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.