Plasma Fluoride Level as a Predictor of Voriconazole-Induced Periostitis in Patients With Skeletal Pain

Background. Voriconazole is a triazole antifungal medication used for prophylaxis or to treat invasive fungalinfections. Inflammation of the periosteum resulting in skeletal pain, known as periostitis, is a reported side effectof long-term voriconazole therapy. The trifluorinated molecular structure of voriconazole suggests a possible linkbetween excess fluoride and periostitis, as elevated blood fluoride has been reported among patients with periostitiswho received voriconazole.Methods. Two hundred sixty-four patients from Michigan were impacted by the multistate outbreak of fungalinfections as a result of contaminated methylprednisolone injections. A retrospective study was conducted among195 patients who received voriconazole therapy at St Joseph Mercy Hospital during this outbreak. Twenty-eight pa-tients who received both bone scan and plasma fluoride measurements for skeletal pain were included in the stat-istical analyses. Increased tracer uptake on bone scan was considered positive for periostitis. The primary outcomemeasure was the correlation between plasma fluoride and bone scan results.Results. Bloodfluoride(P<.001),alkalinephosphatase(P=.020),dailyvoriconazoledose(P<.001),andcumu-lative voriconazole dose (P=.027) were significantly elevated in patients who had periostitis compared with thosewho did not. Discontinuation or dose reduction of voriconazole resulted in improvement of pain in 89% of patients.Conclusions. High plasma fluoride levels coupled with skeletal pain among patients who are on long-term vor-iconazole therapy is highly suggestive of periostitis. Initial measurement of fluoride may be considered when bonescan is not readily available. Early detection should be sought, as discontinuation of voriconazole is effective at re-versing the disease.Keywords. contaminated methylprednisolone injection; fluorosis; fungal infection; periostitis; voriconazole.Contaminated methylprednisolone acetate injectionsresultedinamultistateoutbreakoffungalinfectionsbe-tween 2012 and 2013 [1–4].As of 23 October 2013, theCenters for Disease Control and Prevention (CDC)reported 751 cases in 20 states, with Michigan havingreported 264 cases [5]. Among them, 195 patientswere cared for at St Joseph Mercy Hospital (SJMH).Voriconazole was the first-line therapy recommendedby the CDC due to its excellent oral bioavailabilityand central nervous system penetration [6–10]. Visualdisturbances, skin rash, prolongation of QT interval,and hepatic enzyme elevation have been frequently ob-served among patients taking voriconazole [11–15].Periostitis, skeletal fluorosis, and exostoses have alsobeen reported [16–28].Because of itstrifluorinated mo-lecular structure, several studies have suggested a linkbetween excess fluoride intake from voriconazoletherapy and the development of periostitis [19, 25,27].Patientswho aretaking theFoodandDrugAdmin-istration–recommended voriconazole maintenancedose of 200 mg every 12 hours are consuming an aver-age of 65 mg offluoride per day [19, 27]. This is 15