Curriculum Vitae

Understanding the interplay of immunomodulatory compounds with the innate immune system in resistant bacterial pneumonia

The global emergence of antimicrobial resistance (AMR), especially antibiotic resistance, poses a severe threat to society. In 2019, 1.27 million deaths were directly related to AMR with lower respiratory infections being the leading cause of AMR-associated death [1]. With a lack of new antibiotics in clinical development [2] and a decline in the effectiveness of antibiotic therapy, alternative strategies to improve antibacterial treatment outcomes are urgently needed. The use of modulators to the innate immune response as adjunct to antibiotic treatment presents as a promising strategy [3].

In order to effectively inform drug development for this new modality, the complex interplay between bacterial infections, immunomodulatory compounds, antibiotic treatment, and the innate immune system of the host needs to be understood and quantified. My project focusses on understanding and quantifying the different interactions between these four components by leveraging a pharmacometric approach.

My research is conducted in context of the FAIR project (Flagellin Aerosol therapy as an Immunomodulatory adjunct to the antibiotic treatment of drug-Resistant bacterial pneumonia), which investigates the immunomodulatory compound flagellin as an adjunct treatment to antibiotics in drug-resistant bacterial pneumonia [4]. Flagellin is a common surface protein of bacteria that triggers the innate immune response via the Toll-like receptor 5 (TLR5) [5]. Due to the novelty of the drug and its way of administration, there are many challenges to overcome during clinical development. I aim to quantify the interactions between patient, drugs, and disease, by combining knowledge from preclinical in vivo and in vitro studies as well as prior knowledge from literature. This will allow me to develop a comprehensive PK/PD framework enabling also translation between different species. Subsequently this pharmacometric modelling framework can be leveraged to understand changes connected to the characteristics of the infection itself (e.g., the pathogen or the severity of the infection) and identify predictive biomarkers to evaluate treatment response. Ultimately, by combining all these aspects, the design of clinical trials at later stages of drug development can be informed to increase their chances of success and provide new therapeutic approaches for antibiotic-resistant pneumonia.

References:

[1]          C.J. Murray, K.S. Ikuta, F. Sharara u. a. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399: 629–655 (2022).

[2]          World Health Organization. 2021 Antibacterial agents in clinical and preclinical development: an overview and analysis. (2022).

[3]          V. Cattoir, B. Felden. Future antibacterial strategies: From basic concepts to clinical challenges. J. Infect. Dis. 220: 350–360 (2019).

[4]          FAIR Flagellin Aerosol Therapy. https://fair-flagellin.eu/ (last access 28 Aug 2024)

[5]          I. Ramirez-Moral, X. Yu, J.M. Butler u. a. mTOR-driven glycolysis governs induction of innate immune responses by bronchial epithelial cells exposed to the bacterial component flagellin. Mucosal Immunol. 14: 594–604 (2021).