To study the in vitro and in vivo activity of LZD, VAN and its combinations with RIF in a rabbit meningitis model, caused by two strains of S. aureus with different susceptibilities to glycopeptides. Methods In vitro MICs (mg/L): Strain A (LZD = 2, VAN = 1, RIF = 0.018) and B (LZD = 4, VAN = 8, RIF = 512). The bactericidal activity and synergy (time-kill curves) were studied over 24 h. Drugs were tested for a range of concentrations according to their MICs and achievable human serum levels (1/4x-4xMIC) against both strains. In vivo New Zealand rabbits (2.5-3 kg) were used, with an inoculum of 8.5-9 Log cfu/mL. PK/PD parameters (blood and CSF) were determined (Cmax [mg/L]; AUC [mg.h/L]; t1/2 [h]; t > MIC [h]; AUC/MIC) after a single dose of each antimicrobial on infected rabbits. In the therapy experiments, animals (n = 6 per schedule) were grouped in untreated (CON), or treated with LZD (20 mg/kg), VAN (25 mg/kg every 4 hours, 4 doses), RIF (15 mg/kg) every 24 hours (1 dose), LZD+RIF or VAN+RIF. CSF variables analyzed at 0, 4, 6 and 24 h of treatment were: bacterial from Infectious diseases of the nervous system: pathogenesis and worldwide impact Paris, France. 10
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