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. 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.