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Voriconazole-loaded beads may help treat fungal osteomyelitis
Polymethylmethacrylate and calcium sulfate bone cements released the antifungal over two weeks in an in vitro experiment.
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OTTAWA — Investigators have used polymethylmethacrylate and calcium sulfate beads in an in vitro study to deliver the antifungal drug voriconazole and treat fungal osteomyelitis. The results could pave the way for general clinical use for treating this uncommon but difficult-to-treat condition.
Christopher Grimsrud, MD, PhD, of the University of California reported study results at the Orthopaedic Trauma Association 21st Annual Meeting here. Working in the laboratory of Hubert Kim, MD, PhD, senior author of the study, Grimsrud and colleagues aimed to determine how effectively new antifungals, such as voriconazole (Vfend, Pfizer Inc.), elute from the beads. They found that voriconazole remained biologically active for two weeks, researchers said.
Earlier studies showed the successful use of polymethylmethacrylate (PMMA) and calcium sulfate beads loaded with another antifungal drug — amphotericin (Amphocin, Pfizer Inc.) — to treat deep fungal infections. And physicians have used antimicrobial beads since the 1970s to treat bacterial osteomyelitis. “They’re useful because they fill space in wounds and they also deliver high concentrations of antibiotics to the site of infection without having consequences in terms of systemic side effects,� Grimsrud said.
Amphotericin vs. voriconazole
Some physicians have used amphotericin to treat fungal osteomyelitis with no negative effects. However, the drug has the nickname “amphoterrible� because it can cause severe systemic adverse events.
Voriconazole is less toxic, has “relatively benign side effects� and is effective in treating a wide variety of fungi and yeasts, Grimsrud said. “It’s expensive but useful, primarily in treatment of resistant fungal infections,� he said.
Grimsrud and his co-authors began the study with the hypothesis that antifungals would elute from the PMMA and calcium sulfate beads in a “controlled fashion� and would remain biologically active. They mixed voriconazole and amphotericin with Palacos PMMA and Osteoset calcium sulfate, combining the antibiotics and cements in a 1:10 weight ratio. They molded beads from the mixture, placed the beads in a 2.5 ml phosphate-buffered normal saline bath at room temperature and shook them.
The researchers took samples at three, six, 12, 24 and 48 hours, one week and two weeks. They determined the beads’ antifungal concentrations by using high pressure liquid chromatography (HPLC). They gauged the samples’ bioactivities by using macrobroth dilution and plate diffusion methods, Grimsrud said.
High antifungal levels
The PMMA beads eluted very high voriconazole levels (100 µg/ml/24 hours) for the first two days. Levels decreased to 33 µg/ml/24 hours by day 14. The calcium sulfate beads also eluted high amounts of voriconazole (>100 µg/mg/24 hours) for 14 days. Antifungal levels remained high for 14 days in all cases. Bioactivity correlated with the amount of voriconazole measured by HPLC. Calcium sulfate beads eluted more voriconazole over time than PMMA beads, Grimsrud said.
The eluted antifungal killed candida, the sample yeast, in a laboratory dish at all time points, proving that the antifungal was biologically active, Grimsrud said.
“The drugs are biologically active and elute out of beads and we can then use this as the scientific basis for using the beads clinically for treating fungal osteomyelitis,� he said.
For more information:
- Grimsrud C, Raven R, Fothergill, AW, et al. Paper Session II. The in vitro elution characteristics of antifungal-loaded polymethylmethacrylate (PMMA) and calcium sulfate bone cements. Presented at the Orthopaedic Trauma Association 21st Annual Meeting. Oct. 19-22, 2005. Ottawa.