Flucloxacillin Results in Suboptimal Plasma Voriconazole Concentrations

Abstract

Combining voriconazole and flucloxacillin is indicated in patient cohorts experiencing both invasive aspergillosis and Gram-positive infections (e.g., patients with chronic granulomatous disease or postinfluenza pulmonary aspergillosis). We report a highly relevant interaction between voriconazole and flucloxacillin, resulting in subtherapeutic plasma voriconazole concentrations in more than 50% of patients, that poses a severe threat if not managed properly.

Keywords: aspergillosis; drug interactions; exposure; influenza; pharmacokinetics.

FIG 1

Plasma voriconazole concentrations impacted by flucloxacillin, showing the day of flucloxacillin treatment on the x axis, flucloxacillin and voriconazole doses on the left y axis, and plasma voriconazole concentrations on the right y axis. A 12-year-old girl with relapsed acute lymphatic leukemia received flucloxacillin at 12 g/day (226 mg/kg/day) for Staphylococcus aureus sepsis and was started at 5 days after flucloxacillin initiation on voriconazole at 12 mg/kg/day for proven pulmonary and possible cerebral aspergillosis. Plasma voriconazole concentrations were routinely monitored and were extremely low on days 3, 6, 9, and 12 of voriconazole therapy (range, undetectable to 0.142 mg/liter) despite dose increases to 18 and 24 mg/kg/day. Voriconazole therapy was discontinued and switched to liposomal amphotericin B. Restart of voriconazole at 18 mg/kg/day on day 73 of flucloxacillin treatment did not lead to therapeutic voriconazole concentrations. Therefore, posaconazole was administered instead. Two weeks after discontinuation of flucloxacillin, posaconazole was switched back to voriconazole at 18 mg/kg/day, leading to adequate plasma voriconazole concentrations. A plasma voriconazole concentration increase to 7.3 mg/liter required a voriconazole dose reduction to 12 mg/kg/day. Rechallenge with a single dose of flucloxacillin again resulted in subtherapeutic plasma voriconazole concentrations.