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JAC Advance Access published online on November 16, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl464
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received June 29, 2006
Revised September 18, 2006
Accepted October 17, 2006

Original article

Immunomodulatory effects of fosfomycin in an endotoxin model in human blood

Markus Zeitlinger 1, Claudia Marsik 2 *, Ilka Steiner 1, Robert Sauermann 1, Katja Seir 1, Bernd Jilma 3, Oswald Wagner 2, and Christian Joukhadar 4

1 Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Vienna, Austria
2 Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
3 Department of Clinical Pharmacology, Division of Immunology and Hematology, Medical University of Vienna, Vienna, Austria
4 Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Vienna, Austria; Department of Internal Medicine I, Division of Infectious Diseases and Chemotherapy, Medical University of Vienna, Vienna, Austria

* To whom correspondence should be addressed.
Claudia Marsik, E-mail: claudia.marsik{at}meduniwien.ac.at


  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 µg/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 ~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.

Keywords: sepsis; in vitro; whole blood.
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