title: Voriconazole is cytotoxic at locally delivered concentrations: a pilot study.
abstract: BACKGROUND
  Fungal infections are rare but major problems when they involve orthopaedic implants. Preferred treatment in North America is two-staged: resection and then delayed reconstruction, with local delivery of an antifungal between stages. The effect of voriconazole, a hydrophobic antifungal, on local tissues and wound healing is unclear.
  
  
  OBJECTIVE
  We asked: (1) Is voriconazole cytotoxic to fibroblasts or osteoblasts at target concentrations for local delivery? And (2) if cytotoxic, can fibroblasts or osteoblasts resume proliferation after voriconazole is removed?
  
  
  METHODS
  We exposed 5000 fibroblasts or osteoblasts/well to voriconazole concentrations of 0, 1, 5, 10, 25, 100, 500, 1000, 5000, 10,000, and 20,000 μg/mL (n=4 wells/concentration) in 24-well plates. At 3 and 7 days, cell growth was assessed with alamarBlue® and light microscopy. After Day 7, exposure to voriconazole was stopped and incubation continued for 4 days in medium with no voriconazole. On Day 11, cell growth (recovery) was assessed with alamarBlue® and light microscopy.
  
  
  RESULTS
  Increasing voriconazole concentration to more than 100 μg/mL decreased osteoblast and fibroblast growth. Cell growth recovered after 7 days' exposure to 1000 μg/mL or less.
  
  
  CONCLUSIONS
  Voriconazole is cytotoxic to osteoblasts and fibroblasts, but cell growth recovers over 4 days after exposure to 1000 μg/mL or less.
  
  
  CONCLUSIONS
  Cytotoxicity seen from voriconazole to mouse osteoblasts and fibroblasts occurs at concentrations achievable clinically from local delivery. It may be prudent to limit the dose of voriconazole in antibiotic-loaded bone cement.
authors: Banner Good Samaritan Medical Center, Orthopaedic Residency, 901 E Willetta Street, 2nd Floor, Phoenix, AZ, 85006, USA.
authors: Kenneth
authors: K
authors: Schmidt
authors: Alex
authors: A
authors: McLaren
authors: Christine
authors: C
authors: Pauken
authors: Ryan
authors: R
authors: McLemore
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects*; D051379:Mice; D009181:Mycoses / Q000188:drug therapy; D010006:Osteoblasts / Q000187:drug effects*; D010865:Pilot Projects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use; D014230:Triazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole