italy