Discussion
We described a case of an accidental 20-fold overdose with amphotericin B DOC due to a medication error in a critically ill patient. The patient developed shock, anemia, thrombocytopenia, renal failure, acidosis and hepatic failure. She was treated with supportive care, plasmapheresis and CVVHDF and made a full recovery. In this case report, we reported the pharmacokinetics of amphotericin B extensively, demonstrating a significant shorter half-life than described in literature (49 hours versus 15 days), without the use of extracorporeal elimination techniques [7,8]. The half-life only marginally decreased to 42 hours with plasmapheresis, with two of the three plasmapheresis sessions demonstrated a decrease in amphotericin B serum levels.
A PubMed search using the terms ‘amphotericin B’ and ‘overdose’ revealed nine case reports with 11 pediatric and four adult patients (table 1) [3-6,9-13]. The case reports demonstrate a high mortality rate: only five patients survived the overdose. Of the adult patients, two case reports documented fatal outcomes without plasmapheresis [3,4]. Conversely, two case reports in adults with plasmapheresis reported positive outcomes [5,6]. However, it is worth noting that the amphotericin B DOC overdose in the non-plasmapheresis patients was twice as high as in the plasmapheresis treated patients, which likely contributed to the fatal outcomes. Moreover, pharmacokinetics of amphotericin B were hardly described in these case reports, making it difficult to isolate the sole effect of plasmapheresis.
Little is known about the pharmacokinetics of amphotericin B. After introduction into the intravascular compartment, amphotericin is quickly distributed into the extravascular compartment, followed by a longer equilibrium period [1,14]. Trough concentrations are reached in 24 hours [5]. Amphotericin B has no known metabolites. Amphotericin B undergoes biphasic elimination with a terminal half-life of up to 15 days, which is originally only reported in two adult patients [7,8]. The primary route of elimination is not known. Serum levels are not influenced by hepatic or renal failure [14]. Due to its substantial size (924 Da), high protein binding, lipophilic nature, and large volume of distribution (approximately 4 L/kg), Amphotericin B is deemed unsuitable for dialysis, including CVVHDF [14]. Plasmapheresis can be used to eliminate drugs that are too large and have a high rate of protein binding [14]. However, plasmapheresis is a high-risk procedure, with risks of hypocalcemia, metabolic alkalosis and coagulation deficits. Because of the toxic characteristics of amphotericin B, the reported long half-life of the drug, and earlier case reports of similar medication errors with deadly outcome, plasmapheresis was recommended upon the discovery of the medication error, four days after its occurrence. Drug levels of amphotericin B were monitored extensively pre- and post-plasmapheresis using Ultra Performance Liquid Chromatography with Diode-Array Detection (UPLC-DAD).
Irrespective of plasmapheresis, our patient may have survived the accidental overdose of amphotericin B for several reasons. Unlike the majority of reported cases where young children were involved (9 out of 13 cases), our patient was older. Additionally, our patient received a lower cumulative dose of amphotericin B DOC (5 mg/kg), whereas the majority of cases (8 out of 15) involved either doses exceeding 5 mg/kg or multiple overdoses. Remarkably, the first amphotericin B serum concentration, 50 hours after the medication error, was 1.32 µg/ml, and already within the therapeutic range (reference range 1.2 – 2.4 µg/ml) [1]. Instead of the half-life of 15 days previously documented in case reports, the mean half-life of amphotericin B in our patient pre-plasmapheresis was 49 hours, but fluctuated significantly, which may indicate biphasic elimination. Plasmapheresis may have enhanced the elimination of amphotericin B as the mean half-life decreased to 42 hours, also with great fluctuation. It is questionable whether the patient would have also recovered without plasmapheresis.
Due to the potential confusion regarding L-AmB and amphotericin B DOC administration, our institution has taken action. As a result of recommendations of a root cause analysis, amphotericin B DOC was banned from our hospital. Only L-AmB is now available.