JAC Advance Access originally published online on April 11, 2007
Journal of Antimicrobial Chemotherapy 2007 59(6):1177-1181; doi:10.1093/jac/dkm080
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Effect of recombinant human activated protein C on the bactericidal activity of human monocytes and modulation of pro-inflammatory cytokines in the presence of antimicrobial agents
1 Infectious Disease Research Laboratory, Stratton VA Medical Center, 113 Holland Avenue, Albany, NY 12208, USA 2 Department of Medicine, Albany Medical College, Albany, NY 12208, USA 3 Lilly Research Laboratories, 355 E. Merrill St, Indianapolis, IN 46225, USA
Received 27 September 2006; returned 11 December 2006; revised 10 January 2007; accepted 25 February 2007
* Corresponding author. Tel: +1-518-626-6416; Fax: +1-518-626-6564; E-mail: aldona.baltch{at}med.va.gov
Objectives: To determine the effects of recombinant human activated protein C (rhAPC) on the antimicrobial activity and cytokine production of normal human monocyte-derived macrophages (MDMs) in the presence and absence of Escherichia coli infection, with and without treatment with levofloxacin or ampicillin.
Methods: MDM monolayers were infected with E. coli ATCC 25922 and treated with levofloxacin or ampicillin in the presence or absence of rhAPC. Antimicrobial activity and cytokine (TNF-
, IL-1ß, IL-6 and IL-8) concentrations in the supernatants were measured.
Results: When low concentrations of levofloxacin were used, a therapeutic concentration of rhAPC enhanced intracellular antibacterial activity at all time points. With ampicillin, antibacterial activity increased, was unaffected or diminished depending upon the drug concentration and assay time. Without antibiotics, rhAPC had no antibacterial effect. E. coli caused cytokine production to increase many fold. This increase was significantly greater with antibiotics (P < 0.01). Without antibiotics, rhAPC decreased production of TNF-, IL-1ß and IL-6, but not IL-8. At high levofloxacin concentrations, rhAPC was associated with further increases in the concentrations of these cytokines. Cytokine concentrations at 24 h were unaffected by rhAPC in the presence of ampicillin and E. coli.
Conclusions: rhAPC can affect the bactericidal activity and cytokine production of human MDM in the presence of infection and antibiotic therapy. Importantly, factors such as type and concentration of antibiotics, presence of bacteria and timing must be taken into consideration when evaluating cytokine data from septic patients.
Keywords: sepsis , rhAPC , antibiotics