Cerebrospinal fluid impairs antimicrobial activity of fosfomycin in vitro

Abstract

Objectives: Fosfomycin penetrates well into cerebrospinal fluid (CSF) and is considered for treatment of infections of the central nervous system (CNS). This study evaluated the influence of human CSF on the antimicrobial activity of fosfomycin. Methods: Time-kill curves were performed in Mueller-Hinton broth (MHB) and in pooled human CSF using fosfomycin concentrations ranging from 0.25× to 8× MIC for a clinical Staphylococcus aureus isolate. To estimate the activity of fosfomycin at the target site, the concentration-time curve measured in CSF of a patient at steady state was simulated in vitro in human CSF using two S. aureus isolates. Results: In CSF a higher fosfomycin concentration (8× MIC) was required to achieve sustained bacterial killing than in MHB (1× MIC). In vitro simulation of the pharmacokinetic profile measured in CSF of the selected patient showed initial killing, but terminal re-growth of both test strains. Conclusions: The antibacterial activity of fosfomycin is lower in CSF than in MHB, and drug concentrations slightly exceeding the MIC may not be sufficient to achieve bactericidal effects in the CNS. © The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.