Introduction
Thrombotic Thrombocytopenic Purpura
(TTP) is a type of thrombotic microangiopathy, whose typical clinical
manifestations include severe thrombocytopenic purpura, microangiopathic
hemolytic anemia, neuropsychiatric symptoms, occasionally fever or renal
damage. The main pathogenesis of TTP is associated with severe
deficiency of ADAMTS-13 (von
Willebrand factor-cleaving protease). TTP is considered as
a rare and life-threatening
hematologic critical illness with a mortality rate of up to 10 to 20
percent, even if diagnosed timely and treated properly. Currently, the
first-line treatment for the acute episode of TTP is based on daily
therapeutic plasma exchange (TPE).
TPE is a therapeutic apheresis procedure for removal of pathologic
substances, including anti-ADAMTS-13 antibodies, ADAMTS-13 immune
complexes, and ultra-large VWF multimers. The replacement fluid is
usually a large volume of fresh-frozen plasma containing ADAMTS-13, in
order to maintain oncotic pressure and compensate for blood loss
[1]. The application of TPE has greatly reduced the mortality of TTP
patients and should be started as soon as possible.
The basic procedure for TPE can be
performed through a highly permeable microporous filter with
hemodialysis equipment or centrifugation with an apheresis device.
According to the guidelines, one exchange procedure requires the
replacement of approximately 1 to 1.5 plasma volume (PV) [2,3].
Similar to the mechanisms by which TPE clears pathologic substances,
drugs that do not bind to proteins are more likely to be cleared from
plasma compartment, resulting in sub-therapeutic doses and may affect
therapeutic efficacy. The amount of drug eliminated by TPE is determined
by pharmacokinetic properties of the drug and TPE-specific factors, such
as the time between initiation of TPE and infusion of drug; plasma
exchanged volume and TPE procedure frequency. The pharmacokinetic
properties, especially volume of distribution (Vd) and protein binding
(Pb), were considered to be the most dominant factors in determining
whether a drug is susceptible to removal by TPE [7]. Drugs that
exhibit a higher Pb (>80%) and smaller Vd (<0.2
L kg-1) are more
likely to be eliminated by TPE [5,6,7]. Amphotericin B liposomal,
for instance, with a small Vd (0.1-0.16 L kg-1) and
high Pb (95%) can be significantly removed by TPE.
A study has shown that
supplemental doses are needed after
TPE as therapeutic concentration fell below minimum inhibitory
concentration [8].
Patients with critically ill TTP are often at high risk for
multiple nosocomial infections and need to be treated with a
combination of antibiotics during TPE in the intensive care unit (ICU).
Beta-lactam antibiotics present similar pharmacokinetic properties and
are widely used in current clinical practice. Most β-lactam antibiotics
including ceftazidime, cefepime, and ampicillin showed poor removal by
TPE [9, 10].
Cefoperazone/sulbactam
(CFP/SUL)
is a combination
containing extended spectrum
beta-lactamases (ESBL) inhibitor antibiotic widely used for the
treatment of complicated several bacterial infections, such as
extended-spectrum β-lactamase producing Enterobacteriaceae and
carbapenem resistant Acinetobacter baumannii. Cefoperazone is highly
protein bound (70-93%) with an average Vd of 0.28L
kg-1 and a T1/2 of 1.7 hours, while
sulbactam has a low Pb of 40%, a small Vd of 0.14L
kg-1, and T1/2 of 1 hour in subjects
with normal renal and hepatic function. TPE has the potential to remove
a certain amount of CFP or SUL. To the best of our knowledge, no
information is available about the amount of CFP and SUL removed or
pharmacokinetics changes during TPE. This is the first report to
evaluate the effect of TPE on the pharmacokinetics of
CFP/SUL, aim to provide relevant
clinical suggestions for the optimization of antibiotic dosing regimens.