title: Combination therapy with iron chelation and vancomycin in treating murine staphylococcemia.
abstract: Iron acquisition is a virulence factor for Staphylococcus aureus. We assessed the efficacy of the iron chelator, deferasirox (Def), alone or in combination with vancomycin (Van) against two methicillin-resistant S. aureus (MRSA) strains in vitro and in a murine bacteremia model. In vitro time-kill assays were carried out against MRSA or vancomycin-intermediate S. aureus (VISA) strains. The impact of Def on Van binding to the surface of S. aureus was measured by flow cytometry. Furthermore, we compared the efficacy of Def, Van, or both drugs in treating S. aureus bacteremia in a murine model. Combination therapy reduced MRSA and VISA viability in vitro versus either drug alone or untreated controls (p < 0.005); this outcome was correlated with enhanced Van surface binding to S. aureus cells. In vivo, Def + Van combination therapy significantly reduced the bacterial burden in mice kidneys (p = 0.005) and spleen (p < 0.001), and reduced the severity of infection with MRSA or VISA strains compared to placebo-treated mice. Our results show that Def enhances the in vitro and in vivo capacity of Van-mediated MRSA killing via a mechanism that appears to involve increased binding of Van to the staphylococcal surface. Iron chelation is a promising, novel adjunctive therapeutic strategy for MRSA and VISA infections.
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute, Harbor-University of California Los Angeles (UCLA) Medical Center, 1124 West Carson St., St. John's Cardiovascular Research Center, Torrance, CA, 90502, USA.
authors.forename: G
authors.initials: G
authors.lastname: Luo
authors.forename: B
authors.initials: B
authors.lastname: Spellberg
authors.forename: T
authors.initials: T
authors.lastname: Gebremariam
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Xiong
authors.forename: S W
authors.initials: SW
authors.lastname: French
authors.forename: A
authors.initials: A
authors.lastname: Bayer
authors.forename: A S
authors.initials: AS
authors.lastname: Ibrahim
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy*; D058491:Bacterial Load; D001565:Benzoates / Q000627:therapeutic use*; D002614:Chelating Agents / Q000627:therapeutic use*; D000077588:Deferasirox; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D007501:Iron / Q000378:metabolism; D007668:Kidney / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D012720:Severity of Illness Index; D013154:Spleen / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy*; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*; D014640:Vancomycin / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D001565:Benzoates; D002614:Chelating Agents; D014230:Triazoles; D014640:Vancomycin; D007501:Iron; D000077588:Deferasirox