Communication Dans Un Congrès Année : 2023

Predicting antibacterial efficacy of linezolid on Staphylococcus aureus in cerebral infections using in vitro hollow fiber model and pharmacokinetic-pharmacodynamic modeling

Résumé

Background Linezolid (LNZ) is considered to be a useful treatment option for central nervous system (CNS) infections caused by Staphylococcus aureus in critically ill patients. Despite a good CNS penetration, administration of higher than standard doses of LNZ (600 mg q12 h) should be considered (Luque et al. 2014). The objective was to perform a pharmacokinetic/pharmacodynamic (PKPD) evaluation of LNZ on meticillin-susceptible Staphylococcus aureus (MSSA) by using in vitro time-kill curves (TKC) and hollow fiber infection model (HFIM). Methods TKC (n=3) and HFIM (n=2) were performed on a MSSA strain (ATCC29213, MIC = 4 mg/L) at an inoculum of 106 CFU/mL in Mueller-Hinton broth. TKC were conducted for 30 h with LNZ concentrations ranging from 1 to 64 mg/L. Bacterial counts at various times were used to develop a PD model (Monolix) then combined to a population PK model of LNZ in ICU infected patients (PHRCN 16-0501). Simulations were performed to evaluate different regimens (600 mg and 900 mg q12 h) and corresponding PK profiles in plasma and cerebrospinal fluid (CSF) were then reproduced in HFIM for 96 h. Results Biphasic TKCs were described by a model including two sub-populations: a susceptible and a resting one. The LNZ effect was characterized as an increase of the killing rate of susceptible bacteria according to an Emax model. Simulations using either plasma or CSF concentrations as PK input suggested similar PD effect which was confirmed in HFIM. At 600 mg q12 h, after a short stationary phase, regrowth was observed from 6 h, whereas it occurred later (72 h) for 900 mg q12 h, both reaching bacterial counts observed with the control at 96 h (10^9-10^10 CFU/mL). HFIM data were used to improve the PD model. Conclusions Based on CSF concentrations at the infection site, a transient and limited efficacy of LNZ was observed at the two dosing regimens tested. New dosing regimens are being evaluated. HFIM experiments will be reproduced in artificial CSF.

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hal-04142287 , version 1 (29-06-2023)

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  • HAL Id : hal-04142287 , version 1

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Noémie Prebonnaud, Alexia Chauzy, Claire Dahyot-Fizelier, Sandrine Marchand. Predicting antibacterial efficacy of linezolid on Staphylococcus aureus in cerebral infections using in vitro hollow fiber model and pharmacokinetic-pharmacodynamic modeling. 33rd ECCMID : : European Congress of Clinical Microbiology & Infectious Diseases, Apr 2023, Copenaghen, Denmark. ⟨hal-04142287⟩
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