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.