title: Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus.
abstract: Based on in vitro synergy studies, the addition of nafcillin to daptomycin was used to treat refractory methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Daptomycin is a de facto cationic antimicrobial peptide in vivo, with antistaphylococcal mechanisms reminiscent of innate host defense peptides (HDPs). In this study, the effects of nafcillin on HDP activity against MRSA were examined in vitro and in vivo. Exposures to β-lactam antimicrobials in general, and nafcillin in particular, significantly increased killing of S. aureus by selected HDPs from keratinocytes, neutrophils, and platelets. This finding correlated with enhanced killing of MRSA by whole blood, neutrophils, and keratinocytes after growth in nafcillin. Finally, nafcillin pretreatment ex vivo reduced MRSA virulence in a murine subcutaneous infection model. Despite the lack of direct activity against MRSA, these studies show potent, consistent, and generalized nafcillin-mediated "sensitization" to increased killing of MRSA by various components of the innate host response. The use of nafcillin as adjunctive therapy in MRSA bacteremia merits further study and should be considered in cases refractory to standard therapy.
  
  
  CONCLUSIONS
  Nafcillin has been used as adjunctive therapy to clear persistent MRSA bacteremia. Nafcillin enhances killing of MRSA by a cadre of innate host defense peptides. Nafcillin increases binding of human cathelicidin LL-37 to the MRSA membrane. Nafcillin enhances killing of MRSA by neutrophils. Nafcillin reduces virulence of MRSA in a murine subcutaneous infection model.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA, 92093, USA, gsakoulas@ucsd.edu.
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.forename: Cheryl Y
authors.initials: CY
authors.lastname: Okumura
authors.forename: Wdee
authors.initials: W
authors.lastname: Thienphrapa
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.forename: Poochit
authors.initials: P
authors.lastname: Nonejuie
authors.forename: Quang
authors.initials: Q
authors.lastname: Dam
authors.forename: Abhay
authors.initials: A
authors.lastname: Dhand
authors.forename: Joseph
authors.initials: J
authors.lastname: Pogliano
authors.forename: Michael R
authors.initials: MR
authors.lastname: Yeaman
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hensler
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D002460:Cell Line; D002478:Cells, Cultured; D017576:Daptomycin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D008875:Middle Aged; D009254:Nafcillin / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D054804:Cathelicidins
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D009254:Nafcillin; D017576:Daptomycin; D054804:Cathelicidins