Anti infective drugs during continuous hemodialysis – using the bench to learn what to do at the bedside

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/271593947 Anti-infective drugs during continuous hemodialysis – using the bench to learn what to do at the bedside Article in The International journal of artificial organs · January 2015 DOI: 10.5301/ijao.5000377 · Source: PubMed CITATIONS READS 87 6 authors, including: Anka Roehr Otto Frey Heidenheim General Hospital 59 PUBLICATIONS 223 CITATIONS 22 PUBLICATIONS 37 CITATIONS SEE PROFILE SEE PROFILE Jason Roberts Alexander Brinkmann University of Queensland Klinikum Heidenheim 327 PUBLICATIONS 5,030 CITATIONS 101 PUBLICATIONS 830 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: DIANA study View project Optimising antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis View project All content following this page was uploaded by Alexander Brinkmann on 02 August 2015 The user has requested enhancement of the downloaded file All in-text references underlined in blue are added to the original document and are linked to publications on ResearchGate, letting you access and read them immediately Anti-Infective Drugs during Continuous Haemodialysis – Using the Bench to Learn What to Do At the Bedside Authors Anka C Roehr1, Otto R Frey1, Andreas Koeberer2, Thomas Fuchs2, Jason A Roberts3 and Alexander Brinkmann2 Department of Pharmacy, Heidenheim General Hospital, Heidenheim, Germany Department of Anaesthesiology, Special Pain Management and Intensive Care Medicine, Heidenheim General Hospital, Heidenheim, Germany Burns Trauma and Critical Care Research Centre, University of Queensland, Royal Brisbane and Women’s Hospital, The University of Queensland, Brisbane, Australia Corresponding author: Anka C Roehr Department of Pharmacy Klinikum Heidenheim gGmbH 89522 Heidenheim Germany Phone: 0049-7321-332666; Fax: 0049-7321-2369 anka.roehr@kliniken-heidenheim.de Abstract Background: Significant uncertainty remains for anti-infective dosing regimens in critically ill patients undergoing renal replacement therapy (RRT) The main objective of this study is to investigate the clearance of eleven selected anti-infectives in sodium chloride 0.9% and in human serum albumin (HSA) 5% in an in vitro model of continuous venovenous haemodialysis (CVVHD), in order to suggest rational dosing strategies for clinical practice Methods: Ceftazidime, ciprofloxacin, flucloxacillin, gentamicin, linezolid, meropenem, metronidazole, piperacillin, rifampicin, vancomycin and voriconazole were studied in two different solvents (sodium chloride 0.9% and HSA 5%) using a Multifiltrate® dialysis device by Fresenius Medical Care (mode: CVVHD; blood flow 100 ml/min, dialysate flow 2000 ml/h, no ultrafiltrate, filter unit: Ultraflux AV 600S) For each solution, prefilter, postfilter and dialysate samples were drawn simultaneously during one hour of dialysis Drug assay was performed with validated HPLC with UV-detection and FPIA Results: The clearance of ceftazidime, ciprofloxacin, flucloxacillin, gentamicin, linezolid, meropenem, metronidazole, piperacillin, vancomycin and voriconazole in sodium chloride 0.9% was comparable (mean 1.76 ± 0.11 l/h) The clearance of these agents in human serum albumin solution 5% was reduced by between 5.3 and 72.2% The unbound drug fraction correlated with a lower clearance in HSA 5% (Pearson correlation coefficient r = 0.933; p = 0.00008) No correlation between clearance in HSA 5% and the drugs’ molecular weight was found (Pearson correlation coefficient r = 0.388; p = 0.268) Rifampicin was detected to bind to the surface of the polysulfone filter used (98% adsorption within 15 minutes) Dialysis clearance of ceftazidime, gentamicin, linezolid, meropenem, metronidazole, piperacillin and vancomycin during CVVHD accounted for over 25% of the total body clearance of population pharmacokinetic data for renally impaired patients Conclusion: In vitro studies are useful to predict likely in vivo drug clearances The results from this study highlight that dose adaptations are needed for most of the drugs under investigation for patients undergoing CVVHD, in order to optimise anti-infective dosing regimens Rifampicin should be avoided in patients undergoing CVVHD with polysulfone filters, or should only be used under the guidance of therapeutic drug monitoring to ensure adequate serum levels Keywords: antimicrobial agents, dialysability, drug dosing, in vitro, pharmacokinetics, renal replacement therapy Short summary: This study uses an in vitro model of continuous haemodialysis to describe the main factors affecting the elimination of anti-infective drugs We found that dialysis clearance depends primarily on protein binding rather than on the drugs’ molecular weight We also found that rifampicin binds to the surface of the polysulfone filter under investigation Introduction Anti-infective dosing regimens for critically ill patients undergoing renal replacement therapy (RRT) remain an area of uncertainty in intensive care medicine Although the timely (1) and appropriate (2) administration of antibiotics is known to save patients’ lives, only few rational dosing guidelines on how to optimise treatment during RRT are currently available to clinicians Approximately 5% of critically ill patients undergo continuous RRT (3), with this proportion increasing steadily over time In the past decade, the advent of new dialysis techniques has improved the tolerability of RRT, whilst also changing the efficiency with which solutes like drugs are removed A large number of clinical pharmacokinetic studies have been developing general anti-infective dosing recommendations based on rather small numbers of patient, accepting that this particular patient population is subject to huge pharmacokinetic variability (4) The conflicting results on drug clearances presented by these studies (5) pose a real challenge to clinicians Therefore, controlled in vitro studies are considered to be an ideal way of characterising RRT-drug interactions Furthermore, the pharmacokinetics in patients with acute or chronic kidney diseases undergoing dialysis are commonly altered (6) due to physiological changes Especially, decreased protein binding may affect drug clearances and, as a result, the serum levels of agents characterised by high plasma protein binding The enhanced drug clearance resulting thereof carry the risk of producing undesirably low serum levels of anti-infective agents (7) The aim of this study was to investigate the dialysis clearance (CLHD) of eleven anti-infective drugs during continuous venovenous haemodialysis (CVVHD) in order to assess correlations between drug clearances and protein binding (PB) and the drugs’ molecular weight We also aim to use these results to suggest dosing regimens for these drugs in common CVVHD settings Subjects and Methods: In vitro model of haemodialysis: 1000 ml saline 0.9% solutions and 500 ml human serum albumin 5% (HSA) solutions served as reservoirs for different anti-infective drugs in the RRT model The baseline concentrations were as follows: ceftazidime 80 mg/l, ciprofloxacin 15 mg/l, flucloxacillin 80 mg/l, gentamicin 20 mg/l, linezolid 20 mg/l, meropenem 20 mg/l, metronidazole 30 mg/l, piperacillin 80 mg/l, rifampicin 10 mg/l, vancomycin 40 mg/l and voriconazole 20 mg/l Initial concentrations matched high standard levels, or even higher levels, to ensure appropriate chromatographic conditions, as an extreme loss of substances was predicted to occur during the time of dialysis RRT was performed in line with clinical guidelines using a Multifiltrate® machine (Fresenius Medical Care) All experiments were performed with either saline or HSA solutions Drug solutions were mixed and maintained stable at 37°C by using a magnetic stirrer The dialysis mode chosen was CVVHD, blood flow was 100 ml/min, dialysate flow was 2000 ml/h, and there was no ultrafiltration The filter type used was a polysulfone AV 600S (1.4 m2, Fresenius Medical Care) device; no anticoagulation was applied The dialysis fluid used was bicarbonate buffered solution (MultiBic mmol/l potassium by Fresenius Medical Care) Sampling 500 µl of arterial, venous and dialysate samples were drawn simultaneously at 0, 5, 15, 25, 35, 45 and 55 minutes; the time to reach equilibrium before the start of the dialysis session was minutes for all solutions Analytical methods: Gentamicin and vancomycin were measured using a Fluorescence Polarisation Immuno-Assay (AxSym, Abbott Laboratories) To quantify ceftazidime, ciprofloxacin, flucloxacillin, linezolid, meropenem, metronidazole, piperacillin, rifampicin, and voriconazole, HPLC methods with UV detection were used All HPLC methods have been previously described (8-11) and were in line with the Valistat 2.0 validation criteria as required by the German Society of Toxicology and Forensic Chemistry (GTFCh), linearity was proven to be within the requested concentration range across all drugs, and quality control samples at three different concentrations featured a relative standard deviation (RSD%) for inter- and intraday precision of 1.4 m2 are unlikely to impact the amount of drug dialysed, as complete diffusion has been demonstrated Smaller surface areas, on the other hand, which may no longer be used, could reduce the amount dialysed This might also apply to extremely high blood and dialysate/filtrate flow rates, as occurring under intermittent methods, due to a shorter contact time at the membrane The non-linear pharmacokinetics of voriconazole are highly unpredictable (23) Although the amount of drug elimination during the dialysis process is fairly small compared to total body clearance, it should be monitored by TDM, regardless of RRT The same applies to the use of rifampicin in CVVHD patients with polysulfone filters The main limitation of this study is the in vitro design In critically ill patients, a high variability in the pharmacokinetics of anti-infective drugs has been described (24, 25), with alterations in volume of 11 distribution, elimination half-life, PB, and drug clearance Moreover, the metabolic capacity may vary compared to healthy subjects This makes it difficult to predict serum drug levels which could be used as a basis for calculating drug loss during CVVHD without therapeutic drug monitoring The current study provides a general understanding of the process of elimination during CVVHD, by investigating the influence of PB and molecular weight on CLHD separately It is also the first study describing the binding of rifampicin to a polysulfone filter surface, which has not been observed for any of the other investigated drugs The suggested dose adjustments provide clinicians with the option to identify substances that could potentially be severely underdosed in critically ill patients on CVVHD, as long as no large prospective randomised controlled clinical trials are conducted The study also covers different drugs with various pharmacokinetic profiles, and represents the standard CVVHD procedure and the standard antimicrobial therapy used in our hospital When used in combination with therapeutic drug monitoring, it can be safely used as a standard procedure 12 Transparency declarations: All authors declare that they have no conflict of interest concerning the specific subject of this study OF received lecture fees from Fresenius Medical Care, AB received lecture fees and a research grant from Fresenius Medical Care for another project 13 References: Kumar A, Roberts D, Wood KE et al, Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Crit Care Med 2006 Jun;34(6):1589-96 Kumar A, Ellis P, Arabi Y et al, Initiation of Inappropriate Antimicrobial Therapy Results in a Fivefold Reduction of Survival in Human Septic Shock, Chest 2009;136;1237-1248 Churchwell MD, Mueller BA, Drug dosing during continuous renal replacement therapy Semin Dial 2009 Mar-Apr;22(2):185-8 Gonỗalves-Pereira J, Póvoa P, Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of beta-lactams, Critical Care 2011,15:R206 Pea F, Viale P, Pavan F et al, Pharmacokinetic Considerations for Antimicrobial Therapy in Patients Receiving Renal Replacement Therapy, Clin Pharmacokinet 2007; 46 (12): 997-1038 Heintz BH, Matzke GR, Dager WE, Antimicrobial Dosing Concepts and Recommendations for Critically Ill Patients Receiving Continuous Renal Replacement Therapy or Intermittent Hemodialysis, Pharmacotherapy 2009;29(5):562-577 Seyler L, Cotton F, Taccone FS et al, Recommended b-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy, Critical Care 2011, 15:137-146 D´Avolio A, Baietto L, De Rosa FG et al, A Simple and Fast Method for Quantification of Ertapenem using Meropenem as Internal Standard in Human Plasma in a Clinical Setting, Ther Drug Monit 2008; 30(1):90-94 Bias M, Frey OR, Köberer A, Determination of meropenem in serum by high-performance liquid chromatography, Krankenhauspharmazie 2010;31:482–5 10 Roehr A: Therapeutic Drug Monitoring Antibiotics available under http://www.klinikenheidenheim.de/klinik/Zentrale_Einrichtungen/Klinikapotheke/TDM_Analytical_Methods/HP LC_General_Methods_2013.pdf (2nd April 2014, date last accessed) 14 11 Roehr A: Therapeutic Drug Monitring Antibiotics available under http://www.klinikenheidenheim.de/klinik/Zentrale_Einrichtungen/Klinikapotheke/TDM_Analytical_Methods/HP LC_Single_Methods_Homepage_2013.pdf (2nd April 2014, date last accessed) 12 Ashley C and Currie A, The Renal Drug Handbook, Radcliff publishing, Oxford, UK, 3rd Edition 2009, 131, 160, 310, 345, 436, 463, 477, 645, 703, 763, 778 13 Martin-Facklam M, Rengelshausen J, Tayrouz Y et al, Dose individualisation in patients with renal insufficiency: does drug labelling support optimal management?, Eur J Clin Pharmacol 2005;60(11):807-11 14 Arzuaga A, Isla A, Gascon AR et al, Elimination of Piperacillin and Tazobactam by Renal Replacement Therapies with AN69 and Polysulfone Hemofilters: Evaluation of the Sieving Coefficient, Blood Purif 2006;24:347-354 15 Li AMMY, Gomersall CD, Choi G et al, A systematic review of antibiotic dosing regimens for septic patients receiving continuous renal replacement therapy: current studies supply sufficient data? J Antimicrob Chemother 2009; 64:929-937 16 Tian Q, Gomersall CD, Ip M et al, Adsorption of Amikacin, a Significant Mechanism of Elimination by Hemofiltration, Antimicrobial Agents Chemotherapy 2008; 1009–1013 17 Kronfol NO, Lau AH, Barakat MM, Aminogycoside Binding to Polyacrylonitrile Hemofilter Membranes during Continuous Hemofiltration, Trans Am Soc Artif Intern Org 1987; 33:300303 18 Buxton ILO, General Principles Pharmacokinetics and Pharmacodynamics In: Brunton LL, Goodmann and Gilman´s The Pharmacological Basis of THERAPEUTICS, The McGrawHill Companies, USA, 11th Edition 2006, 7-8 19 Isla A, Gascon AR, Maynar J et al, In vitro AN69 and Polysulphone Membrane Permeability to Ceftazidime and in vivo Pharmacokinetics during Continuous Renal Replacement Therapies, Chemotherapy 2007;53:194-201 20 Roberts JA, Pea F, Lipman J., The clinical relevance of plasma protein binding changes., Clin Pharmacokinet 2013 Jan;52(1):1-8 15 21 Atkinson Jr AJ and Umans JG, Pharmacokinetic Studies in Hemodialysis Patients, Clin Pharm Therapeutics 2009;86(5):548-551 22 Somogyi A, Kong C, Sabto J et al, Disposition and Removal of Metronidazole in Patients Undergoing Haemodialysis, Eur J Clin Pharmacol 1983:25;683-687 23 Hope WW, VanGuilder M, Donnelly JP et al, Software For Dosage Individualization of Voriconazole for Immunocompromised Patients, Antimicrob Agents Chemother Antimicrob Agents Chemother.2013;57(4):1888-1894 24 Udy AA, Roberts JA, Lipman J, Clinical implications of antibiotic pharmacokinetic principles in the critically ill., Intensive Care Med 2013;39(12):2070-82 25 Sime FB, Roberts MS, Peake SL et al, Does Beta-lactam Pharmacokinetic Variability in Critically Ill Patients Justify Therapeutic Drug Monitoring? A Systematic Review, Ann Intensive Care 2012 Jul 28;2(1):35 16 Tables/Figures: 100 90 protein binding [%] 80 70 r = 0.9149 HSA protein binding (measured) 60 plasma protein binding (literature) 50 40 30 r = 0.9333 20 10 0,4 0,6 0,8 1,2 ClHD [l/h] 1,4 1,6 1,8 Fig 1: Correlation of CLHD in HSA 5% with measured HSA 5% PB and plasma protein PB reported in literature (12) 17 1600 molecular weight [Da] 1400 1200 1000 800 600 400 200 r = 0.388 1,55 1,6 1,65 1,7 1,75 1,8 CLHD in saline solution [l/h] Fig 2: Correlation of CLHD in NaCl 0.9% with molecular weight 18 1,85 1,9 1,95 t½ [min] CLHD[l/h] Sd NaCl HSA NaCl HSA 1000 ml 500 ml 1000 ml 500 ml Ceftazidime 21.39 10.25 1.00 Ciprofloxacin 22.14 12.65 Flucloxacillin 20.82 Gentamicin PB [%] NaCl HSA 1.08 1.79 1.70 1.70 1.01 1.04 1.72 1.38 13.79 38.51 1.09 0.13 1.84 0.45 66.66 22.65 12.86 1.01 0.92 1.69 1.36 35.47 Linezolid 23.50 15.47 0.97 0.96 1.63 1.15 25.68 Meropenem 19.86 9.94 1.10 0.82 1.92 1.76 0.0 Metronidazole 20.75 10.70 1.15 1.08 1.84 1.63 3.54 Piperacillin 20.15 11.97 1.04 0.76 1.90 1.46 5.96 Vancomycin 23.82 16.70 0.93 0.88 1.61 1.05 32.41 Voriconazole 22.95 15.44 1.10 -* 1.67 1.13 39.61 46.53 Rifampicin Tab 1: Results for elimination half-life (t1/2), saturation coefficient (Sd), CLHD and protein binding (PB) of anti-infective drugs * Concentrations below limit of detection 19 Literature data (12) (standard patient) Crea-Cl ~ 100 ml/min CLtot Dose [mg] [l/h] Measured Crea-Cl ~ 15 ml/min CLtot15 Crea-Cl ~ 15 ml/min + CVVHD Dose [mg] Cltot15+HD [l/h] Dose [mg] [l/h] Ceftazidime 8.80 3000 2.44 833 4.14 1413 Ciprofloxacin 32.51 1200 17.31 639 18.69 690 Flucloxacillin 6.80 8000 2.69 3172 3.14 3706 Gentamicin 6.20 500 1.46 118* 2,82 227* Linezolid 5.20 1200 3.78 894 4.87 1159 Meropenem 18.20 3000 7.37 1215 9.13 1505 Metronidazole 6.70 1500 5.56 1245 7.19 1611 Piperacillin 12.50 12000 5.06 4860 6.52 6261 Vancomycin 6.80 3000 1.89 833 2.94 1294 Voriconazole 39.90 600 39.22 590 40.35 607 Rifampicin 9.70 1200 7.85 971 not use or under TDM guidance Tab 2: Calculated dose adjustments with the CLHD values measured in HSA 5% Abbreviation: Crea-Cl = creatinine clearance * Prolonged dosing interval preferred to dose reductions 20 View publication stats .. .Anti- Infective Drugs during Continuous Haemodialysis – Using the Bench to Learn What to Do At the Bedside Authors Anka C Roehr1, Otto R Frey1, Andreas Koeberer2,... ill patients (20) The CLHD rates 10 in HSA 5% and their correlation to the amount of PB indicate that protein binding is a key factor in drug loss during the dialysis process Drug elimination during. .. ClHD;drug the resulting CLHD The saturation coefficient (Sd) was calculated using the formula with cdialysate, carterial and cvenous representing the concentrations in the dialysate, the arterial