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Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration
G Model ANTAGE-4425; No. of Pages 4
ARTICLE IN PRESS International Journal of Antimicrobial Agents xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Short Communication
Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration Mahipal G. Sinnollareddy a,b,∗ , Michael S. Roberts a,b , Jeffrey Lipman c,d , Thomas A. Robertson a,b , Sandra L. Peake e , Jason A. Roberts c,d,f,g a
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia c Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia d Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia e Department of Intensive Care Medicine, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia f Pharmacy Department, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia g Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK b
a r t i c l e
i n f o
Article history: Received 12 June 2014 Accepted 29 August 2014 Keywords: Pharmacokinetics Fluconazole Renal replacement therapy Sustained low-efficiency diafiltration Extended daily diafiltration Critically ill patients
a b s t r a c t Fluconazole is a widely used antifungal agent in critically ill patients. It is predominantly (60–80%) excreted unchanged in urine. Sustained low-efficiency diafiltration (SLED-f) is increasingly being utilised in critically ill patients because of its practical advantages over continuous renal replacement therapy. To date, the effect of SLED-f on fluconazole pharmacokinetics and dosing has not been studied. The objective of this study was to describe the pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving SLED-f and to compare this with other forms of renal replacement therapy. Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter before and after SLED-f from three patients during one session. Fluconazole concentrations were measured using a validated chromatography method. Median clearance (CL) and 24-h area under the concentration–time curve (AUC0–24 ) were 2.1 L/h and 152 mg·h/L, respectively, whilst receiving SLED-f. Moreover, 72% of fluconazole was cleared by a single SLED-f session (6 h) compared with previous reports of 33–38% clearance by a 4-h intermittent haemodialysis session. CL and AUC0–24 were comparable with previous observations in a pre-dilution mode of continuous venovenous haemodiafiltration. The observed rebound concentration of fluconazole post SLED-f was <2%. Although a definitive dosing recommendation is not possible due to the small patient number, it is clear that doses >200 mg daily are likely to be required to achieve the PK/PD target for common pathogens because of significant fluconazole clearance by SLED-f. Crown Copyright © 2014 Published by Elsevier B.V. on behalf of International Society of Chemotherapy. All rights reserved.
1. Introduction Fluconazole is a widely used triazole antifungal agent for prophylaxis, pre-emptive and empirical therapy, and treatment of known or suspected Candida spp. infections in intensive care units (ICUs). Acute kidney injury (AKI) is a common complication in ICU patients, with an incidence as high as 42% in patients with severe
∗ Corresponding author. Present address: Therapeutics Research Centre, Level 2, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, Adelaide, South Australia 5011, Australia. Tel.: +61 8 8222 6000; fax: +61 8 8222 6019. E-mail address: [email protected] (M.G. Sinnollareddy).
sepsis or septic shock, depending on the definition used [1]. Renal replacement therapy (RRT) is the commonly employed treatment for AKI. Although continuous renal replacement therapy (CRRT) is commonly used in the ICU, hybrid techniques including sustained low-efficiency dialysis/diafiltration (SLED/SLED-f), also known as slow low-efficiency dialysis or extended daily dialysis/diafiltration (EDD/EDD-f), are being increasingly utilised in ICUs as a more convenient alternative to CRRT [2]. Although no single RRT modality has been shown to be superior to others with respect to clinical outcomes, SLED-f is being increasingly used because of its practical advantages and cost savings over CRRT [2]. However, these advantages present a new set of challenges for drug dosing. Drug dosing in SLED-f may be more difficult and challenging compared with CRRT and intermittent
http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013 0924-8579/Crown Copyright © 2014 Published by Elsevier B.V. on behalf of International Society of Chemotherapy. All rights reserved.
Please cite this article in press as: Sinnollareddy MG, et al. Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013
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haemodialysis (IHD) owing to variations in clearance during and after SLED-f because of its intermittent nature and the dynamic physiological changes in critically ill patients compared with chronic renal failure patients, respectively. This is further compounded by the paucity of pharmacokinetic studies available to rationalise antifungal dosing in patients receiving SLED-f [2]. Moreover, membrane types, flow rates and the duration of SLED-f treatment used in different studies have not been sufficiently uniform to inform clinicians as to how they may adapt dosing for their setting. In addition, given the common use of high-flux filters during SLED-f, drug dosing recommendations based on older practices and equipment may result in suboptimal dosing. Owing to an increasing incidence of Candida spp. infections, use of fluconazole, use of SLED-f in ICUs and lack of fluconazole dose sufficiency studies in SLED-f, the objective of this study was to describe the pharmacokinetics of fluconazole during SLED-f and to compare the results with those reported in other forms of RRT.
2. Materials and methods This was a prospective, open-label, pharmacokinetic study conducted at the ICU of The Queen Elizabeth Hospital (Adelaide, Australia). Critically ill patients who met the following criteria were eligible for inclusion: (i) age ≥18 years; (ii) present in the ICU and undergoing/planned to undergo SLED-f; (iii) arterial line in situ or planned insertion; (iv) indwelling urinary catheter in situ or planned insertion; and (v) informed consent from the patient or the substitute decision-maker. Patients who met one or more of the following criteria were excluded: (i) known or suspected allergy to triazole antifungal agents; and (ii) pregnancy.
2.1. Fluconazole administration and sample collection Fluconazole (200 mg) was administered as an intravenous infusion over 60 min at 4–6 h prior to initiation of SLED-f. One patient received 200 mg twice daily, whereas the other two patients received 200 mg daily. Blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from the arterial catheter before and after the SLED-f treatment period. The aim was to collect blood samples before initiation of the infusion and at 60, 120, 240 and 300 or 360 min following commencement of the infusion; during SLED-f, at 60, 120, 180, 240, 300 and 360 min (SLED-f completion); post SLED-f at 30, 60, 120 min and prior to next dose where possible. Ultrafiltration samples were not able to be collected due to use of an online water inlet and outlet system common to SLED-f circuitry.
2.2. Sustained low-efficiency diafiltration prescription SLED-f was performed in all patients using a 4008S haemodialysis machine (Fresenius Medical Care, Bad Homburg, Germany) with an AV600S Ultraflux® Polysulfone® filter (1.4 m2 surface area; Fresenius Medical Care). A standardised prescription consisted of haemodiafiltration with target duration of 6–8 h (with 12 L/h of blood and dialysate flow and 3.96 L/h of pre-dilution). The biochemical composition of the dialysate and bicarbonate-based replacement fluid was set according to the patient’s biochemistry. Data on the precise times for SLED-f commencement and cessation, due to blood clotting on the filter or the end of treatment, were recorded. Vascular access in all patients was achieved via a doublelumen catheter inserted in either the internal jugular or the femoral vein.
2.3. Assay Plasma concentrations of fluconazole were analysed with a high-performance liquid chromatography (HPLC) system (Shimadzu Corp., Kyoto, Japan) with electrospray mass spectrometer detector (LC/MS–MS) (API 2000TM ; Applied Biosystems, Foster City, CA). Briefly, the method was as follows: 300 L of plasma was mixed with 50 L of internal standard (voriconazole 1 g/mL) and was precipitated with 150 L of 10% trichloroacetic acid. The samples were centrifuged at 12 000 × g for 6 min at 4 ◦ C after thoroughly vortexing for 30 s. Analytes were separated through an Agilent ZORBAX Eclipse XDB-c18 (2.1 mm × 150 mm, 3.5 m particle size) (Agilent Technologies Inc., Santa Clara, CA) by gradient elution using mobile phase A (water containing 0.1% formic acid) and mobile phase B (methanol containing 0.1% formic acid) with a total flow rate of 0.3 mL/min and were detected by an electrospray positive-ionisation mode of tandem mass spectrometry. Mass-tocharge ratios (m/z) in multiple-reaction monitoring were 307.3/127 for fluconazole and 349.9/224 for the internal standard. The calibration curve was linear over the concentration range 0.1–20 mg/L. The intraday and interday coefficients of variation were validated to be within 10% at low, medium and high concentrations of the calibration range. Assays were validated and conducted using criteria from the US Food and Drug Administration (FDA) guidance on bioanalysis [3]. 2.4. Pharmacokinetic analysis Non-compartmental pharmacokinetic analysis for the data was performed. The maximum concentration in plasma (Cmax ) and the time to reach Cmax after drug administration were obtained directly by visual examination of concentration–time data. The area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞ ) was calculated by the log-linear trapezoidal rule until the time of the last quantifiable plasma concentration and then extrapolated to infinity using the quotient of the last measurable concentration to the terminal phase rate constant (ˇ). The terminal elimination rate constant (ˇ) was estimated from the slope of the terminal exponential phase of the logarithmic plasma concentration–time profile. The elimination half-life (t1/2ˇ ) was determined as 0.693/ˇ. Clearance (CL) was determined as dose/AUC0–∞ . The dialyser clearance (CLdial ) was estimated from concentrations before (Cin ) and directly after (Cout ) the SLED-f filter as CLdial = (Qin ·Cin − Qout ·Cout )/Cin , where the plasma flow in (Qin ) and out (Qout ) of the dialyser were estimated using the blood flow, haematocrit and ultrafiltration rate. The rebound concentration (Crebound ) was estimated from concentrations immediately after SLED-f completion (SLED-f Cmin ) and maximum measured concentration after SLED-f (SLED-f Cmax ) as Crebound = (SLED-f Cmin − SLED-f Cmax )/SLED-f Cmax . The fraction of drug removed by the dialyser was estimated using AUC as (AUCwithout SLED-f − AUCwith SLED-f )/AUCwithout SLED-f . 3. Results Three AKI patients with anuria (urine output <100 mL) were recruited. Two patients had received fluconazole for 10 days and the other for 5 days prior to enrolment into the study. All three patients received SLED-f for 6 h with fluid removal of 0.40 ± 0.08 L/h. Total effluent flow achieved in this study was 16.36 ± 0.08 L/h. Blood samples were collected post completion of SLED-f for only two patients because a 12-hourly dosing regimen was chosen by the treating team in the third patient, making it impossible to further describe elimination-phase concentrations.
Please cite this article in press as: Sinnollareddy MG, et al. Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013
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Fig. 1. Pre- and post-filter fluconazole plasma concentrations following administration of a 200 mg intravenous dose in three intensive care unit patients with acute kidney injury receiving sustained low-efficiency diafiltration (SLED-f).
Table 1 Demographic and clinical characteristics of patients receiving sustained low-efficiency diafiltration (SLED-f).
Age (years) Weight (kg) APACHE II score (24 h prior to enrolment) SOFA score Serum Cr (mmol/L) (on the day of SLED-f) Invasive ventilation Vasopressor/inotropic supporta ICU admission diagnosis Outcome (ICU survival)
Patient 1
Patient 2
Patient 3
42 80 32 6 321 Yes No ARDS/pneumonia Yes
64 76 38 8 456 Yes No Sepsisb /infected aortobifemoral bypass graft No
69 65 22 7 270 No No Sepsis/bile leak post MRCP Yes
APACHE, Acute Physiology and Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment; Cr, creatinine; ICU, intensive care unit; ARDS, acute respiratory distress syndrome; MRCP, magnetic resonance cholangiopancreatography. a Received one of the following to maintain clinician-targeted mean arterial pressure: noradrenaline; adrenaline; dopamine; vasopressin; or dobutamine. b Sepsis is defined as suspected or confirmed infection and two or more systemic inflammatory response syndrome (SIRS) criteria documented in the previous 24 h: white blood cells >12 000/mm3 or <4000/mm3 , or >10% immature (band) forms; temperature >38 ◦ C or <36 ◦ C; heart rate >90 beats/min; respiratory rate >20 breaths/min or PaCO2 (arterial partial pressure of CO2 ) <32 mmHg or mechanical ventilation.
Post-SLED-f blood samples were collected for 2 h in one patient and for 6 h in the other patient. Timing of the blood samples was not uniform to the schedule mentioned in Section 2.1 because of the difficulty in coinciding fluconazole administration and the clinically required SLED-f initiation. The plasma concentration–time profile of fluconazole in pre-filter and post-filter lines of SLED-f for three patients is presented in Fig. 1. Tables 1 and 2 describe the demographic and clinical characteristics of the subjects and the pharmacokinetic parameter estimates for fluconazole, respectively. These values were compared against published data for fluconazole in other RRTs [4–9]. Clearance during dialysis (CLSLED-f ) was found to be 2.06 L/h (compared with 0.9–1.4 L/h in patients with normal renal function), which was
comparable with clearance in the pre-dilution mode of continuous venovenous haemodiafiltration (CVVHDF) but lower than that reported during the post-dilution mode of CVVHDF. Seventy-two percent of fluconazole was cleared by SLED-f during the 6-h treatment. The fluconazole half-life during SLED-f was 10.4 h and the rebound concentration was <2% based on the data available from two patients. 4. Discussion To the best of our knowledge, this is the first report of fluconazole pharmacokinetics during SLED-f. Fluconazole is a widely used antifungal agent in critically ill patients and yet information
Table 2 Pharmacokinetic parameters of fluconazole in intensive care unit patients receiving sustained low-efficiency diafiltration (SLED-f) compared with other renal replacement therapies.
No. of patients RF mode Membrane type/SA (m2 ) Qb , Qd (L/h) Quf (L/h) t1/2on RRT (h)b CLon RRT (L/h)b AUC0–24 (mg·h/L)b Dose administered (mg) Recommended dose/day (mg) Urine output (mL) Dialyser clearance (%)b
SLED-f (this Study)
IHD [7,8]
CVVHF [5]
CVVHDF [6]
CVVHDF [9]
CVVHDF [4]a
3 Pre dilution PS Ultraflux/1.4 12, 12 4.4 10.4 (2.9) 2.1 (0.5) 152 (38) 200 ≥400 Anuric (<100) 72 (13)
5 NR NR NR NR NR NR NR 50–200 NR NR 33–38
6 8 Pre dilution PS High-flux/1.3 11–12, NA 11–12, NA 1 2 33.3 (15) 24.8 (9) 0.7 (0.1) 1.1 (0.8) 473 (131) 385 (116) 800 800 800 800 NR NR 44 (23) 49 (35)
6 Pre dilution AN High-flux/0.9 5.4, 1 1 21.5 (6) 1.6 (0.2) 195 (137) 400 Up to 1000 NR 80 (12)
4 Post dilution CTA High-flux/1.5 6.3, 1.2 2.2 9.1 (1.6) 3.2 (2.2) 297 (202) 800 1000–1200 Oliguric (<500) NR
10 Pre dilution AN High-flux 12, 1 2 NR 1.7 (1.4–1.9c ) NR 200 800 NR 62 (20d )
IHD, intermittent haemodialysis; CVVHF, continuous venovenous haemofiltration; CVVHDF, continuous venovenous haemodiafiltration; RF, replacement fluid; NR, not reported; SA, surface area; PS, Polysulfone® ; AN, acrylonitrile; CTA, cellulose triacetate; Qb , blood flow rate; Qd , dialysis flow rate; NA, not applicable; Quf , ultrafiltration rate; t1/2on RRT , half-life during renal replacement therapy; CLon RRT , clearance during renal replacement therapy; AUC0–24 , area under the concentration–time curve from 0–24 h. a Only study that used population pharmacokinetics and Monte Carlo simulations to determine the optimal dose to attain pharmacokinetic/pharmacodynamic target. b Data are presented as median (interquartile range). c 95th percentile. d Between-subject variability.
Please cite this article in press as: Sinnollareddy MG, et al. Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013
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on the effect of SLED-f on its dosing requirements is lacking [10,11]. Although limited data are available from IHD studies in end-stage renal disease patients [7,8,12], these cannot be extrapolated to SLED-f, particularly in the context of critical illness due to longer RRT treatment times, frequency of treatment, filter types, blood flow rates, dialysate flow rates and the additional ultrafiltration component. The data from this report also indicate that the clearance of fluconazole differs from that of IHD. Oono et al. [7] and Toon et al. [8] have reported that approximately 33–38% of the administered dose was eliminated during one IHD session (4 h) in patients with end-stage renal disease compared with the value of 72% observed in the current study (Table 2). RRT settings have not been consistently reported in the previous studies in RRT preventing an accurate interpretation of the effect of changes in RRT settings on fluconazole clearance. The longer treatment time (4 h vs. 6 h) and possibly higher efficiency dialyser are likely explanations for the higher fluconazole clearance observed in the present study. This suggests that the dose recommended for IHD and some other RRT techniques could lead to suboptimal dosing in patients receiving SLED-f. Clearance (CLSLED-f ), half-life (t1/2 ), 24-h area under the concentration–time curve (AUC0–24 ) and fraction cleared by the dialyser obtained from this study were comparable with those reported in CVVHDF studies (Table 2). This demonstrates that although drug elimination per unit time is greater during SLEDf, the shorter duration of therapy means that drug clearance over 24 h is comparable for both modalities. Importantly, this study does not provide definitive dosing guidance due to the small number of patients, but we hypothesise that fluconazole could be dosed as in patients receiving CVVHDF using a pre-dilution mode. However, it should be noted that as in CRRT, fluconazole clearance in patients receiving SLED-f will neither be constant nor predictable because of higher clearance during SLED-f and potentially impaired clearance when not receiving SLED-f. Therefore, it is important to pay attention to residual renal function, to the duration of RRT and the relevant pharmacokinetic/pharmacodynamic index, namely the ratio of free-drug area under the concentration–time curve from 0–24 h to minimum inhibitory concentration (fAUC0–24 /MIC) of 100 for fluconazole [13]. Knowledge of these issues can help procure appropriate doses and timing of those doses relative to use of SLED-f. This approach was recently demonstrated for the aminoglycoside antibacterial gentamicin that has concentration-dependent killing activity [14]. Importantly, the mean AUC0–24 observed in this study was 152 mg·h/L, which would not be sufficient to attain a fAUC0–24 /MIC of 100 for a MIC ≥ 2 mg/L. Another important factor to consider is that some ICUs use SLED for up to 12 h and some use it in a continuous mode, in which circumstances fluconazole clearance will be higher than reported in this study. Accordingly, in such circumstances higher doses would be required to attain the required fAUC0–24 /MIC. The observed rebound concentration in this study was <2%. Whilst previous reports suggest that fluconazole moves rapidly from tissues into the systemic circulation during IHD [7], rebounds in concentrations have not been observed after IHD [8]. Therefore, it is not surprising that fluconazole rebound was very low in SLED-f and is unlikely to be clinically significant. Although a final dosing recommendation cannot be provided based on the data from this report, we suggest a dose higher than 200 mg in patients with anuria receiving SLED-f with the above settings. Loading doses would remain appropriate and maintenance
doses on non-SLED-f days should be adjusted to the patient’s renal function. As it can be challenging to accurately predict required doses because of the variability in critically ill patients receiving RRT, dose individualisation techniques using Bayesian estimation methods might help to provide more accurate dosing. 5. Conclusion This study is the first to describe the pharmacokinetics of fluconazole during SLED-f in ICU patients. Despite the limitation of the small patient number, this study provides a valuable insight into fluconazole disposition in critically ill patients receiving SLEDf. A definitive dosing recommendation cannot be made due to the low patient number. However, it is evident based on the observed AUC0–24 that fluconazole doses >200 mg are likely to be required in patients with anuria receiving SLED-f. Funding: No funding sources. Competing interests: None declared. Ethical approval: Institutional Human Research Ethics Committee [HREC/12/TQEHLMH/44/AM01] and University of South Australia, Adelaide Human Ethics Committee [0000031129]. References [1] Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 2004;351:159–69. [2] Bogard KN, Peterson NT, Plumb TJ, Erwin MW, Fuller PD, Olsen KM. Antibiotic dosing during sustained low-efficiency dialysis: special considerations in adult critically ill patients. Crit Care Med 2011;39:560–70. [3] US Food and Drug Administration. Guidance for industry. Bioanalytical method validation. Rockville, MD: FDA; 2001. http://www.fda.gov/downloads/ Drugs/Guidances/ucm070107.pdf [accessed 25.09.13]. [4] Patel K, Roberts JA, Lipman J, Tett SE, Deldot ME, Kirkpatrick CM. Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration: using Monte Carlo simulations to predict doses for specified pharmacodynamic targets. Antimicrob Agents Chemother 2011;55:5868–73. [5] Bergner R, Hoffmann M, Riedel KD, Mikus G, Henrich DM, Haefeli WE, et al. Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg. Nephrol Dial Transplant 2006;21: 1019–23. [6] Muhl E, Martens T, Iven H, Rob P, Bruch HP. Influence of continuous venovenous haemodiafiltration and continuous veno-venous haemofiltration on the pharmacokinetics of fluconazole. Eur J Clin Pharmacol 2000;56:671–8. [7] Oono S, Tabei K, Tetsuka T, Asano Y. The pharmacokinetics of fluconazole during haemodialysis in uraemic patients. Eur J Clin Pharmacol 1992;42:667–9. [8] Toon S, Ross CE, Gokal R, Rowland M. An assessment of the effects of impaired renal function and haemodialysis on the pharmacokinetics of fluconazole. Br J Clin Pharmacol 1990;29:221–6. [9] Yagasaki K, Gando S, Matsuda N, Kameue T, Ishitani T, Hirano T, et al. Pharmacokinetics and the most suitable dosing regimen of fluconazole in critically ill patients receiving continuous hemodiafiltration. Intensive Care Med 2003;29:1844–8. [10] Sinnollareddy M, Peake SL, Roberts MS, Lipman J, Roberts JA. Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review. Int J Antimicrob Agents 2012;39:1–10. [11] Roberts JA, Mehta RL, Lipman J. Sustained low efficiency dialysis allows rational renal replacement therapy, but does it allow rational drug dosing? Crit Care Med 2011;39:602–3. [12] Berl T, Wilner KD, Gardner M, Hansen RA, Farmer B, Baris BA, et al. Pharmacokinetics of fluconazole in renal failure. J Am Soc Nephrol 1995;6:242–7. [13] European Committee on Antimicrobial Susceptibility Testing—Subcommittee on Antifungal Susceptibility Testing (EUCAST-AFST). EUCAST technical note on fluconazole. Clin Microbiol Infect 2008;14:193–5 [Erratum in: Clin Microbiol Infect 2009;15:103]. [14] Roberts JA, Field J, Visser A, Whitbread R, Tallot M, Lipman J, et al. Using population pharmacokinetics to determine gentamicin dosing during extended daily diafiltration in critically ill patients with acute kidney injury. Antimicrob Agents Chemother 2010;54:3635–40.
Please cite this article in press as: Sinnollareddy MG, et al. Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013
ARTICLE IN PRESS International Journal of Antimicrobial Agents xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Short Communication
Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration Mahipal G. Sinnollareddy a,b,∗ , Michael S. Roberts a,b , Jeffrey Lipman c,d , Thomas A. Robertson a,b , Sandra L. Peake e , Jason A. Roberts c,d,f,g a
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia c Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia d Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia e Department of Intensive Care Medicine, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia f Pharmacy Department, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia g Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK b
a r t i c l e
i n f o
Article history: Received 12 June 2014 Accepted 29 August 2014 Keywords: Pharmacokinetics Fluconazole Renal replacement therapy Sustained low-efficiency diafiltration Extended daily diafiltration Critically ill patients
a b s t r a c t Fluconazole is a widely used antifungal agent in critically ill patients. It is predominantly (60–80%) excreted unchanged in urine. Sustained low-efficiency diafiltration (SLED-f) is increasingly being utilised in critically ill patients because of its practical advantages over continuous renal replacement therapy. To date, the effect of SLED-f on fluconazole pharmacokinetics and dosing has not been studied. The objective of this study was to describe the pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving SLED-f and to compare this with other forms of renal replacement therapy. Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter before and after SLED-f from three patients during one session. Fluconazole concentrations were measured using a validated chromatography method. Median clearance (CL) and 24-h area under the concentration–time curve (AUC0–24 ) were 2.1 L/h and 152 mg·h/L, respectively, whilst receiving SLED-f. Moreover, 72% of fluconazole was cleared by a single SLED-f session (6 h) compared with previous reports of 33–38% clearance by a 4-h intermittent haemodialysis session. CL and AUC0–24 were comparable with previous observations in a pre-dilution mode of continuous venovenous haemodiafiltration. The observed rebound concentration of fluconazole post SLED-f was <2%. Although a definitive dosing recommendation is not possible due to the small patient number, it is clear that doses >200 mg daily are likely to be required to achieve the PK/PD target for common pathogens because of significant fluconazole clearance by SLED-f. Crown Copyright © 2014 Published by Elsevier B.V. on behalf of International Society of Chemotherapy. All rights reserved.
1. Introduction Fluconazole is a widely used triazole antifungal agent for prophylaxis, pre-emptive and empirical therapy, and treatment of known or suspected Candida spp. infections in intensive care units (ICUs). Acute kidney injury (AKI) is a common complication in ICU patients, with an incidence as high as 42% in patients with severe
∗ Corresponding author. Present address: Therapeutics Research Centre, Level 2, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, Adelaide, South Australia 5011, Australia. Tel.: +61 8 8222 6000; fax: +61 8 8222 6019. E-mail address: [email protected] (M.G. Sinnollareddy).
sepsis or septic shock, depending on the definition used [1]. Renal replacement therapy (RRT) is the commonly employed treatment for AKI. Although continuous renal replacement therapy (CRRT) is commonly used in the ICU, hybrid techniques including sustained low-efficiency dialysis/diafiltration (SLED/SLED-f), also known as slow low-efficiency dialysis or extended daily dialysis/diafiltration (EDD/EDD-f), are being increasingly utilised in ICUs as a more convenient alternative to CRRT [2]. Although no single RRT modality has been shown to be superior to others with respect to clinical outcomes, SLED-f is being increasingly used because of its practical advantages and cost savings over CRRT [2]. However, these advantages present a new set of challenges for drug dosing. Drug dosing in SLED-f may be more difficult and challenging compared with CRRT and intermittent
http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013 0924-8579/Crown Copyright © 2014 Published by Elsevier B.V. on behalf of International Society of Chemotherapy. All rights reserved.
Please cite this article in press as: Sinnollareddy MG, et al. Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013
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haemodialysis (IHD) owing to variations in clearance during and after SLED-f because of its intermittent nature and the dynamic physiological changes in critically ill patients compared with chronic renal failure patients, respectively. This is further compounded by the paucity of pharmacokinetic studies available to rationalise antifungal dosing in patients receiving SLED-f [2]. Moreover, membrane types, flow rates and the duration of SLED-f treatment used in different studies have not been sufficiently uniform to inform clinicians as to how they may adapt dosing for their setting. In addition, given the common use of high-flux filters during SLED-f, drug dosing recommendations based on older practices and equipment may result in suboptimal dosing. Owing to an increasing incidence of Candida spp. infections, use of fluconazole, use of SLED-f in ICUs and lack of fluconazole dose sufficiency studies in SLED-f, the objective of this study was to describe the pharmacokinetics of fluconazole during SLED-f and to compare the results with those reported in other forms of RRT.
2. Materials and methods This was a prospective, open-label, pharmacokinetic study conducted at the ICU of The Queen Elizabeth Hospital (Adelaide, Australia). Critically ill patients who met the following criteria were eligible for inclusion: (i) age ≥18 years; (ii) present in the ICU and undergoing/planned to undergo SLED-f; (iii) arterial line in situ or planned insertion; (iv) indwelling urinary catheter in situ or planned insertion; and (v) informed consent from the patient or the substitute decision-maker. Patients who met one or more of the following criteria were excluded: (i) known or suspected allergy to triazole antifungal agents; and (ii) pregnancy.
2.1. Fluconazole administration and sample collection Fluconazole (200 mg) was administered as an intravenous infusion over 60 min at 4–6 h prior to initiation of SLED-f. One patient received 200 mg twice daily, whereas the other two patients received 200 mg daily. Blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from the arterial catheter before and after the SLED-f treatment period. The aim was to collect blood samples before initiation of the infusion and at 60, 120, 240 and 300 or 360 min following commencement of the infusion; during SLED-f, at 60, 120, 180, 240, 300 and 360 min (SLED-f completion); post SLED-f at 30, 60, 120 min and prior to next dose where possible. Ultrafiltration samples were not able to be collected due to use of an online water inlet and outlet system common to SLED-f circuitry.
2.2. Sustained low-efficiency diafiltration prescription SLED-f was performed in all patients using a 4008S haemodialysis machine (Fresenius Medical Care, Bad Homburg, Germany) with an AV600S Ultraflux® Polysulfone® filter (1.4 m2 surface area; Fresenius Medical Care). A standardised prescription consisted of haemodiafiltration with target duration of 6–8 h (with 12 L/h of blood and dialysate flow and 3.96 L/h of pre-dilution). The biochemical composition of the dialysate and bicarbonate-based replacement fluid was set according to the patient’s biochemistry. Data on the precise times for SLED-f commencement and cessation, due to blood clotting on the filter or the end of treatment, were recorded. Vascular access in all patients was achieved via a doublelumen catheter inserted in either the internal jugular or the femoral vein.
2.3. Assay Plasma concentrations of fluconazole were analysed with a high-performance liquid chromatography (HPLC) system (Shimadzu Corp., Kyoto, Japan) with electrospray mass spectrometer detector (LC/MS–MS) (API 2000TM ; Applied Biosystems, Foster City, CA). Briefly, the method was as follows: 300 L of plasma was mixed with 50 L of internal standard (voriconazole 1 g/mL) and was precipitated with 150 L of 10% trichloroacetic acid. The samples were centrifuged at 12 000 × g for 6 min at 4 ◦ C after thoroughly vortexing for 30 s. Analytes were separated through an Agilent ZORBAX Eclipse XDB-c18 (2.1 mm × 150 mm, 3.5 m particle size) (Agilent Technologies Inc., Santa Clara, CA) by gradient elution using mobile phase A (water containing 0.1% formic acid) and mobile phase B (methanol containing 0.1% formic acid) with a total flow rate of 0.3 mL/min and were detected by an electrospray positive-ionisation mode of tandem mass spectrometry. Mass-tocharge ratios (m/z) in multiple-reaction monitoring were 307.3/127 for fluconazole and 349.9/224 for the internal standard. The calibration curve was linear over the concentration range 0.1–20 mg/L. The intraday and interday coefficients of variation were validated to be within 10% at low, medium and high concentrations of the calibration range. Assays were validated and conducted using criteria from the US Food and Drug Administration (FDA) guidance on bioanalysis [3]. 2.4. Pharmacokinetic analysis Non-compartmental pharmacokinetic analysis for the data was performed. The maximum concentration in plasma (Cmax ) and the time to reach Cmax after drug administration were obtained directly by visual examination of concentration–time data. The area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞ ) was calculated by the log-linear trapezoidal rule until the time of the last quantifiable plasma concentration and then extrapolated to infinity using the quotient of the last measurable concentration to the terminal phase rate constant (ˇ). The terminal elimination rate constant (ˇ) was estimated from the slope of the terminal exponential phase of the logarithmic plasma concentration–time profile. The elimination half-life (t1/2ˇ ) was determined as 0.693/ˇ. Clearance (CL) was determined as dose/AUC0–∞ . The dialyser clearance (CLdial ) was estimated from concentrations before (Cin ) and directly after (Cout ) the SLED-f filter as CLdial = (Qin ·Cin − Qout ·Cout )/Cin , where the plasma flow in (Qin ) and out (Qout ) of the dialyser were estimated using the blood flow, haematocrit and ultrafiltration rate. The rebound concentration (Crebound ) was estimated from concentrations immediately after SLED-f completion (SLED-f Cmin ) and maximum measured concentration after SLED-f (SLED-f Cmax ) as Crebound = (SLED-f Cmin − SLED-f Cmax )/SLED-f Cmax . The fraction of drug removed by the dialyser was estimated using AUC as (AUCwithout SLED-f − AUCwith SLED-f )/AUCwithout SLED-f . 3. Results Three AKI patients with anuria (urine output <100 mL) were recruited. Two patients had received fluconazole for 10 days and the other for 5 days prior to enrolment into the study. All three patients received SLED-f for 6 h with fluid removal of 0.40 ± 0.08 L/h. Total effluent flow achieved in this study was 16.36 ± 0.08 L/h. Blood samples were collected post completion of SLED-f for only two patients because a 12-hourly dosing regimen was chosen by the treating team in the third patient, making it impossible to further describe elimination-phase concentrations.
Please cite this article in press as: Sinnollareddy MG, et al. Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013
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Fig. 1. Pre- and post-filter fluconazole plasma concentrations following administration of a 200 mg intravenous dose in three intensive care unit patients with acute kidney injury receiving sustained low-efficiency diafiltration (SLED-f).
Table 1 Demographic and clinical characteristics of patients receiving sustained low-efficiency diafiltration (SLED-f).
Age (years) Weight (kg) APACHE II score (24 h prior to enrolment) SOFA score Serum Cr (mmol/L) (on the day of SLED-f) Invasive ventilation Vasopressor/inotropic supporta ICU admission diagnosis Outcome (ICU survival)
Patient 1
Patient 2
Patient 3
42 80 32 6 321 Yes No ARDS/pneumonia Yes
64 76 38 8 456 Yes No Sepsisb /infected aortobifemoral bypass graft No
69 65 22 7 270 No No Sepsis/bile leak post MRCP Yes
APACHE, Acute Physiology and Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment; Cr, creatinine; ICU, intensive care unit; ARDS, acute respiratory distress syndrome; MRCP, magnetic resonance cholangiopancreatography. a Received one of the following to maintain clinician-targeted mean arterial pressure: noradrenaline; adrenaline; dopamine; vasopressin; or dobutamine. b Sepsis is defined as suspected or confirmed infection and two or more systemic inflammatory response syndrome (SIRS) criteria documented in the previous 24 h: white blood cells >12 000/mm3 or <4000/mm3 , or >10% immature (band) forms; temperature >38 ◦ C or <36 ◦ C; heart rate >90 beats/min; respiratory rate >20 breaths/min or PaCO2 (arterial partial pressure of CO2 ) <32 mmHg or mechanical ventilation.
Post-SLED-f blood samples were collected for 2 h in one patient and for 6 h in the other patient. Timing of the blood samples was not uniform to the schedule mentioned in Section 2.1 because of the difficulty in coinciding fluconazole administration and the clinically required SLED-f initiation. The plasma concentration–time profile of fluconazole in pre-filter and post-filter lines of SLED-f for three patients is presented in Fig. 1. Tables 1 and 2 describe the demographic and clinical characteristics of the subjects and the pharmacokinetic parameter estimates for fluconazole, respectively. These values were compared against published data for fluconazole in other RRTs [4–9]. Clearance during dialysis (CLSLED-f ) was found to be 2.06 L/h (compared with 0.9–1.4 L/h in patients with normal renal function), which was
comparable with clearance in the pre-dilution mode of continuous venovenous haemodiafiltration (CVVHDF) but lower than that reported during the post-dilution mode of CVVHDF. Seventy-two percent of fluconazole was cleared by SLED-f during the 6-h treatment. The fluconazole half-life during SLED-f was 10.4 h and the rebound concentration was <2% based on the data available from two patients. 4. Discussion To the best of our knowledge, this is the first report of fluconazole pharmacokinetics during SLED-f. Fluconazole is a widely used antifungal agent in critically ill patients and yet information
Table 2 Pharmacokinetic parameters of fluconazole in intensive care unit patients receiving sustained low-efficiency diafiltration (SLED-f) compared with other renal replacement therapies.
No. of patients RF mode Membrane type/SA (m2 ) Qb , Qd (L/h) Quf (L/h) t1/2on RRT (h)b CLon RRT (L/h)b AUC0–24 (mg·h/L)b Dose administered (mg) Recommended dose/day (mg) Urine output (mL) Dialyser clearance (%)b
SLED-f (this Study)
IHD [7,8]
CVVHF [5]
CVVHDF [6]
CVVHDF [9]
CVVHDF [4]a
3 Pre dilution PS Ultraflux/1.4 12, 12 4.4 10.4 (2.9) 2.1 (0.5) 152 (38) 200 ≥400 Anuric (<100) 72 (13)
5 NR NR NR NR NR NR NR 50–200 NR NR 33–38
6 8 Pre dilution PS High-flux/1.3 11–12, NA 11–12, NA 1 2 33.3 (15) 24.8 (9) 0.7 (0.1) 1.1 (0.8) 473 (131) 385 (116) 800 800 800 800 NR NR 44 (23) 49 (35)
6 Pre dilution AN High-flux/0.9 5.4, 1 1 21.5 (6) 1.6 (0.2) 195 (137) 400 Up to 1000 NR 80 (12)
4 Post dilution CTA High-flux/1.5 6.3, 1.2 2.2 9.1 (1.6) 3.2 (2.2) 297 (202) 800 1000–1200 Oliguric (<500) NR
10 Pre dilution AN High-flux 12, 1 2 NR 1.7 (1.4–1.9c ) NR 200 800 NR 62 (20d )
IHD, intermittent haemodialysis; CVVHF, continuous venovenous haemofiltration; CVVHDF, continuous venovenous haemodiafiltration; RF, replacement fluid; NR, not reported; SA, surface area; PS, Polysulfone® ; AN, acrylonitrile; CTA, cellulose triacetate; Qb , blood flow rate; Qd , dialysis flow rate; NA, not applicable; Quf , ultrafiltration rate; t1/2on RRT , half-life during renal replacement therapy; CLon RRT , clearance during renal replacement therapy; AUC0–24 , area under the concentration–time curve from 0–24 h. a Only study that used population pharmacokinetics and Monte Carlo simulations to determine the optimal dose to attain pharmacokinetic/pharmacodynamic target. b Data are presented as median (interquartile range). c 95th percentile. d Between-subject variability.
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on the effect of SLED-f on its dosing requirements is lacking [10,11]. Although limited data are available from IHD studies in end-stage renal disease patients [7,8,12], these cannot be extrapolated to SLED-f, particularly in the context of critical illness due to longer RRT treatment times, frequency of treatment, filter types, blood flow rates, dialysate flow rates and the additional ultrafiltration component. The data from this report also indicate that the clearance of fluconazole differs from that of IHD. Oono et al. [7] and Toon et al. [8] have reported that approximately 33–38% of the administered dose was eliminated during one IHD session (4 h) in patients with end-stage renal disease compared with the value of 72% observed in the current study (Table 2). RRT settings have not been consistently reported in the previous studies in RRT preventing an accurate interpretation of the effect of changes in RRT settings on fluconazole clearance. The longer treatment time (4 h vs. 6 h) and possibly higher efficiency dialyser are likely explanations for the higher fluconazole clearance observed in the present study. This suggests that the dose recommended for IHD and some other RRT techniques could lead to suboptimal dosing in patients receiving SLED-f. Clearance (CLSLED-f ), half-life (t1/2 ), 24-h area under the concentration–time curve (AUC0–24 ) and fraction cleared by the dialyser obtained from this study were comparable with those reported in CVVHDF studies (Table 2). This demonstrates that although drug elimination per unit time is greater during SLEDf, the shorter duration of therapy means that drug clearance over 24 h is comparable for both modalities. Importantly, this study does not provide definitive dosing guidance due to the small number of patients, but we hypothesise that fluconazole could be dosed as in patients receiving CVVHDF using a pre-dilution mode. However, it should be noted that as in CRRT, fluconazole clearance in patients receiving SLED-f will neither be constant nor predictable because of higher clearance during SLED-f and potentially impaired clearance when not receiving SLED-f. Therefore, it is important to pay attention to residual renal function, to the duration of RRT and the relevant pharmacokinetic/pharmacodynamic index, namely the ratio of free-drug area under the concentration–time curve from 0–24 h to minimum inhibitory concentration (fAUC0–24 /MIC) of 100 for fluconazole [13]. Knowledge of these issues can help procure appropriate doses and timing of those doses relative to use of SLED-f. This approach was recently demonstrated for the aminoglycoside antibacterial gentamicin that has concentration-dependent killing activity [14]. Importantly, the mean AUC0–24 observed in this study was 152 mg·h/L, which would not be sufficient to attain a fAUC0–24 /MIC of 100 for a MIC ≥ 2 mg/L. Another important factor to consider is that some ICUs use SLED for up to 12 h and some use it in a continuous mode, in which circumstances fluconazole clearance will be higher than reported in this study. Accordingly, in such circumstances higher doses would be required to attain the required fAUC0–24 /MIC. The observed rebound concentration in this study was <2%. Whilst previous reports suggest that fluconazole moves rapidly from tissues into the systemic circulation during IHD [7], rebounds in concentrations have not been observed after IHD [8]. Therefore, it is not surprising that fluconazole rebound was very low in SLED-f and is unlikely to be clinically significant. Although a final dosing recommendation cannot be provided based on the data from this report, we suggest a dose higher than 200 mg in patients with anuria receiving SLED-f with the above settings. Loading doses would remain appropriate and maintenance
doses on non-SLED-f days should be adjusted to the patient’s renal function. As it can be challenging to accurately predict required doses because of the variability in critically ill patients receiving RRT, dose individualisation techniques using Bayesian estimation methods might help to provide more accurate dosing. 5. Conclusion This study is the first to describe the pharmacokinetics of fluconazole during SLED-f in ICU patients. Despite the limitation of the small patient number, this study provides a valuable insight into fluconazole disposition in critically ill patients receiving SLEDf. A definitive dosing recommendation cannot be made due to the low patient number. However, it is evident based on the observed AUC0–24 that fluconazole doses >200 mg are likely to be required in patients with anuria receiving SLED-f. Funding: No funding sources. Competing interests: None declared. Ethical approval: Institutional Human Research Ethics Committee [HREC/12/TQEHLMH/44/AM01] and University of South Australia, Adelaide Human Ethics Committee [0000031129]. References [1] Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 2004;351:159–69. [2] Bogard KN, Peterson NT, Plumb TJ, Erwin MW, Fuller PD, Olsen KM. Antibiotic dosing during sustained low-efficiency dialysis: special considerations in adult critically ill patients. Crit Care Med 2011;39:560–70. [3] US Food and Drug Administration. Guidance for industry. Bioanalytical method validation. Rockville, MD: FDA; 2001. http://www.fda.gov/downloads/ Drugs/Guidances/ucm070107.pdf [accessed 25.09.13]. [4] Patel K, Roberts JA, Lipman J, Tett SE, Deldot ME, Kirkpatrick CM. Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration: using Monte Carlo simulations to predict doses for specified pharmacodynamic targets. Antimicrob Agents Chemother 2011;55:5868–73. [5] Bergner R, Hoffmann M, Riedel KD, Mikus G, Henrich DM, Haefeli WE, et al. Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg. Nephrol Dial Transplant 2006;21: 1019–23. [6] Muhl E, Martens T, Iven H, Rob P, Bruch HP. Influence of continuous venovenous haemodiafiltration and continuous veno-venous haemofiltration on the pharmacokinetics of fluconazole. Eur J Clin Pharmacol 2000;56:671–8. [7] Oono S, Tabei K, Tetsuka T, Asano Y. The pharmacokinetics of fluconazole during haemodialysis in uraemic patients. Eur J Clin Pharmacol 1992;42:667–9. [8] Toon S, Ross CE, Gokal R, Rowland M. An assessment of the effects of impaired renal function and haemodialysis on the pharmacokinetics of fluconazole. Br J Clin Pharmacol 1990;29:221–6. [9] Yagasaki K, Gando S, Matsuda N, Kameue T, Ishitani T, Hirano T, et al. Pharmacokinetics and the most suitable dosing regimen of fluconazole in critically ill patients receiving continuous hemodiafiltration. Intensive Care Med 2003;29:1844–8. [10] Sinnollareddy M, Peake SL, Roberts MS, Lipman J, Roberts JA. Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review. Int J Antimicrob Agents 2012;39:1–10. [11] Roberts JA, Mehta RL, Lipman J. Sustained low efficiency dialysis allows rational renal replacement therapy, but does it allow rational drug dosing? Crit Care Med 2011;39:602–3. [12] Berl T, Wilner KD, Gardner M, Hansen RA, Farmer B, Baris BA, et al. Pharmacokinetics of fluconazole in renal failure. J Am Soc Nephrol 1995;6:242–7. [13] European Committee on Antimicrobial Susceptibility Testing—Subcommittee on Antifungal Susceptibility Testing (EUCAST-AFST). EUCAST technical note on fluconazole. Clin Microbiol Infect 2008;14:193–5 [Erratum in: Clin Microbiol Infect 2009;15:103]. [14] Roberts JA, Field J, Visser A, Whitbread R, Tallot M, Lipman J, et al. Using population pharmacokinetics to determine gentamicin dosing during extended daily diafiltration in critically ill patients with acute kidney injury. Antimicrob Agents Chemother 2010;54:3635–40.
Please cite this article in press as: Sinnollareddy MG, et al. Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013