Plasma fluoride levels tied to voriconazole-induced periostitis

LAS VEGAS – Check fluoride levels in patients on long-term voriconazole who present with new-onset bone pain, researchers at St. Joseph Mercy Hospital in Ann Arbor, Mich., advised after a retrospective investigation of 28 patients who were on the antifungal for a couple of months.

Plasma fluoride levels above 8 micromol/L are 95% sensitive (95% CI, 0.76-0.99) and 100% specific (95% CI, 0.59-1.0) for periostitis triggered by the fluorine atoms in the voriconazole molecule. Stopping the antifungal – or switching to one that does not contain fluorine, like itraconazole – is likely to clear the bone pain in a few weeks or months.

If bone scans can’t be ordered – or are too expensive – in voriconazole patients with skeletal pain, "getting a fluoride level is worthwhile. It’s much cheaper, and is very predictive" for voriconazole periostitis, said lead investigator Dr. Woo Moon of St. Joseph’s.

"One hundred percent of the patients who had periostitis had either involvement of the rib or ulna, and both in almost half of the cases," he said, noting that this is puzzling because previous reports of fluoride periostitis have been in the lower extremities.

The findings come in the wake of CNS fungal infections and abscesses caused by contaminated methylprednisolone injections in 2012 and 2013; 195 patients were treated at the hospital with voriconazole, as suggested by the Centers for Disease Control & Prevention because of the drug’s superior CNS penetration and activity against suspected pathogens.

Up to 59 patients (30%) reported pain in the ribs and arms after a couple months of treatment. The current investigation involved the 28 adult patients who had both fluoride level measurements and full-body scans to check for periostitis.

Plasma fluoride levels were significantly higher in the 21 (75%) who turned out to have periostitis (12.78 vs. 3.61 micromol/L, P less than .001). They were also on significantly higher doses of voriconazole (780 vs. 450 mg/day; P less than .001) and had significantly higher serum alkaline phosphatase levels (273 vs. 117 IU/L; P = .02). There were no differences in alanine transaminase, bilirubin, or creatinine levels.

Pain "improved dramatically" from 2 weeks to 5 months after discontinuation in 17 of the 19 (89%) patients who had pain outcomes noted in their records. Pain did not improve in the two others, Dr. Moon said at the annual meeting of the Society of Hospital Medicine.

Each molecule of voriconazole contains three fluorine atoms. At the recommended maintenance dose of 200 mg twice daily, "you’re taking in 65 mg of fluoride per day, 15 times the United States Department of Agriculture’s daily allowance," he said.

Voriconazole periostitis has been reported before in case studies and small series. However, because of the rib and ulna involvement, quick resolution after discontinuation, and strong predictive value of fluoride measurements, "we thought it was worthwhile to report our findings," he said.

Dr. Moon said she has no relevant financial disclosures, and the work received no outside funding.

[email protected]

LAS VEGAS – Check fluoride levels in patients on long-term voriconazole who present with new-onset bone pain, researchers at St. Joseph Mercy Hospital in Ann Arbor, Mich., advised after a retrospective investigation of 28 patients who were on the antifungal for a couple of months.

Plasma fluoride levels above 8 micromol/L are 95% sensitive (95% CI, 0.76-0.99) and 100% specific (95% CI, 0.59-1.0) for periostitis triggered by the fluorine atoms in the voriconazole molecule. Stopping the antifungal – or switching to one that does not contain fluorine, like itraconazole – is likely to clear the bone pain in a few weeks or months.

If bone scans can’t be ordered – or are too expensive – in voriconazole patients with skeletal pain, "getting a fluoride level is worthwhile. It’s much cheaper, and is very predictive" for voriconazole periostitis, said lead investigator Dr. Woo Moon of St. Joseph’s.

"One hundred percent of the patients who had periostitis had either involvement of the rib or ulna, and both in almost half of the cases," he said, noting that this is puzzling because previous reports of fluoride periostitis have been in the lower extremities.

The findings come in the wake of CNS fungal infections and abscesses caused by contaminated methylprednisolone injections in 2012 and 2013; 195 patients were treated at the hospital with voriconazole, as suggested by the Centers for Disease Control & Prevention because of the drug’s superior CNS penetration and activity against suspected pathogens.

Up to 59 patients (30%) reported pain in the ribs and arms after a couple months of treatment. The current investigation involved the 28 adult patients who had both fluoride level measurements and full-body scans to check for periostitis.

Plasma fluoride levels were significantly higher in the 21 (75%) who turned out to have periostitis (12.78 vs. 3.61 micromol/L, P less than .001). They were also on significantly higher doses of voriconazole (780 vs. 450 mg/day; P less than .001) and had significantly higher serum alkaline phosphatase levels (273 vs. 117 IU/L; P = .02). There were no differences in alanine transaminase, bilirubin, or creatinine levels.

Pain "improved dramatically" from 2 weeks to 5 months after discontinuation in 17 of the 19 (89%) patients who had pain outcomes noted in their records. Pain did not improve in the two others, Dr. Moon said at the annual meeting of the Society of Hospital Medicine.

Each molecule of voriconazole contains three fluorine atoms. At the recommended maintenance dose of 200 mg twice daily, "you’re taking in 65 mg of fluoride per day, 15 times the United States Department of Agriculture’s daily allowance," he said.

Voriconazole periostitis has been reported before in case studies and small series. However, because of the rib and ulna involvement, quick resolution after discontinuation, and strong predictive value of fluoride measurements, "we thought it was worthwhile to report our findings," he said.

Dr. Moon said she has no relevant financial disclosures, and the work received no outside funding.

[email protected]

LAS VEGAS – Check fluoride levels in patients on long-term voriconazole who present with new-onset bone pain, researchers at St. Joseph Mercy Hospital in Ann Arbor, Mich., advised after a retrospective investigation of 28 patients who were on the antifungal for a couple of months.

Plasma fluoride levels above 8 micromol/L are 95% sensitive (95% CI, 0.76-0.99) and 100% specific (95% CI, 0.59-1.0) for periostitis triggered by the fluorine atoms in the voriconazole molecule. Stopping the antifungal – or switching to one that does not contain fluorine, like itraconazole – is likely to clear the bone pain in a few weeks or months.

If bone scans can’t be ordered – or are too expensive – in voriconazole patients with skeletal pain, "getting a fluoride level is worthwhile. It’s much cheaper, and is very predictive" for voriconazole periostitis, said lead investigator Dr. Woo Moon of St. Joseph’s.

"One hundred percent of the patients who had periostitis had either involvement of the rib or ulna, and both in almost half of the cases," he said, noting that this is puzzling because previous reports of fluoride periostitis have been in the lower extremities.

The findings come in the wake of CNS fungal infections and abscesses caused by contaminated methylprednisolone injections in 2012 and 2013; 195 patients were treated at the hospital with voriconazole, as suggested by the Centers for Disease Control & Prevention because of the drug’s superior CNS penetration and activity against suspected pathogens.

Up to 59 patients (30%) reported pain in the ribs and arms after a couple months of treatment. The current investigation involved the 28 adult patients who had both fluoride level measurements and full-body scans to check for periostitis.

Plasma fluoride levels were significantly higher in the 21 (75%) who turned out to have periostitis (12.78 vs. 3.61 micromol/L, P less than .001). They were also on significantly higher doses of voriconazole (780 vs. 450 mg/day; P less than .001) and had significantly higher serum alkaline phosphatase levels (273 vs. 117 IU/L; P = .02). There were no differences in alanine transaminase, bilirubin, or creatinine levels.

Pain "improved dramatically" from 2 weeks to 5 months after discontinuation in 17 of the 19 (89%) patients who had pain outcomes noted in their records. Pain did not improve in the two others, Dr. Moon said at the annual meeting of the Society of Hospital Medicine.

Each molecule of voriconazole contains three fluorine atoms. At the recommended maintenance dose of 200 mg twice daily, "you’re taking in 65 mg of fluoride per day, 15 times the United States Department of Agriculture’s daily allowance," he said.

Voriconazole periostitis has been reported before in case studies and small series. However, because of the rib and ulna involvement, quick resolution after discontinuation, and strong predictive value of fluoride measurements, "we thought it was worthwhile to report our findings," he said.

Dr. Moon said she has no relevant financial disclosures, and the work received no outside funding.

[email protected]