Immunomodulatory effects of fosfomycin in an endotoxin model in human blood.
OBJECTIVE
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.
Zeitlinger
Markus
M
Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna Vienna, Austria.
Marsik
Claudia
C
Steiner
Ilka
I
Sauermann
Robert
R
Seir
Katja
K
Jilma
Bernd
B
Wagner
Oswald
O
Joukhadar
Christian
C
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001770:Blood Bactericidal Activity / Q000187:drug effects / Q000276:immunology; D004731:Endotoxins / Q000097:blood*; D005578:Fosfomycin / Q000494:pharmacology*; D006801:Humans; D007155:Immunologic Factors / Q000096:biosynthesis / Q000097:blood*; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood
D000900:Anti-Bacterial Agents; D004731:Endotoxins; D007155:Immunologic Factors; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005578:Fosfomycin