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Cerebrospinal fluid impairs antimicrobial activity of fosfomycin in vitro
Robert Sauermann1, Richard Schwameis, Manfred Fille
1Department 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
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 0.25x 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.
Insights
Fosfomycin
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Fosfomycin demonstrates good penetration into cerebrospinal fluid (CSF), making it a candidate for treating central nervous system (CNS) infections.
- Understanding the drug's activity within the CNS environment is crucial for effective treatment.
Purpose of the Study:
- To evaluate how human cerebrospinal fluid (CSF) affects the antimicrobial efficacy of fosfomycin.
- To compare fosfomycin's activity in CSF versus standard laboratory media.
Main Methods:
- Time-kill kinetics were assessed for Staphylococcus aureus in Mueller-Hinton broth (MHB) and human CSF across various fosfomycin concentrations (0.25x to 8x MIC).
- In vitro simulations replicated a patient's in vivo CSF pharmacokinetic profile to assess bacterial response.
Main Results:
- Higher fosfomycin concentrations (8x MIC) were needed for sustained bacterial killing in CSF compared to MHB (1x MIC).
- Simulated CSF drug concentrations led to initial bacterial killing but were followed by bacterial regrowth, indicating insufficient sustained activity.
Conclusions:
- Fosfomycin exhibits reduced antimicrobial activity in human CSF compared to standard MHB.
- Fosfomycin doses that only slightly exceed the minimum inhibitory concentration (MIC) may be inadequate for achieving bactericidal effects in CNS infections.
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