ED Sciences de la Vie et de la Santé
Clinical and experimental approaches to the antibiotic treatment of central nervous system infections caused by methicillin-resistant staphylococci: real-life study and murine models of cerebrospinal fluid penetration
by Marin LAHOUATI (Biologie des maladies cardiovasculaires)
The defense will take place at 14h00 - Salle de Séminaire INSERM U1034 1 Avenue de Magellan, 33600 Pessac
in front of the jury composed of
- Fabien XUEREB - Maître de conférences - praticien hospitalier - Université de Bordeaux - Directeur de these
- Pierre TATTEVIN - Professeur des universités - praticien hospitalier - CHU de Rennes - Rapporteur
- Guillaume SAINT-LORANT - Maître de conférences - praticien hospitalier - CHU de Caen - Rapporteur
- Antoine DUPUIS - Professeur des universités - praticien hospitalier - CHU de Poitiers - Examinateur
Central nervous system (CNS) bacterial infections are serious diseases associated with high morbidity and mortality, with limited therapeutic options—particularly when caused by methicillin-resistant Staphylococcus. We conducted a narrative review of the literature on antibiotics active against methicillin-resistant Staphylococcus and their potential application in the treatment of CNS infections. Vancomycin and linezolid are currently the two agents recommended by international guidelines. However, to date, no comparative data on their clinical efficacy in CNS infections were available. We performed a real-life observational study comparing the clinical outcomes of patients with CNS staphylococcal infections treated with either vancomycin or linezolid. Patients treated with vancomycin appeared to have a higher risk of therapeutic failure, supporting the use of linezolid. Unfortunately, the increasing resistance of staphylococci to linezolid highlights the need to consider alternative antibiotics, for which data on CNS penetration are scarce. We developed murine models designed to assess antibiotic penetration into cerebrospinal fluid (CSF) and present data on delafloxacin CSF penetration. This model also allows for the incorporation of specific experimental conditions, such as blood-brain barrier (BBB) disruption caused by systemic inflammation or inhibition of efflux transporters (such as P-gp and OATs). BBB disruption due to inflammation has no impact on CSF penetration of linezolid unlike tedizolid, whose CSF penetration ratio increased. Regarding pharmacological inhibition of efflux transporters, inhibition of P-gp significantly increased the CSF penetration of linezolid. In conclusion, this work provides additional clinical and experimental data to guide the management of CNS infections and introduces a preclinical model for improving our understanding of antibiotics penetration into the CNS.
Role of gamma-Protocadherins in the molecular encoding of olivo-cerebellar connections
by Elena BAZ BADILLO (Institut Interdisciplinaire de Neurosciences)
The defense will take place at 10h00 - Auditorium Centre Broca Nouvelle-Aquitaine 146 rue Léo Saignat CS 61292 Case 130 33076 Bordeaux Cedex
in front of the jury composed of
- Mathieu LETELLIER - Chargé de recherche - Université de Bordeaux - Directeur de these
- Fekrije SELIMI - Directrice de recherche - Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France, UMR7241, U1050 - Rapporteur
- Peter SCHEIFFELE - Professor - Biozentrum, University of Basel - Rapporteur
- Emilie PACARY - Chargée de recherche - Neurocentre Magendie - INSERM U 1215 - Examinateur
During development, millions of neurons in the brain must choose their synaptic partners and undergo deep functional and molecular changes to stabilize specific connections. The olivo-cerebellar circuit presents a highly stereotyped development, with synapse selection happening during strict critical periods, making it a perfect model to study these phenomena. Early after birth, multiple climbing fibers (CF) emerging from the inferior olivary nucleus innervate each Purkinje cell (PC) in the cerebellum cortex. Over the three first postnatal weeks, supernumerary CF are pruned until each PC is mono-innervated by a single CF. Beyond the established role of activity in afferent selection, the molecular mechanisms underlying cell-cell interaction and recognition in this circuit remain unknown. The highly diverse family of gamma Protocadherins (γPCDH) has been recurrently proposed as part of a “molecular code of connectivity” in the cerebellum, although experimental evidence remains scarce. Here, using PatchSeq we show that during CF elimination, the diversity of γPCDH isoforms expressed by individual PC gradually decreases. In addition, overexpressing single isoforms to mimic a premature decrease in γPCDH diversity in single PCs significantly accelerates CF selection in a hindbrain explant model. Furthermore, we detected a higher similarity in γPCDH repertoire expressed by PCs connected by the same CF, suggesting that γPCDH expression in PCs is determined by the presynaptic neuron identity. Overall, our results support the role of γPCDH as part of the cerebellar molecular code of connectivity with a direct effect in CF-to-PC synapse specificity, and a not random γPCDH isoform expression.