Daptomycin does not exert immunomodulatory effects in an experimental endotoxin model of human whole blood.
BACKGROUND
Recent studies have shown that distinct classes of antimicrobial agents might exert immunomodulatory effects in experimental settings. Daptomycin is the first member of the class of cyclic lipopeptide antibiotics, which exert their antimicrobial activity via a unique mode of action on the bacterial cytoplasmic membrane. Thus, we tested its ability to influence pro-inflammatory cytokines by use of an established experimental model of human endotoxemia.


METHODS
A controlled experimental study design with 4 parallel groups was used. Whole blood from 10 healthy male volunteers was incubated either with saline (negative control), daptomycin (40 microg/ml, control), lipopolysaccharide (LPS; 50 pg/ml, positive control), or the combination of daptomycin plus LPS for 4 h. Real-time polymerase chain reaction was utilized for the measurement of selected pro-inflammatory cytokines, namely IL-1 beta, IL-6 (high sensitivity) and TNF-alpha on the mRNA level. Protein concentrations of these respective cytokines were measured in the supernatant using a commercially available ELISA.


RESULTS
Incubation of whole blood with LPS significantly increased protein and mRNA levels of cytokines compared to baseline (p < 0.05). However, the combination of daptomycin plus LPS did not exert any significant effect on mRNA and protein levels of IL-1 beta, IL-6 (high sensitivity) and TNF-alpha after 2 and 4 h of incubation compared to LPS incubation alone.


CONCLUSIONS
Daptomycin does not affect pro-inflammatory cytokines in the early phase of endotoxemia. This is most likely due to the unique mode of action of daptomycin, its low potential to penetrate into human cells and its high affinity to bacterial cytoplasmic membranes.
Thallinger
Christiane
C
Division of Clinical Pharmacokinetics, Department of Clinical Pharmacology, University of Vienna, Vienna, Austria.
Rothenburger
Markus
M
Marsik
Claudia
C
Wuenscher
Sonja
S
Popovic
Martin
M
Endler
Georg
G
Wagner
Oswald
O
Joukhadar
Christian
C
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood*; D017576:Daptomycin / Q000494:pharmacology*; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D016207:Cytokines; D012333:RNA, Messenger; D017576:Daptomycin