Linezolid and Continuous Venovenous Hemofiltration

Florian Thalhammer

Linezolid and Continuous Venovenous Hemofiltration

Florian Thalhammer

2006, Clinical Infectious Diseases

visibility

…

description

2 pages

link

1 file

a consultant to and is a member of the speakers’ bureau for Pfizer. All other authors: no conflicts. Federico Pea,1 Luigia Scudeller,2 Manuela Lugano,3 Umberto Baccarani,4 Federica Pavan,1 Marcello Tavio,2 Mario Furlanut,1 Giorgio Della Rocca,3 Fabrizio Bresadola,4 and Pierluigi Viale2 1 Institute of Clinical Pharmacology and Toxicology, Department of Experimental and Clinical Pathology and Medicine, 2Clinic of Infectious Diseases, Department of Medical and Morphological Research, and Departments of 3Anesthesiology and Intensive Care and 4Surgery and Transplantation, Medical School, University of Udine, Udine, Italy References 1. Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005; 44:1009–34. 2. Pea F, Viale P, Lugano M, et al. Linezolid disposition after standard dosages in critically ill patients undergoing continuous venovenous hemofiltration: a report of 2 cases. Am J Kidney Dis 2004; 44:1097–102. 3. Boselli E, Breilh D, Rimmele T, et al. Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. Crit Care Med 2005; 33:1529–33. 4. Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med 2003; 348:86–7. 5. Kopterides P, Papadomichelakis E, Armaganidis A. Linezolid use associated with lactic acidosis. Scand J Infect Dis 2005; 37:153–4. 6. Palenzuela L, Hahn NM, Nelson RP Jr, et al. Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis? Clin Infect Dis 2005; 40:e113–6. 7. Egle H, Trittler R, Kummerer K, Lemmen SW. Linezolid and rifampin: drug interaction contrary to expectations? Clin Pharmacol Ther 2005; 77:451–3. 8. Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 2003; 305: 197–204. Reprints or correspondence: Dr. Federico Pea, Institute of Clinical Pharmacology and Toxicology, DPMSC, University of Udine, P.le S. Maria della Misericordia 3, 33100 Udine, Italy (federico.pea@med.uniud.it). Clinical Infectious Diseases 2006; 42:434–5 2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4203-0026$15.00 Acknowledgments Linezolid and Continuous Venovenous Hemofiltration Potential conflicts of interest. F.P. is a member of the speakers’ bureau for Pfizer. P.V. has been Sir—In their report, Trotman et al. [1] reviewed the literature for studies that gave pharmacokinetic data on antibiotics frequently used to treat critically ill patients receiving continuous renal replacement therapy. Regarding linezolid, they report the data from patients with various degrees of renal failure, as well as from case studies of patients receiving hemodialysis and patients receiving continuous venovenous hemofiltration [1]. They infer that a dosage of 600 mg of linezolid every 12 h “provides a serum trough concentration of 14mg/L, which is the upper limit of the MIC range for drug-susceptible Staphylococcus species” (p. 1161). Trotman et al. [1] conclude that no dosage adjustment is necessary for patients receiving any form of continuous renal replacement therapy. We recently demonstrated, in a series of 20 critically ill patients undergoing continuous venovenous hemofiltration, that linezolid is significantly eliminated by continuous venovenous hemofiltration [2]. In our study, the total clearance was ∼25% higher and the trough serum concentration was ∼50% lower than in normal conditions. Using a standard dosage of 600 mg every 12 h, we calculated a time that linezolid concentration in the blood remained above the minimum inhibitory concentration (t 1 MIC) of 93% of the dosing interval for pathogens with an MIC of 2 mg/L. However, the mean t 1 MIC (SD) was only 57% of the dosing interval (32%) for pathogens with an MIC of 4 mg/L. With regard to the large interindividual variability, we conclude that the standard dosage of 600 mg every 12 h might be ineffective for some patients receiving continuous venovenous hemofiltration; that is, it might be an ineffective treatment for the least-susceptible pathogens that have an MIC of ⭓4 mg/L. We conclude that dose escalation (600 mg of linezolid every 8 h) might be warranted in selected patients to assure optimal antibacterial activity. In our study, we recently demonstrated that both of the main metabolites of linezolid—PNU-142300 and PNU142585—show significant accumulation CORRESPONDENCE • CID 2006:42 (1 February) • 435 Downloaded from https://academic.oup.com/cid/article-abstract/42/3/435/380277 by guest on 11 June 2020 presented with drug accumulation. Accordingly, it could be hypothesized that the time at which hyperlactacidemia occurs could be related to drug exposure (e.g., late-onset hyperlactacidemia could occur after very prolonged exposure to normal drug doses, and early-onset hyperlactacidemia could occur during unexpected drug overexposure). The interindividual pharmacokinetic variability of linezolid has been reported to be mild [3], which is consistent with mainly nonrenal, nonenzymatic clearance pathways. However, to our knowledge, we describe the second patient to have presented with a plasma level of linezolid that was 4–6-fold higher than expected [2]. Actually, it is very difficult even to hypothesize about which mechanism may have caused this drug accumulation. Perhaps the critical status of the patient affected drug clearance. Additionally, a drugdrug interaction might have occurred. In a recent case report, concurrent treatment with rifampin and linezolid was considered to be a possible cause of linezolid underexposure [7]. The authors suggested that linezolid could be a substrate of P-glycoprotein and that its accelerated clearance might have been caused by a rifampin-related induction of P-glycoprotein expression [7]. Conversely, inhibition of P-glycoprotein activity could lead to impaired linezolid clearance. Interestingly, while receiving linezolid therapy, our patient was also being administered sertraline—a very potent inhibitor of P-glycoprotein—for the treatment of major depression [8]. In this particular case, it may be speculated that sertraline could have potentially impaired linezolid clearance by blocking P-glycoprotein activity. This case suggests that early-onset hyperlactacidemia during linezolid therapy may be related to unexpected drug overexposure. Additional studies are needed to confirm its pathogenesis. in anuric patients receiving continuous venovenous hemofiltration [2]. The clinical relevance of these inactive metabolites is essentially unknown. Moreover, because prolonged use of linezolid might be associated with severe hematopoietic and neurologic adverse effects, special attention has to be paid to the potential toxicity associated with linezolid accumulation. Potential conflicts of interest. B.M. and F.T.: no conflicts. Brigitte Meyer1,2 and Florian Thalhammer1 1 Department of Internal Medicine I, Division of Infectious Diseases, and 2Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria References 1. Trotman RL, Williamson JC, Shoemaker DM, Salzer WL. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infect Dis 2005; 41: 1159–66. 2. Meyer B, Kornek GV, Nikfardjam M, et al. Multiple-dose pharmacokinetics of linezolid during continuous venovenous hemofiltration. J Antimicrob Chemother 2005; 56:172–9. Reprints or correspondence: Dr. F. Thalhammer, Dept. of Internal Medicine I, Div. of Infectious Diseases, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria (florian.thalhammer@meduniwien.ac.at). Clinical Infectious Diseases 2006; 42:435–6 2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4203-0027$15.00 Sir—We applaud the efforts of Trotman et al. [1] to bring the pharmacokinetic tailoring of treatment with anti-infective agents in continuous renal replacement therapy to the forefront of infectious diseases clinical practice; however, we feel that the tables presented in their article [1] may represent an oversimplified dosing algorithm. The authors [1] readily disclose that the recommendations are based on a dearth of clinical data. With this caveat, they suggest dosages for agents used for patients undergoing continuous venovenous hemofiltration (CVVH) at ultrafiltration rates of 1 L/h and for patients undergoing continuous venovenous hemodialysis or continuous venovenous hemodiafiltration with an ultrafiltration rate of 1 L/h and a dialysate flow rate of 1 L/ h. Although this provides a quick clinical guide to low flow-rate continuous renal replacement therapy, it does not allow practitioners the latitude to calculate dosages based on varying ultrafiltration flow rates or clotted vascular lines. With data suggesting that use of a high-volume ultrafiltration rate (35mL/kg/h) with CVVH decreases the mortality rate among patients with acute renal failure, the need to adjust medication prescribing patterns to reflect this continuous renal replacement therapy modality is apparent [2]. As illustrated in table 1, with ultrafiltration rates of 3–4 L/h, anti-infective agents with low volumes of distribution or low protein binding may require more aggressive dosing (table 1). The reason for prescribing supplemental dosages for patients undergoing continuous renal replacement therapy beyond typical dosages for anephric patients, as Trotman et al. [1] suggest, is the additional removal of the drug by the extracorporeal dialysis unit. The clearance by the extracorporeal unit (CLextr) can be calculated for CVVH when the sieving coefficient (Sc), or the ability of the solute to transverse the membrane, and the ultrafiltration rate (UFR) are known [3, 4], with the equation CLextr p Sc ⫻ UFR. When the sieving coefficient is not known, the fraction unbound (Fu) can be used to estimate it. For clinical calculations, this can be estimated with the equations Fu p 1 ⫺ protein binding percentage and Fu ≈ Sc [3– 6]. Drug clearance must be calculated to determine a maintenance dose. The serum concentration at steady state (Cpss, measured in mg/L) multiplied by the extracorporeal clearance rate (measured in L/ h) provides the practitioner with the amount of drug specifically removed by ultrafiltration per hour under steady-state conditions [7]. This allows for calculation of varying maintenance dosages based on the ultrafiltration rate and duration. One Table 1. Recommended dosages of selected antimicrobials for patients undergoing central venovenous hemofiltration (CVVH). Sieving coefficient Targeted average serum steady-state concentration, in mg/L For anephric patients 1 L/h 2 L/h 3 L/h 4 L/h Unknown 130 500 mg q8h 1 g q8h 2 g q12h 2 g q8h 2 g q6h Unknown 95 1 g q24h 1 g q12h 1 g q12h 1 g q8h 1 g q8h 0.510.01 100 2 g q24h 1 g q8h 1 g q6h 2 g q8h 2 g q6h 60 1 g q24h 1 g q12h 2 g q12h 2 g q8h 2 g q8h 1.2 20 500 mg q12h 500 mg q8h 500 mg q6h 1 g q8h 1 g q6h Unknown 120 3 g q12h 4 g q12h 4 g q8h 3 g q6h 4 g q6h Drug Normal volume of distribution in L/kg Normal half-life, in h Fraction unbound Aztreonam 0.2 1.7–2.9 0.5 Cefazolin 0.13 1.5–2.5 0.2 Cefotaxime 0.15 0.8–1.4 0.62 Ceftazidime 0.23 1.0–2.0 0.9 0.9 Imipenem 0.14–0.23 1 0.8 Piperacillin 0.18–0.30 0.5–1.5 0.78–0.84 NOTE. Data are given as values, ranges, or mean SD. 436 • CID 2006:42 (1 February) • CORRESPONDENCE Recommended dosage By CVVH rate Downloaded from https://academic.oup.com/cid/article-abstract/42/3/435/380277 by guest on 11 June 2020 Acknowledgments Adjustment of Antimicrobial Dosages for Continuous Venovenous Hemofiltration Based on Patient-Specific Information

Log In

Linezolid and Continuous Venovenous Hemofiltration

Sign up for access to the world's latest research

Related papers

Related papers

Related topics