Abstract
(1) Purpose of this study: determination of adsorption and transmembrane clearances (CLTM) of imipenem and relebactam in ex vivo continuous hemofiltration (CH) and continuous hemodialysis (CHD) models. These clearances were incorporated into a Monte Carlo Simulation (MCS), to develop drug dosing recommendations for critically ill patients requiring continuous renal replacement therapy (CRRT); (2) Methods: A validated ex vivo bovine blood CH and CHD model using two hemodiafilters. Imipenem/relebactam and urea CLTM at different ultrafiltrate/dialysate flow rates were evaluated in both CH and CHD. MCS was performed to determine dose recommendations for patients receiving CRRT; (3) Results: Neither imipenem nor relebactam adsorbed to the CRRT apparatus. The CLTM of imipenem, relebactam, and urea approximated the effluent rates (ultrafiltrate/dialysate flow rates). The types of hemodiafilter and effluent rates did not influence CLTM except in a dialysis flow rate of 1 L/h and 6 L/h in the CHD with relebactam (p < 0.05). Imipenem and relebactam 200 mg/100 mg every 6 h were sufficient to meet the standard time above the MIC pharmacodynamic targets in the modeled CRRT regimen of 25 kg/mL/h. (4) Conclusions: Imipenem and relebactam are not removed by adsorption to the CRRT apparatus, but readily cross the hemodiafilter membrane in CH and CHD. Dosage adjustment of imipenem/relebactam is likely required for critically ill patients receiving CRRT.
Highlights
Introduction published maps and institutional affilImipenem/relebactam, a novel combination of carbapenem/dehydropeptidase and beta-lactamase inhibitor, has demonstrated activity against multi-drug resistant (MDR)strains of P. aeruginosa and many Klebsiella pneumoniae carbapenemases (KPC)-producingEnterobacteriaceae in previous in vitro studies [1,2,3]
Neither imipenem nor relebactam adsorption was observed with either hemodiafilter type
The CLTM were dependent on the dialysate flow rate during continuous hemodialysis (CHD) (Figure 2a,b)
Summary
Introduction published maps and institutional affilImipenem/relebactam, a novel combination of carbapenem/dehydropeptidase and beta-lactamase inhibitor, has demonstrated activity against multi-drug resistant (MDR)strains of P. aeruginosa and many Klebsiella pneumoniae carbapenemases (KPC)-producingEnterobacteriaceae in previous in vitro studies [1,2,3]. Strains of P. aeruginosa and many Klebsiella pneumoniae carbapenemases (KPC)-producing. The emergence of MDR pathogens such as P. aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp. limit the use of many antibiotic agents [4], because antibiotics are generally not effective against these pathogens [5]. The pharmacokinetics of imipenem/cilastatin in critically ill patients receiving CRRT have been previously studied [6,7,8,9]. There are no published imipenem/relebactam pharmacokinetic data from critically ill patients receiving CRRT. Clearance by adsorption must be considered, since drugs, such as colistin, can adsorb to the CRRT apparatus [10,11]. The purpose of this study was to determine adsorption and transmembrane clearances (CLTM ) of imipenem and relebactam in ex vivo iations
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