Project: Optimization and implementation of ceftazidime or ceftazidime-avibactam combined with fosfomycin against highly resistant gram-negative bacteria
| Acronym | CAVIFOS (Reference Number: JPIAMR2022-089) |
| Duration | 01/05/2023 - 30/04/2026 |
| Project Topic | Carbapenemase-producing Enterobacterales are a major health problem. One of the few treatment options is ceftazidime/avibactam. However, relapse of infection may occur, often associated with resistance development. Empiric use of continuous infusion and combination therapies, in particular the addition of fosfomycin to ceftazidime/avibactam, seems to be associated with improved outcomes as compared to ceftazidime/avibactam alone. Indeed, also in preclinical models, fosfomycin is often highly synergistic and reduced resistance development is observed in combination with beta-lactams. Yet, the dosing rationale is unclear and massive doses of up to 24 g of fosfomycin are empirically 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.Therefore, we will use state-of-the-art preclinical PK/PD models (hollow-fibreer, humanized-PK mouse model) with patient-derived bacterial isolates and pharmacometrics to define optimised dosing regimens. Using whole genome sequencing/artificial intelligence, we will define the link between genetics and the phenotypic bacterial susceptibility as well as synergistic effects, which could be developed into a rapid test to rapidly identity patients that will benefit most from the optimised combination treatment. Lastly, we will implement the optimised, pharmacometrics-guided dosing approach in a proof-of-concept controlled trial. |
| Website | visit project website |
| Network | JPIAMR-ACTION |
| Call | 2nd JPIAMR-ACTION Joint Call 2022 |
Project partner
| Number | Name | Role | Country |
|---|---|---|---|
| 1 | Inserm U1070 | Coordinator | France |
| 2 | University of Hamburg | Partner | Germany |
| 3 | Ben Gurion University of the Negev | Partner | Israel |
| 4 | University of Geneva / Geneva University Hospitals | Partner | Switzerland |
| 5 | IRCCS Azienda Ospedaliero/University Alma Mater Studiorum of Bologna | Partner | Italy |
| 6 | University of Sevilla / Hospital Virgen Macarena | Partner | Spain |