Cerebrospinal fluid impairs antimicrobial activity of fosfomycin in vitro.
OBJECTIVE
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 0.25x to 8x 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 (8x MIC) was required to achieve sustained bacterial killing than in MHB (1x 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.
Sauermann
Robert
R
Department of Clinical Pharmacology, Section of Molecular Pharmacokinetics and Imaging, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. robert.sauermann@meduniwien.ac.at
Schwameis
Richard
R
Fille
Manfred
M
Ligios
Maria Luciana Camuz
ML
Zeitlinger
Markus
M
D000900:Anti-Bacterial Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D005578:Fosfomycin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D050296:Microbial Viability; D008962:Models, Theoretical; D013211:Staphylococcus aureus / Q000187:drug effects*; D013997:Time Factors
D000900:Anti-Bacterial Agents; D005578:Fosfomycin