title: Photodynamic therapy using intra-articular Photofrin for murine MRSA arthritis: biphasic light dose response for neutrophil-mediated antibacterial effect.
abstract: OBJECTIVE
  Bacterial arthritis does not respond well to antibiotics and moreover multidrug resistance is spreading. We previously tested photodynamic therapy (PDT) mediated by systemic Photofrin® in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) arthritis, but found that neutrophils were killed by PDT and therefore the infection was potentiated.
  
  
  METHODS
  The present study used an intra-articular injection of Photofrin® and optimized the light dosimetry in order to maximize bacterial killing and minimize killing of host neutrophils. MRSA (5 × 10(7)  CFU) was injected into the mouse knee followed 3 days later by 1 µg of Photofrin® and 635-nm diode laser illumination with a range of fluences within 5 minutes. Synovial fluid was sampled 6 hours or 1-3, 5, and 7 days after PDT to determine MRSA colony-forming units (CFU), neutrophil numbers, and levels of cytokines.
  
  
  RESULTS
  A biphasic light dose response was observed with the greatest reduction of MRSA CFU seen with a fluence of 20 J cm(-2), whereas lower antibacterial efficacy was observed with fluences that were either lower or higher. Consistent with these results, a significantly higher concentration of macrophage inflammatory protein-2, a CXC chemokine, and greater accumulation of neutrophils were seen in the infected knee joint after PDT with a fluence of 20 J cm(-2) compared to fluences of 5 or 70 J cm(-2).
  
  
  CONCLUSIONS
  PDT for murine MRSA arthritis requires appropriate light dosimetry to simultaneously maximize bacterial killing and neutrophil accumulation into the infected site, while too little light does not kill sufficient bacteria and too much light kills neutrophils and damages host tissue as well as bacteria and allows bacteria to grow unimpeded by host defense.
authors.affiliation: Department of Orthopedic Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Tanaka
authors.forename: Manabu
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshihara
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
authors.forename: Shuhji
authors.initials: S
authors.lastname: Seki
authors.forename: Koichi
authors.initials: K
authors.lastname: Nemoto
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hamblin
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy; D001170:Arthritis, Infectious / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy; D017323:Dihematoporphyrin Ether / Q000008:administration & dosage / Q000627:therapeutic use*; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D006414:Hematoporphyrin Photoradiation; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000276:immunology / Q000473:pathology*; D054023:Lasers, Semiconductor / Q000627:therapeutic use; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism*; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy; D013582:Synovial Fluid / Q000276:immunology / Q000382:microbiology
chemical_list: D017319:Photosensitizing Agents; D017323:Dihematoporphyrin Ether