Background/Aims: To study transmembrane clearance (CLTM) and adsorption of tedizolid, a novel oxazolidinone antibiotic, in continuous hemofiltration (CVVH) and continuous hemodialysis (CVVHD). Methods: In vitro CVVH/CVVHD models with polysulfone and AN69 hemodiafilters were used. Tedizolid CLTM during CVVH/CVVHD was assessed at various ultrafiltrate (Quf) and dialysate rates (Qd). Tedizolid adsorption was tested in a recirculating CVVH model over 4 h. Results: In CVVH, CLTM did not differ between filter types. In CVVHD, tedizolid CLTM was significantly higher with the polysulfone hemodiafilter at Qd 6 l/h (p < 0.02). Tedizolid exhibited irreversible adsorption to the CRRT apparatus and bound significantly higher to the polysulfone hemodiafilter. Conclusion: Tedizolid's CLTM is dependent on Qd, Quf, and hemodiafilter type. At conventional CRRT rates, tedizolid CLTM appears modest relative to total body clearance and is unlikely to require dose adjustments. CRRT adsorption in the clinical setting is likely less than what we observed in this in vitro, continuously recirculating blood model.

1.
SIVEXTRO® (tedizolid phosphate): SIVEXTRO Prescribing Information. Lexington, MA, Cubist Pharmaceuticals, 2014.
2.
Ong V, Flanagan S, Fang E, Dreskin HJ, Locke JB, Bartizal K, Prokocimer P: Absorption, distribution, metabolism, and excretion of the novel antibacterial prodrug tedizolid phosphate. Drug Metab Dispos 2014;42:1275-1284.
3.
Kanafani ZA, Corey GR: Tedizolid (TR-701): a new oxazolidinone with enhanced potency. Expert Opin Investig Drugs 2012;21:515-522.
4.
Prokocimer P, De Anda C, Fang E, Mehra P, Das A: Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trials. JAMA 2013;309:559-569.
5.
Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P: Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2014;14:696-705.
6.
Flanagan S, Minassian SL, Morris D, Ponnuraj R, Marbury TC, Alcorn HW, Fang E, Prokocimer P: Pharmacokinetics of tedizolid in subjects with renal or hepatic impairment. Antimicrob Agents Chemother 2014;58:6471-6476.
7.
Choi G, Gomersall CD, Lipman J, Wong A, Joynt GM, Leung P, Ramsay SJ, Ho OM: The effect of adsorption, filter material and point of dilution on antibiotic elimination by haemofiltration an in vitro study of levofloxacin. Int J Antimicrob Agents 2004;24:468-472.
8.
Churchwell MD, Pasko DA, Mueller BA: Daptomycin clearance during modeled continuous renal replacement therapy. Blood Purif 2006;24:548-554.
9.
Stevenson JM, Patel JH, Churchwell MD, Vilay AM, DePestel DD, Sörgel F, Kinzig M, Jakob V, Mueller BA: Ertapenem clearance during modeled continuous renal replacement therapy. Int J Artif Organs 2008;31:1027-1034.
10.
Tian Q, Gomersall CD, Ip M, Tan PE, Joynt GM, Choi GY: Adsorption of amikacin, a significant mechanism of elimination by hemofiltration. Antimicrob Agents Chemother 2008;52:1009-1013.
11.
Vilay AM, Shah KH, Churchwell MD, Patel JH, DePestel DD, Mueller BA: Modeled dalbavancin transmembrane clearance during intermittent and continuous renal replacement therapies. Blood Purif 2010;30:37-43.
12.
Flanagan SD, Bien PA, Muñoz KA, Minassian SL, Prokocimer PG: Pharmacokinetics of tedizolid following oral administration: single and multiple dose, effect of food, and comparison of two solid forms of the prodrug. Pharmacotherapy 2014;34:240-250.
13.
Flanagan S, Fang E, Muñoz KA, Minassian SL, Prokocimer PG: Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid. Pharmacotherapy 2014;34:891-900.
14.
Schetz M: Drug dosing in continuous renal replacement therapy: general rules. Curr Opin Crit Care 2007;13:645-651.
15.
Matzke GR, Frye RF, Joy MS, Palevsky PM: Determinants of ceftriaxone clearance by continuous venovenous hemofiltration and hemodialysis. Pharmacotherapy 2000;20:635-643.
16.
Golper TA: Update on drug sieving coefficients and dosing adjustments during continuous renal replacement therapies. Contrib Nephrol 2001;132:349-353.
17.
Fuhrmann V, Schenk P, Mittermayer C, El menyawi I, Ratheiser K, Thalhammer F: Single-dose pharmacokinetics of ofloxacin during continuous venovenous hemofiltration in critical care patients. Am J Kidney Dis 2003;42:310-314.
18.
Bouman CS, van Kan HJ, Koopmans RP, Korevaar JC, Schultz MJ, Vroom MB: Discrepancies between observed and predicted continuous venovenous hemofiltration removal of antimicrobial agents in critically ill patients and the effects on dosing. Intensive Care Med 2006;32:2013-2019.
19.
SAFE Study Investigators, Finfer S, Bellomo R, McEvoy S, Lo SK, Myburgh J, Neal B, Norton R: Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ 2006;333:1044.
20.
Eyler RF, Vilay AM, Nader AM, Heung M, Pleva M, Sowinski KM, DePestel DD, Sörgel F, Kinzig M, Mueller BA: Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration. Antimicrob Agents Chemother 2014;58:1320-1326.
21.
INVANZ® (ertapenem): INVANZ Prescribing Information. Whitehouse, NJ, Merck & Co., Inc., 2014.
22.
Yamamoto T, Yasuno N, Katada S, Hisaka A, Hanafusa N, Noiri E, Yahagi N, Fujita T, Suzuki H: Proposal of a pharmacokinetically optimized dosage regimen of antibiotics in patients receiving continuous hemodiafiltration. Antimicrob Agents Chemother 2011;55:5804-5812.
23.
Markou N, Fousteri M, Markantonis SL, Zidianakis B, Hroni D, Boutzouka E, Baltopoulos G: Colistin pharmacokinetics in intensive care unit patients on continuous venovenous haemodiafiltration: an observational study. J Antimicrob Chemother 2012;67:2459-2462.
24.
Ricci Z, Ronco C, D'Amico G, De Felice R, Rossi S, Bolgan I, Bonello M, Zamperetti N, Petras D, Salvatori G, Dan M, Piccinni P: Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. Nephrol Dial Transplant 2006;21:690-696.
25.
Levy G: Pharmacokinetics in renal disease. Am J Med 1977;62:461-465.
26.
Kraft MD, Pasko DA, DePestel DD, Ellis JJ, Peloquin CA, Mueller BA: Linezolid clearance during continuous venovenous hemodiafiltration: a case report. Pharmacotherapy 2003;23:1071-1075.
27.
Pea F, Viale P, Lugano M, Pavan F, Scudeller L, Della Rocca G, Furlanut M: Linezolid disposition after standard dosages in critically ill patients undergoing continuous venovenous hemofiltration: a report of 2 cases. Am J Kidney Dis 2004;44:1097-1102.
28.
Meyer B, Kornek GV, Nikfardjam M, Karth GD, Heinz G, Locker GJ, Jaeger W, Thalhammer F: Multiple-dose pharmacokinetics of linezolid during continuous venovenous haemofiltration. J Antimicrob Chemother 2005;56:172-179.
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