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Combination therapy with iron chelation and vancomycin in treating murine staphylococcemia

G Luo1, B Spellberg, T Gebremariam

  • 1Division 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.

European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology
|December 3, 2013
PubMed

Insights

Deferasirox (Def) combined with vancomycin (Van) effectively kills methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) in vitro and in mice. This combination enhances vancomycin

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Iron acquisition is a critical virulence factor for Staphylococcus aureus.
  • Antibiotic resistance in S. aureus, particularly MRSA and VISA strains, necessitates novel therapeutic strategies.
  • Iron chelators are being explored as potential adjunctive treatments for bacterial infections.

Purpose of the Study:

  • To evaluate the efficacy of deferasirox (Def), an iron chelator, alone and in combination with vancomycin (Van) against MRSA and VISA strains.
  • To investigate the mechanism by which Def might enhance Van's activity, specifically its binding to S. aureus surface.
  • To assess the in vivo therapeutic potential of Def and Van combination therapy in a murine model of S. aureus bacteremia.

Main Methods:

  • In vitro time-kill assays were performed using MRSA and VISA strains exposed to Def, Van, or both.
  • Flow cytometry was utilized to quantify the impact of Def on Van's surface binding to S. aureus.
  • A murine bacteremia model was employed to compare the in vivo efficacy of Def, Van, and their combination in reducing bacterial burden and infection severity.

Main Results:

  • Combination therapy with Def and Van significantly reduced MRSA and VISA viability in vitro compared to monotherapy or controls (p < 0.005).
  • Deferasirox treatment was correlated with enhanced surface binding of vancomycin to S. aureus cells.
  • In vivo, Def + Van significantly decreased bacterial load in mouse kidneys and spleen and reduced overall infection severity for both MRSA and VISA strains.

Conclusions:

  • Deferasirox enhances the killing efficacy of vancomycin against MRSA and VISA, both in vitro and in vivo.
  • The enhanced killing appears to be mediated, at least in part, by increased vancomycin binding to the staphylococcal surface.
  • Iron chelation represents a promising adjunctive therapeutic approach for treating challenging S. aureus infections, including resistant strains.

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