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: Solen Pichereau, John J M Moran, Mary S Hayney, Sanjay K Shukla, George Sakoulas, Warren E Rose
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 67 Issue 1 Pg. 123-9 (Jan 2012) ISSN: 1460-2091 [Electronic] England
• PMID: 21980070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Infective Agents
• Bacterial Toxins
• Cytokines

Topics

• Anti-Infective Agents (pharmacology)
• Bacterial Toxins (immunology)
• Blood (immunology)
• Cells, Cultured
• Cytokines (metabolism)
• Humans
• Leukocytes, Mononuclear (drug effects, immunology)
• Staphylococcus aureus (immunology)