Voriconazole is cytotoxic at locally delivered concentrations: a pilot study.

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. QUESTIONS/PURPOSES: 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. CLINICAL RELEVANCE: 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.