title: IFN-gamma enhances killing of methicillin-resistant Staphylococcus aureus by human monocytes more effectively than GM-CSF in the presence of daptomycin and other antibiotics.
abstract: Because cytokines have been utilized in treatment of sepsis in neonates, we studied the effects of interferon-gamma (IFN-gamma) and GM-CSF on killing of intracellular methicilin-resistant Staphylococcus aureus (MRSA) by human monocyte derived macrophages (MDM) in the presence of daptomycin (Dap), rifampin (Rif), gentamicin (Gen), and combinations of these drugs. MDM infected with MRSA were treated with Dap (1 x MIC), Gen (0.5 x MIC), or Rif (1 x MIC), singly or in combination, with or without cytokines. MDM were lysed and viable bacteria counted. With antibiotics, MDM activated by IFN-gamma had a more rapid and prolonged bacterial killing effect than MDM activated by GM-CSF. This effect was most obvious with the triple-drug combination. In contrast, GM-CSF reduced intracellular killing under most experimental conditions compared to the effect of antibiotics alone. Dap alone and two- and three-drug combinations demonstrated significant killing effect for the 48 h of the assay. IFN-gamma enhanced rapid intracellular killing of MRSA in the presence of triple-drug treatment or Dap alone. GM-CSF in combination with the antibiotics reduced killing under most conditions studied. Further studies to confirm these observations with IFN-gamma-activated MDM and other MRSA strains are needed to support clinical trials for difficult-to-treat MRSA infections.
authors.affiliation: Stratton VA Medical Center, 113 Holland Avenue, Albany, NY 12208, USA. Raymond.smith1@va.gov
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Smith
authors.forename: Aldona L
authors.initials: AL
authors.lastname: Baltch
authors.forename: William J
authors.initials: WJ
authors.lastname: Ritz
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Michelsen
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Bopp
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D017576:Daptomycin / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017576:Daptomycin