Ceftaroline fosamil in the treatment of experimental meningitis caused by methicillin-resistant Staphylococcus aureus

Background Meningitis caused by methicillin resistant Staphylococcus aureus (MRSA) is rare and often fatal. The recommended treatment for MRSA meningitis, vancomycin, is limited by poor cerebrospinal fluid (CSF) penetration. Ceftaroline fosamil is a novel fifth-generation cephalosporin with potent antibacterial activity in vitro against MRSA. Several case reports in humans suggest that ceftaroline might be a potential treatment option for MRSA meningitis. Our primary objective was to com­pare the efficacy of ceftaroline and vancomycin for the treatment of MRSA meningitis using a rabbit meningitis model. We then characterized CSF drug concentrations over time.Methods Ninety rabbits received a direct intracisternal injection of 5 x 105 CFU S. aureus (MRSA 252). Following a 16-hour incubation period, approximately 0.5ml of CSF was withdrawn via intracisternal aspiration immediately prior to treatment for quantitative bacterial counts and CSF antibiotic concentrations. Rabbits then received (by 1:1:1 random assignment) either no treatment (control group), vancomycin 20 mg/kg at 0 and 12hrs, or ceftaroline 40mg/kg at 0 and 4 hrs via marginal ear vein. CSF collection was repeated every 12 hours for up to 40 hours. All animals were humanely euthanized at 40 hours post inoculation. The primary endpoint (difference in bacterial load [expressed as CFU/mL] for each animal between the initial (T1) and terminal (T3) taps were characterized and compared between groups using the Kruskal-Wallis test. CSF drug concentrations were determined using liquid chromatography with tandem mass spectrometry (LC/MS/MS) assay.ResultsAmong the forty-three evaluable animals with established MRSA meningitis, there was no statistical difference in median CFU observed between the groups in pretreatment CFU counts (p=0.16). Reductions in bacterial load from baseline were 88%, 79% and 75% in the control, ceftaroline and vancomycin-treated groups, respectively. There was no statistical difference observed between vancomycin and either control or ceftaroline at any time point. While animals treated with ceftaroline exhibited a significant increase in clearance rate (log ∆) between T1 and T2 when compared to control (p = 0.019), these differences were no longer statistically significant by T3 (p= 0.43) as CSF ceftaroline concentrations were undetectable by that time point.Conclusions While ceftaroline may be a reasonable alternative to vancomycin for MRSA meningitis, additional animal and clinical studies are required to determine optimal dosing to establish its effectiveness.