Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2015

Open Access 01-12-2015 | Research

A multicenter study on the effect of continuous hemodiafiltration intensity on antibiotic pharmacokinetics

Authors: Darren M Roberts, Xin Liu, Jason A Roberts, Priya Nair, Louise Cole, Michael S Roberts, Jeffrey Lipman, Rinaldo Bellomo, On behalf of the RENAL Replacement Therapy Study Investigators

Published in: Critical Care | Issue 1/2015

Login to get access

Abstract

Introduction

Continuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing. In a nested cohort within a large randomized controlled trial, we assessed the effect of higher (40 mL/kg per hour) and lower (25 mL/kg per hour) intensity CRRT on antibiotic pharmacokinetics.

Methods

We collected serial blood samples to measure ciprofloxacin, meropenem, piperacillin-tazobactam, and vancomycin levels. We calculated extracorporeal clearance (CL), systemic CL, and volume of distribution (Vd) by non-linear mixed-effects modelling. We assessed the influence of CRRT intensity and other patient factors on antibiotic pharmacokinetics.

Results

We studied 24 patients who provided 179 pairs of samples. Extracorporeal CL increased with higher-intensity CRRT but the increase was significant for vancomycin only (mean 28 versus 22 mL/minute; P = 0.0003). At any given prescribed CRRT effluent rate, extracorporeal CL of individual antibiotics varied widely, and the effluent-to-plasma concentration ratio decreased with increasing effluent flow. Overall, systemic CL varied to a greater extent than Vd, particularly for meropenem, piperacillin, and tazobactam, and large intra-individual differences were also observed. CRRT dose did not influence overall (systemic) CL, Vd, or half-life. The proportion of systemic CL due to CRRT varied widely and was high in some cases.

Conclusions

In patients receiving CRRT, there is great variability in antibiotic pharmacokinetics, which complicates an empiric approach to dosing and suggests the need for therapeutic drug monitoring. More research is required to investigate the apparent relative decrease in clearance at higher CRRT effluent rates.

Trial registration

ClinicalTrials.gov NCT00221013. Registered 14 September 2005.
Appendix
Available only for authorised users
Literature
1.
Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2:431–9.PubMed
2.
Parmar A, Langenberg C, Wan L, May CN, Bellomo R, Bagshaw SM. Epidemiology of septic acute kidney injury. Curr Drug Targets. 2009;10:1169–78.PubMed
3.
Roberts JA. Using PK/PD to optimize antibiotic dosing for critically ill patients. Curr Pharm Biotechnol. 2011;12:2070–9.PubMed
4.
Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58:1072–83.PubMed
5.
Roberts JA, Kruger P, Paterson DL, Lipman J. Antibiotic resistance–what's dosing got to do with it? Crit Care Med. 2008;36:2433–40.PubMed
6.
Roberts DM. The relevance of drug clearance to antibiotic dosing in critically ill patients. Curr Pharm Biotechnol. 2011;12:2002–14.PubMed
7.
Ulldemolins M, Rello J. The relevance of drug volume of distribution in antibiotic dosing. Curr Pharm Biotechnol. 2011;12:1996–2001.PubMed
8.
Choi G, Gomersall CD, Tian Q, Joynt GM, Freebairn R, Lipman J. Principles of antibacterial dosing in continuous renal replacement therapy. Crit Care Med. 2009;37:2268–82.PubMed
9.
Roberts DM, Roberts JA, Roberts MS, Liu X, Nair P, Cole L, et al. Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy – a multicentre pharmacokinetic study. Crit Care Med. 2012;40:1523–8.PubMed
10.
Seyler L, Cotton F, Taccone FS, De Backer D, Macours P, Vincent JL, et al. Recommended beta-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy. Crit Care. 2011;15:R137.PubMedPubMedCentral
11.
Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson DL, et al. Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents. 2010;36:332–9.PubMed
12.
Li AM, Gomersall CD, Choi G, Tian Q, Joynt GM, Lipman J. A systematic review of antibiotic dosing regimens for septic patients receiving continuous renal replacement therapy: do current studies supply sufficient data? J Antimicrob Chemother. 2009;64:929–37.PubMed
13.
Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, et al. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med. 2009;361:1627–38.PubMed
14.
Schetz M, Ferdinande P, Van den Berghe G, Verwaest C, Lauwers P. Pharmacokinetics of continuous renal replacement therapy. Intensive Care Med. 1995;21:612–20.PubMed
15.
Boeckmann AJ, Sheiner LB, Beal SL. NONMEM Users Guide - Part V: Introductory Guide. San Francisco, CA: University of California; 1994.
16.
Conil JM, Georges B, de Lussy A, Khachman D, Seguin T, Ruiz S, et al. Ciprofloxacin use in critically ill patients: pharmacokinetic and pharmacodynamic approaches. Int J Antimicrob Agents. 2008;32:505–10.PubMed
17.
Malone RS, Fish DN, Abraham E, Teitelbaum I. Pharmacokinetics of levofloxacin and ciprofloxacin during continuous renal replacement therapy in critically ill patients. Antimicrob Agents Chemother. 2001;45:2949–54.PubMedPubMedCentral
18.
Forrest A, Ballow CH, Nix DE, Birmingham MC, Schentag JJ. Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin. Antimicrob Agents Chemother. 1993;37:1065–72.PubMedPubMedCentral
19.
Thalhammer F, Schenk P, Burgmann H, El Menyawi I, Hollenstein UM, Rosenkranz AR, et al. Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration. Antimicrob Agents Chemother. 1998;42:2417–20.PubMedPubMedCentral
20.
Thalhammer F, Horl WH. Pharmacokinetics of meropenem in patients with renal failure and patients receiving renal replacement therapy. Clin Pharmacokinet. 2000;39:271–9.PubMed
21.
Taccone FS, Laterre PF, Dugernier T, Spapen H, Delattre I, Wittebole X, et al. Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14:R126.PubMedPubMedCentral
22.
Isla A, Rodriguez-Gascon A, Troconiz IF, Bueno L, Solinis MA, Maynar J, et al. Population pharmacokinetics of meropenem in critically ill patients undergoing continuous renal replacement therapy. Clin Pharmacokinet. 2008;47:173–80.PubMed
23.
Krueger WA, Schroeder TH, Hutchison M, Hoffmann E, Dieterich HJ, Heininger A, et al. Pharmacokinetics of meropenem in critically ill patients with acute renal failure treated by continuous hemodiafiltration. Antimicrob Agents Chemother. 1998;42:2421–4.PubMedPubMedCentral
24.
Giles LJ, Jennings AC, Thomson AH, Creed G, Beale RJ, McLuckie A. Pharmacokinetics of meropenem in intensive care unit patients receiving continuous veno-venous hemofiltration or hemodiafiltration. Crit Care Med. 2000;28:632–7.PubMed
25.
Tegeder I, Neumann F, Bremer F, Brune K, Lotsch J, Geisslinger G. Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration. Clin Pharmacol Ther. 1999;65:50–7.PubMed
26.
Robatel C, Decosterd LA, Biollaz J, Eckert P, Schaller MD, Buclin T. Pharmacokinetics and dosage adaptation of meropenem during continuous venovenous hemodiafiltration in critically ill patients. J Clin Pharmacol. 2003;43:1329–40.PubMed
27.
Ververs TF, van Dijk A, Vinks SA, Blankestijn PJ, Savelkoul JF, Meulenbelt J, et al. Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration. Crit Care Med. 2000;28:3412–6.PubMed
28.
van der Werf TS, Mulder PO, Zijlstra JG, Uges DR, Stegeman CA. Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH). Intensive Care Med. 1997;23:873–7.PubMed
29.
Valtonen M, Tiula E, Takkunen O, Backman JT, Neuvonen PJ. Elimination of the piperacillin/tazobactam combination during continuous venovenous haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother. 2001;48:881–5.PubMed
30.
Buck C, Bertram N, Ackermann T, Sauerbruch T, Derendorf H, Paar WD. Pharmacokinetics of piperacillin-tazobactam: intermittent dosing versus continuous infusion. Int J Antimicrob Agents. 2005;25:62–7.PubMed
31.
Capellier G, Cornette C, Boillot A, Guinchard C, Jacques T, Blasco G, et al. Removal of piperacillin in critically ill patients undergoing continuous venovenous hemofiltration. Crit Care Med. 1998;26:88–91.PubMed
32.
Arzuaga A, Maynar J, Gascon AR, Isla A, Corral E, Fonseca F, et al. Influence of renal function on the pharmacokinetics of piperacillin/tazobactam in intensive care unit patients during continuous venovenous hemofiltration. J Clin Pharmacol. 2005;45:168–76.PubMed
33.
Krueger WA, Neeser G, Schuster H, Schroeder TH, Hoffmann E, Heininger A, et al. Correlation of meropenem plasma levels with pharmacodynamic requirements in critically ill patients receiving continuous veno-venous hemofiltration. Chemotherapy. 2003;49:280–6.PubMed
34.
Mueller SC, Majcher-Peszynska J, Hickstein H, Francke A, Pertschy A, Schulz M, et al. Pharmacokinetics of piperacillin-tazobactam in anuric intensive care patients during continuous venovenous hemodialysis. Antimicrob Agents Chemother. 2002;46:1557–60.PubMedPubMedCentral
35.
DelDot ME, Lipman J, Tett SE. Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration. Br J Clin Pharmacol. 2004;58:259–68.PubMedPubMedCentral
36.
Boereboom FT, Ververs FF, Blankestijn PJ, Savelkoul TJ, van Dijk A. Vancomycin clearance during continuous venovenous haemofiltration in critically ill patients. Intensive Care Med. 1999;25:1100–4.PubMed
37.
Santre C, Leroy O, Simon M, Georges H, Guery B, Beuscart C, et al. Pharmacokinetics of vancomycin during continuous hemodiafiltration. Intensive Care Med. 1993;19:347–50.PubMed
38.
Bouchard J, Roberts DM, Roy L, Ouellet G, Decker BS, Mueller BA, et al. Principles and operational parameters to optimize poison removal with extracorporeal treatments. Semin Dial. 2014;27:371–80.PubMed
39.
Padrini R, Canova C, Conz P, Mancini E, Rizzioli E, Santoro A. Convective and adsorptive removal of beta2-microglobulin during predilutional and postdilutional hemofiltration. Kidney Int. 2005;68:2331–7.PubMed
40.
Brunet S, Leblanc M, Geadah D, Parent D, Courteau S, Cardinal J. Diffusive and convective solute clearances during continuous renal replacement therapy at various dialysate and ultrafiltration flow rates. Am J Kidney Dis. 1999;34:486–92.PubMed
41.
Claure-Del Granado R, Macedo E, Chertow GM, Soroko S, Himmelfarb J, Ikizler TA, et al. Effluent volume in continuous renal replacement therapy overestimates the delivered dose of dialysis. Clin J Am Soc Nephrol. 2011;6:467–75.PubMedPubMedCentral
42.
Sakiyama R, Ishimori I, Akiba T, Mineshima M. Effect of blood flow rate on internal filtration in a high-flux dialyzer with polysulfone membrane. J Artif Organs. 2012;15:266–71.PubMed
43.
Schneditz D, Zierler E, Jantscher A, Vanholder R, Eloot S. Internal filtration in a high-flux dialyzer quantified by mean transit time of an albumin-bound indicator. ASAIO J. 2013;59:505–11.PubMed
44.
Pea F, Viale P, Pavan F, Furlanut M. Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy. Clin Pharmacokinet. 2007;46:997–1038.PubMed
45.
Macias WL, Mueller BA, Scarim SK. Vancomycin pharmacokinetics in acute renal failure: preservation of nonrenal clearance. Clin Pharmacol Ther. 1991;50:688–94.PubMed
Metadata
Title
A multicenter study on the effect of continuous hemodiafiltration intensity on antibiotic pharmacokinetics
Authors
Darren M Roberts
Xin Liu
Jason A Roberts
Priya Nair
Louise Cole
Michael S Roberts
Jeffrey Lipman
Rinaldo Bellomo
On behalf of the RENAL Replacement Therapy Study Investigators
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2015
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-015-0818-8

Other articles of this Issue 1/2015

Critical Care 1/2015 Go to the issue

Research

Hydroxyethyl starch versus other fluids for non-septic patients in the intensive care unit: a meta-analysis of randomized controlled trials

Review

Clinical review: intensive care unit acquired weakness

Review

Bench-to-bedside review: the effects of hyperoxia during critical illness

Research

Increase in cerebral oxygenation during advanced life support in out-of-hospital patients is associated with return of spontaneous circulation

Research

Non-invasive monitoring of mitochondrial oxygenation and respiration in critical illness using a novel technique

Research

Adequate antibiotic therapy prior to ICU admission in patients with severe sepsis and septic shock reduces hospital mortality