Case study
A 62-year old woman with a recent history of an aneurysmal subarachnoid hemorrhage with an extraventricular drain (EVD) as treatment for hydrocephalus was admitted to the intensive care unit (ICU) for suspected ventriculitis. Upon arrival to the ICU, the patient had a low Glasgow Coma Scale (GCS) score of 6 and a fever of 400C, blood pressure was 190/80 mm Hg, heart rate 107 beats/min. Further physical examination was without abnormalities. Initial laboratory results revealed serum leukocytes of 13.8 x 109/l. A previous liquor culture was positive forAcinobacter baumanni spp.. She had to be intubated and mechanically ventilated due to her low GCS. The EVD was removed and she was treated with 3000 mg meropenem daily for 14 days. An external lumbar drain was placed 24 hours later. Her GCS did improve to E4M6V4 and she could be extubated after 10 days in the ICU. Two days later, a subsequent liquor culture became positive for Candida albicansspecies, raising suspicion of a ventricular fungal coinfection, for which L-AmB 5mg/kg once-daily and flucytosine 25 mg/kg four times daily was started after consultation with the clinical microbiologist. She received a first dose of 465 mg L-AmB and flucytosine 2330 mg. The next day, the patient inadvertently received the same dose amphotericin B DOC intravenously over 60 minutes instead of the prescribed L-AmB. She reported abdominal pain and general malaise within two hours. She was vomiting and in respiratory distress, had a fever of 39.5oC, her GCS dropped to E4M6V2 and systolic blood pressure dropped below 100 mmHg. She was in shock, had to be re-intubated and mechanical ventilation, fluid infusion, vasopressors and inotropics had to be started. Laboratory results revealed anemia (Hemoglobin 3.9 mmol/L, mean corpuscular volume 90), thrombocytopenia (platelets 138 x 109/L), acidosis (serum pH 7.16, bicarbonate 16 mmol/L, lactate 12.7 mmol/L), renal failure (serum creatinine 167 µmol/L, urea 12.3 mmol/L) and hepatic failure (serum aspartate aminotransferase 710 mmol/L, alanine aminotransferase 371 mmol/L) within 24 hours. As usual causes for new onset clinical deterioration, such as sepsis, were considered unlikely due to the clinical course, an adverse drug reaction was therefore suspected and antifungal medication was immediately discontinued. We performed an extensive medication review, and discovered the medication error in four days. Upon the discovery of the medication error, plasmapheresis was started as amphotericin B DOC has a half-life of 15 days, assuming toxic levels were still present. Her plasma was calculated at 5 L. Three plasmapheresis sessions with a substitution volume of 5000 mL per session were done over a time course of three days. The serum amphotericin B concentration was 1.32 µg/mL 50 hours after the amphotericin B DOC administration and dropped to 0.85, 0.68 and 0.62 µg/mL at t = 72, 93 and 103 hours after the amphotericin B DOC dose, respectively (Figure 1), without the use of extracorporeal elimination techniques. The half-life was 35, 65 and 75 hours between t = 50 - 72 hours, t = 72 - 93 hours and t = 93 - 103 hours after dose. The mean half-life in the first 103 hours after administration was 49 hour and slightly increased over time. Serum concentrations amphotericin B further dropped to 0.48 and 0.26 µg/mL after the first and second plasmapheresis sessions (t = 111 and 124 hours after dose), demonstrating a half-life of 17 hours. Consequently, amphotericin B redistributed modestly from tissue to serum with an increase in amphotericin B concentration to 0.28 µg/mL (t = 144 hours). The third plasmapheresis had no effect on serum concentration (0.29 µg/mL at t = 149 hours). Over the entire course of plasmapheresis sessions, the amphotericin B half-life was 42 hours. Following plasmapheresis, the patient required CVVHDF therapy for renal failure for five days, which had no effect on amphotericin B serum levels. She remained hemodynamically stable during her time in the ICU. She was extubated 20 days after the erroneous dose and was subsequently discharged to the general ward 24 days after the medication error, where she made a full recovery.