Optimization and implementation of ceftazidime or ceftazidime-avibactam combined with fosfomycin against highly resistant gram-negative bacteria

Therapeutics

Research Project: 2023-05-01 - 2026-04-30
Total sum awarded: €1 421 231

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.

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  • Sandrine MARCHAND, INSERM U1070, French National Institute of Health and Medical Research, France (Coordinator)
  • Sebastian WICHA, University of Hamburg, Germany (Partner)
  • Jacob Moran-Gilad, Ben-Gurion University, Israel (Partner)
  • Angela HUTTNER, University of Geneva, Switzerland (Partner)
  • Maddalena GIANNELLA, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (Partner)
  • Fernando DOCOBO-PEREZ, University of Sevilla / Hospital Virgen Macarena, Spain (Partner)

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 randomized controlled trial.

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2022 - Disrupting drug resistance using innovative design