Related Experiment Video
Updated: Jul 18, 2026
Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation
Published on: May 16, 2016
Immunomodulatory effects of fosfomycin in an endotoxin model in human blood
Markus Zeitlinger1, Claudia Marsik, Ilka Steiner
1Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna Vienna, Austria.
Objectives:
Although a wide range of therapeutic strategies have been developed to improve the outcome of severe sepsis, a convincing reduction in mortality is lacking. Recently, increasing attention has been paid to immunomodulatory effects of antimicrobials. This study set out to explore the immunomodulatory effects of fosfomycin, a broad-spectrum antibiotic frequently used in septic patients, at the protein and molecular levels in vitro.
Methods:
Whole blood from 11 healthy volunteers was incubated with 50 pg/mL endotoxin and 100 microg/mL fosfomycin or physiological sodium chloride for 4 h. Real-time RT-PCR was performed for various pro- and anti-inflammatory cytokines. Concentrations of tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 in the supernatant were measured using a commercially available ELISA.
Results:
Incubation of human leucocytes with endotoxin increased messenger RNA (mRNA) levels of cytokines several thousand fold compared with baseline. The addition of fosfomycin significantly inhibited mRNA levels of pro-inflammatory cytokines such as IL-1-alpha, IL-6 and TNF-alpha after 2 h (P < 0.01), while no significant reduction was observed for the anti-inflammatory cytokines IL-4, IL-10 and IL-13 (P = 0.26). At the protein level, the concentrations of IL-6 and TNF-alpha increased approximately 3000- and 600-fold after 4 h of incubation with lipopolysaccharide as compared with baseline, respectively. Addition of fosfomycin significantly reduced cytokine levels by 56% and 73% for IL-6 and TNF-alpha, respectively.
Conclusions:
Fosfomycin extensively decreased mRNA levels and release of pro-inflammatory cytokines in human blood. The broad antimicrobial coverage of fosfomycin and its immunosuppressive effects could be clinically useful in patients with sepsis.
Insights
Fosfomycin significantly reduced pro-inflammatory cytokine mRNA and protein levels in human blood stimulated with endotoxin. These findings suggest fosfomycin
Area of Science:
- Immunology
- Pharmacology
- Microbiology
Background:
- Severe sepsis treatment lacks mortality reduction strategies.
- Antimicrobials' immunomodulatory effects are gaining attention.
- Fosfomycin is a broad-spectrum antibiotic used in sepsis.
Purpose of the Study:
- To investigate the in vitro immunomodulatory effects of fosfomycin.
- To assess fosfomycin's impact on pro- and anti-inflammatory cytokines at molecular and protein levels.
Main Methods:
- Human whole blood incubated with endotoxin and fosfomycin or saline.
- Real-time RT-PCR for cytokine mRNA analysis.
- ELISA for measuring cytokine protein concentrations (TNF-alpha, IL-6).
Main Results:
- Endotoxin significantly increased cytokine mRNA and protein levels.
- Fosfomycin inhibited mRNA levels of pro-inflammatory cytokines (IL-1-alpha, IL-6, TNF-alpha).
- Fosfomycin reduced protein concentrations of IL-6 by 56% and TNF-alpha by 73%.
Conclusions:
- Fosfomycin significantly decreases pro-inflammatory cytokine production in human blood.
- Fosfomycin's broad-spectrum activity and immunosuppressive effects may benefit sepsis patients.
