Are dose adjustments of linezolid necessary when treating a patient with continuous renal replaceme

Fråga: Are dose adjustments of linezolid necessary when treating a patient with continuous renal replacement therapy?

The question relates to a patient being treated with linezolid (Zyvoxid) due to Staphylococcus aureus sepsis. Renal replacement therapy in the form of continuous venovenous hemodiafiltration (CVVHD) has been started and the effect of linezolid is considered non-sufficient.

Sammanfattning: Linezolid is eliminated during continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHD), however, data is sparse. Total and renal clearance has in most patients been in the same range as in studies with healthy volunteers. Usually dose adjustment is not considered necessary but close monitoring of the patient is recommended. Through concentrations below the MIC for certain species may appear in some patients. Since therapeutic drug monitoring of linezolid is not currently available, dosing three times daily in patients with a severe infection and insufficient effect can be tried.

Svar: Linezolid is a synthetic antibacterial of a new class of antibiotics, oxazolidones. It has inhibitory activity against a broad range of Gram-positive bacteria, including Staphylococcus aureus, and some Gram-negative bacteria and anaerobic microorganisms (1). The in vitro activity of linezolid has been assessed using the minimum inhibitory concentration (MIC) required to inhibit bacterial growth. The breakpoint concentration for linezolid against susceptible pathogens suggests that Staphylococcus species have a MIC of < 4 mg/l (2). Linezolid exhibits time dependent antibacterial activity, so the time during which plasma concentration persists over MIC has been considered the major determinant of efficacy (t > MIC) (3).

Linezolid has a low molecular weight (337 D), low plasma protein binding (30%) and a moderately large volume of distribution (40-50 L), and is expected to be cleared by dialysis. Fifty percent of the dose is metabolised into two inactive metabolites and approximately 35% is excreted in the urine as unchanged drug. The total systemic clearance of linezolid is 100-200 ml/min, the renal clearance is 30-50 ml/min and it has a half-life of 5-7 hours in healthy volunteers (4).

Linezolid is generally a well tolerated drug. However, thrombocytopenia has beeen reported in patients receiving linezolid. Thrombocytopenia in connection to linezolid treatment appears to be dependent on the duration of therapy, and generally occurs after two weeks of treatment, and platelet counts return to the normal range after discontinuation of therapy (2).

Approximately 30% of the administered dose of linezolid is removed by a three-hour hemodialysis session. The manufacturer recommends that linezolid should be administered after the dialysis during intermittent hemodialysis (1). No recommendations are available for the use of linezolid during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHD), but a few studies and case reports in critically ill patients have been published.

In the first study twenty anuric patients received linezolid at a standard dose (600 mg every 12 hours). Due to clotting of the hemofilter and other diagnostic and therapeutic procedures, only eight patients completed the study period of 72 hours. The total clearance was in average 155 ml/min and the through concentration was 1.9 mg/l. Calculating the t > MIC in these CVVH patients, the standard dose regimen resulted in a percent t > MIC of 57+/-32% for pathogens with a MIC up to 4 mg/l. Dose escalation might therefore be needed in certain cases to achieve maximal antibacterial activity (5). In the other study, 15 patients had renal replacement therapy, and two of these underwent a single session of CVVH (10.5 and 12 hours, respectively). In these patients, CVVH clearance was 19.3 ml/min and 21.4 ml/min, respectively, and 12-18% of the dose was removed by the diafiltrate. However, at the end of the session, the antibiotic level was < 4 mg/L in both patients on CVVH (1.35 and 3.98 mg/l, respectively) (6).

In a publication, two critically ill patients received linezolid at a standard dose. Linezolid total clearance was 30 ml/min and 91 ml/min and clearance through CVVH was 21 ml/min and 26 ml/min, respectively. In both patients the plasma through levels were higher than the MIC (21.7 and 6.5 mg/L, respectively). Despite potential overexposure in the first patient, no severe linezolid related toxicity was observed (3). In another case report a critically ill patient received intravenous linezolid at a standard dose, and thereafter CVVHD was applied for 27 days. A total clearance of 87 ml/min, a clearance through CVVHD of 36.5 ml/min and a half-life 7.5 hours were calculated. His through concentrations were measured twice (7.2 and 6.2 mg/l), suggesting concentrations well above the MIC during the CVVHD (7). Finally, one patient received CVVHD and initiated linezolid at standard dose. He had total clearance of 187 ml/min and a clearance of linezolid through CVVHD of 22 ml/min (8). Zyvoxid. Summary of product characteristics (SPC). Pfizer. Perry CM, Jarvis B. Linezolid. A review of its use in the management of serious gram-positive infections. Drugs 2001;61(4):525-51. 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(6):1097-1102. Stalker DJ, Jungbluth GL. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet 2003;42(13):1129-40. Meyer B, Kornek GV, Nikfardjam M, Karth GD, Heinz G, Locker GJ et al. Multiple-dose pharmacokinetics of linezolid during continous venovenous hemofiltration. J Antimicrob Chemother 2005;56:172-9. Fiaccadori E, Maggiore U, Rotelli C, Giacosa R, Parenti E, Picetti E et al. Removal of linezolid by conventional intermittent hemodialysis, sustained low-efficiency dialysis, or continuous venovenous hemofiltration in patients with acute renal failure. Crit Care Med 2004;32:2437-42. Kraft MD, Pasko DA, DePestel DD, Ellis JJ, Peloquin CA, Mueller BA. Linezolid clearance during continuous venovenous hemodiafiltration: a case report. Pharmacotherapy 2003;23(8):1071-5. Mauro LS, Peloquin CA, Schmide K, Assaly R, Malhotra D. Clearance of linezolid via continuous venovenous hemodiafiltration. Am J Kidney Dis 2006;47(6):E83-6.