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JAC Advance Access originally published online on November 16, 2006
Journal of Antimicrobial Chemotherapy 2007 59(2):219-223; 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
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Immunomodulatory effects of fosfomycin in an endotoxin model in human blood

Markus Zeitlinger1, Claudia Marsik2,*, Ilka Steiner1, Robert Sauermann1, Katja Seir1, Bernd Jilma3, Oswald Wagner2 and Christian Joukhadar1,4

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 Internal Medicine I, Division of Infectious Diseases and Chemotherapy, Medical University of Vienna Vienna, Austria

Received 29 June 2006; returned 27 July 2006; revised 18 September 2006; accepted 17 October 2006

*Corresponding author. Tel: +43-1-40400-2981; Fax: +43-1-40400-2998; E-mail: claudia.marsik{at}meduniwien.ac.at

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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