Immunomodulatory effects of fosfomycin in an endotoxin model in human blood.

Abstract

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.

• Authors: Markus Zeitlinger, Claudia Marsik, Ilka Steiner, Robert Sauermann, Katja Seir, Bernd Jilma, Oswald Wagner, Christian Joukhadar
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 59 Issue 2 Pg. 219-23 (Feb 2007) ISSN: 0305-7453 [Print] England
• PMID: 17114176 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Endotoxins
• Immunologic Factors
• Interleukin-6
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Fosfomycin

Topics

• Anti-Bacterial Agents (pharmacology)
• Blood Bactericidal Activity (drug effects, immunology)
• Endotoxins (blood)
• Fosfomycin (pharmacology)
• Humans
• Immunologic Factors (biosynthesis, blood)
• In Vitro Techniques
• Interleukin-6 (biosynthesis, blood)
• Leukocytes (drug effects, immunology)
• Male
• RNA, Messenger (biosynthesis, blood)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Necrosis Factor-alpha (biosynthesis, blood)