Cerebral Antibiotic PBPK/PD Optimization and Evaluation of Innovative Regimens against Antibioresistance in ICU patients with cerebral infections – CAPOEIRA

Nosocomial central nervous system (CNS) infections in intensive care unit (ICU) patients remain therapeutically challenging because of drug- and disease-related factors that contribute to suboptimal antibiotic concentrations in CNS. Moreover, antibiotic dosing regimens recommendations for meningitis treatment are currently based on generic pharmacokinetic/pharmacodynamic (PK/PD) targets that have not been specifically defined for the treatment of CNS infections. Therefore, a better knowledge of antibiotic CNS distribution and PK/PD relationship is crucial to treat such infections and to prevent resistance. The objective of the project is to optimize antibiotic exposure in ICU patients with CNS infections by developing new approaches including physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models. First, a generic PBPK model characterizing the CNS distribution of 9 antibiotics with different physicochemical properties will be developed with plasma and cerebrospinal fluid (CSF) concentrations previously measured in infected and uninfected patients. The PBPK model will be used to quantify the impact of infection on CNS penetration and to search for relationships between antibiotic characteristics and their CNS distribution to extrapolate model predictions to other antibiotics. Thereafter, human CSF concentrations simulated with the PBPK model will be reproduced in artificial CSF in a dynamic hollow-fiber infection model over several days to quantify the effect of some selected antibiotics on reference and clinical strains. Different dosing regimens will be tested, and resistance mechanisms will be investigated by whole genome sequencing and RT-qPCR. Finally, semi-mechanistic PK/PD modelling techniques will be applied to link the antibiotic unbound CSF concentrations with their antimicrobial effect. The resulting so-called PBPK/PD model will be used to find the most promising dosing regimens for the treatment of difficult-to-treat CNS infections.