title: Concentration-dependent effects of antimicrobials on Staphylococcus aureus toxin-mediated cytokine production from peripheral blood mononuclear cells.
abstract: BACKGROUND
  Toxins contribute to the pathogenicity of Staphylococcus aureus infections by inducing a dysregulated inflammatory response. This study evaluated the impact of anti-staphylococcal antibiotic exposures over an increasing concentration range on cytokine production from peripheral blood mononuclear cells (PBMCs) after S. aureus toxin exposures.
  
  
  METHODS
  Human PBMCs were suspended in complete Roswell Park Memorial Institute (RPMI) 1640 medium with 10% fetal bovine serum at 10(6) cells/mL with 100 ng/mL S. aureus toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxin A (SEA), α-toxin or Panton-Valentine leucocidin (PVL). Vancomycin, trimethoprim/sulfamethoxazole, tigecycline, daptomycin, linezolid, clindamycin and azithromycin were added at a concentration range of 0.5-100 mg/L. Cytokine [interleukin-1β (IL-1β), IL-6, IL-8, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α)] concentrations were measured in duplicate by ELISA following exposure and were compared with response with toxin alone.
  
  
  RESULTS
  At concentrations approximating serum C(max), tigecycline decreased IL-6 by 52%-57% and IFN-γ production by 43%-53% compared with toxin alone (P ≤ 0.05) and linezolid inhibited TNF-α by 12%-35% and IL-8 by 25%-42% (P ≤ 0.02). However, trimethoprim/sulfamethoxazole increased TNF-α and IL-8 production (P = 0.002). Clindamycin, daptomycin, vancomycin and azithromycin had no consistent significant effect at approximate serum C(max) concentrations. All antibiotics had a concentration-dependent effect on cytokine production, with tigecycline, clindamycin and trimethoprim/sulfamethoxazole being the most potent inhibitors of cytokine production at concentrations exceeding 25 mg/L.
  
  
  CONCLUSIONS
  S. aureus toxins stimulate production of inflammatory cytokines in PBMCs. Antimicrobials with high tissue penetration, including tigecycline, clindamycin, trimethoprim/sulfamethoxazole and linezolid, reduced cytokine production, which, along with their antimicrobial effects, may have importance in the therapeutic outcome of severe infections.
authors: Pharmacy Practice Division,  University of Wisconsin-Madison School of Pharmacy, Madison, WI 53705,  USA.
authors: Solen
authors: S
authors: Pichereau
authors: John J M
authors: JJ
authors: Moran
authors: Mary S
authors: MS
authors: Hayney
authors: Sanjay K
authors: SK
authors: Shukla
authors: George
authors: G
authors: Sakoulas
authors: Warren E
authors: WE
authors: Rose
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000276:immunology*; D001769:Blood / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology
chemical_list: D000890:Anti-Infective Agents; D001427:Bacterial Toxins; D016207:Cytokines