Pharmacokinetics of piperacillin in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration

Pharmacokinetics of piperacillin in critically ill patients with acute kidney injury receiving... Abstract Background Piperacillin is a β-lactam penicillin antibiotic commonly used for the empirical therapy of sepsis and other hospital-acquired infections. However, knowledge regarding the effect of sustained low-efficiency diafiltration (SLED-f), a technique increasingly being used in ICUs, on piperacillin pharmacokinetics (PK) and dosing in critically ill patients is lacking. Objectives To describe the PK of piperacillin during SLED-f and compare the results with those reported for other forms of renal replacement therapies. Methods Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f in one session and from an arterial catheter during sampling without SLED-f. Piperacillin concentrations were measured using a validated chromatography method. Non-compartmental PK analysis of the data was performed. Results The median clearance and area under the concentration–time curve during SLED-f were 6 L/h and 532 mg·h/L, respectively. Fifty-eight percent of piperacillin was cleared by a single SLED-f session (6 h) compared with previous reports of 30%–45% clearance by a 3.5 h intermittent haemodialysis session. Clearance, half-life and area under the concentration–time curve during SLED-f obtained from this study were comparable with those reported in the post-dilution mode of continuous veno-venous haemodiafiltration studies. Conclusions As it can be challenging to accurately predict when SLED-f will be initiated in the critically ill, a maintenance dose of at least 4 g every 12 h with at least a 2 g replacement dose post-SLED-f would be a practical approach to piperacillin dosing in ICU patients with anuria receiving SLED-f with a duration similar to the current study. Introduction Infection and related sepsis/septic shock are the most common causes of acute kidney injury (AKI) in ICU patients. It is associated with a high (up to 60%) in-hospital mortality. The mortality associated with the combination of sepsis and AKI is significantly higher compared with AKI alone.1,2 Therefore, as with all other interventional measures, an early and appropriate antibiotic regimen is important for improving patient outcomes. Renal replacement therapy (RRT) is an integral part of the management of AKI in critically ill patients. Although continuous RRT (CRRT) is commonly employed, hybrid techniques, including sustained low-efficiency dialysis/diafiltration (SLED/SLED-f), also known as slow low-efficiency dialysis and extended daily dialysis/diafiltration (EDD/EDD-f), are being used because of their practical advantages and cost savings over CRRT with similar haemodynamic stability and no difference in mortality.3,4 SLED-f was developed as an intermediate mode of therapy between CRRT and intermittent haemodialysis (IHD). SLED-f is typically used for only 6–12 h per day, although rarely some units employ it as a continuous modality.4 However, these advantages present a new set of challenges for drug dosing owing to variations in CL during and after SLED-f because of its intermittent nature. Drug dosing studies have been conducted on <20% of the currently used drugs in CRRT and <1% of the hybrid techniques.4–6 This is further complicated by the pathophysiological changes and related pharmacokinetic (PK) and pharmacodynamic (PD) variation in critically ill patients.7 Piperacillin is a β-lactam penicillin antibiotic commonly used for the empirical therapy of sepsis and other hospital-acquired infections in critically ill patients. Renal elimination of piperacillin accounts for ∼50%–60% of the dose administered and involves glomerular filtration and tubular secretion.8 Although dosing requirements for piperacillin/tazobactam have been relatively well established in CRRTs, the dosages required to attain the PD targets during SLED-f have not been established.9 The objective of the study was to describe the PK of piperacillin during SLED-f and compare the results with those reported in other forms of RRT. Methods Ethics Ethics approval was granted by the Institutional Human Research Ethics Committee (HREC/12/TQEHLMH/44/AM01) and University of South Australia, Adelaide Human Ethics Committee (0000031129). This was a prospective, open-labelled PK study conducted at the ICU of The Queen Elizabeth Hospital (Adelaide, Australia). Critically ill patients who met the following criteria were enrolled after obtaining written informed consent either from the patient or the patient’s legally authorized representative: (i) receiving piperacillin in combination with tazobactam; (ii) age ≥18 years; (iii) present in ICU and undergoing/planning to undergo SLED-f; (iv) arterial line in situ or planned insertion; and (v) indwelling urinary catheter in situ or planned insertion. Patients who met one or both of the following criteria were excluded: (i) known or suspected allergy to penicillin agents; and (ii) pregnancy. Piperacillin/tazobactam administration and sample collection Piperacillin in combination with tazobactam was initiated at the discretion of the treating physician based on the clinical requirement. Piperacillin (4 g) was administered in combination with tazobactam as an intravenous infusion over 30 min. Sampling occurred during two dosing intervals: one during SLED-f and another without SLED-f. Piperacillin/tazobactam was administered 30 min prior to initiation of SLED-f when sampling with SLED-f. Blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter during sampling without SLED-f. Blood samples were collected before initiation of the infusion and at 30, 60, 120, 180, 240, 300 and 360 min post-commencement of the infusion. Ultrafiltration samples could not be collected owing to use of an online water inlet and outlet system common to SLED-f circuitry. SLED-f was performed in all patients using a 4008S haemodialysis machine (Fresenius Medical Care, Bad Homburg, Germany) with an AV600S polysulphone ultra-flux filter (1.4 m2 surface area, Fresenius Medical Care, Bad Homburg, Germany). A standardized prescription consisted of haemodiafiltration with a target duration of 6–8 h (with 12 L/h blood and dialysate flow and 4 L/h pre-dilution). Data on the precise times for SLED-f commencement and cessation, owing to blood clotting on the filter or the end of treatment, were recorded. Plasma concentrations of piperacillin were analysed with a previously validated HPLC system with an electrospray mass spectrometer detector (LC/MS–MS) (AB Sciex Pty Ltd API3200; Shimadzu HPLC, Kyoto, Japan).10 PK and statistical analysis Non-compartmental PK analysis of the data was performed. Cmax and Tmax after drug administration were obtained directly by visual examination of concentration–time data. The terminal Kel was estimated from the slope of the terminal exponential phase of the logarithmic plasma concentration–time profile, and t½ was determined as 0.693/Kel. CL was determined as dose/plasma AUC0–∞. The amount of piperacillin removed owing to SLED-f was estimated from concentrations before (Cin) and directly after (Cout) the SLED-f filter: (Qin·Cin − Qout·Cout)/Cin, where plasma flows in (Qin) and out (Qout) of the dialyser were estimated using the blood flow, haematocrit and ultrafiltration rate. The Mann–Whitney U-test was used to compare the PK parameters with and without SLED-f using GraphPad Prism version 7.00 for Windows (GraphPad Software, La Jolla, CA, USA; www.graphpad.com) and P < 0.05 was considered to be statistically significant. Results Six AKI patients with anuria (urine output <100 mL) and sepsis were recruited. Sampling occurred in six patients during SLED-f and in five patients without SLED-f. In all patients sampling occurred at least 2 days after treatment initiation with piperacillin/tazobactam. All six patients received SLED-f for 6 h with a total fluid removal of 2.08 ± 0.92 L. The total effluent flow achieved in this study was 16.36 ± 0.18 L/h. The cumulative fluid balance was positive (6.30 ± 3.90 L). All patients received 12 hourly piperacillin dosing except one who received 24 hourly piperacillin. Tables 1 and 2 describe the demographic and clinical characteristics of the subjects and the PK parameter estimates for piperacillin with and without SLED-f, respectively. A statistically significant difference (P < 0.05) was observed for CL and t½ with and without SLED-f. We compared the PK parameters observed in this study against the published data for piperacillin in other RRTs (Table 3).8,11–14 Fifty-eight percent of piperacillin was cleared by SLED-f during the 6 h treatment. Table 1. Demographic and clinical characteristics of critically ill patients receiving SLED-f and piperacillin Number of patients 6 Dose (mg) 4000 Age (years), median (IQR) 58 (12) Weight (kg), median (IQR) 80 (25) Male/female, n/n 4/2 APACHE II score, median (IQR) 34 (10) SOFA score, median (IQR) 9 (2.7) Invasive ventilation, n (%) 6 (100) Vasopressor/inotropic supporta, n (%) 3 (50) Number of patients 6 Dose (mg) 4000 Age (years), median (IQR) 58 (12) Weight (kg), median (IQR) 80 (25) Male/female, n/n 4/2 APACHE II score, median (IQR) 34 (10) SOFA score, median (IQR) 9 (2.7) Invasive ventilation, n (%) 6 (100) Vasopressor/inotropic supporta, n (%) 3 (50) a Received one of the following to maintain clinician-targeted mean arterial pressure: noradrenaline, adrenaline, dopamine, vasopressin or dobutamine. Table 1. Demographic and clinical characteristics of critically ill patients receiving SLED-f and piperacillin Number of patients 6 Dose (mg) 4000 Age (years), median (IQR) 58 (12) Weight (kg), median (IQR) 80 (25) Male/female, n/n 4/2 APACHE II score, median (IQR) 34 (10) SOFA score, median (IQR) 9 (2.7) Invasive ventilation, n (%) 6 (100) Vasopressor/inotropic supporta, n (%) 3 (50) Number of patients 6 Dose (mg) 4000 Age (years), median (IQR) 58 (12) Weight (kg), median (IQR) 80 (25) Male/female, n/n 4/2 APACHE II score, median (IQR) 34 (10) SOFA score, median (IQR) 9 (2.7) Invasive ventilation, n (%) 6 (100) Vasopressor/inotropic supporta, n (%) 3 (50) a Received one of the following to maintain clinician-targeted mean arterial pressure: noradrenaline, adrenaline, dopamine, vasopressin or dobutamine. Table 2. Piperacillin PK with and without SLED-f in critically ill patients Parameter With SLED-f, median (IQR) Without SLED-f, median (IQR) Cmax (mg/L) 197 (34) 197 (115) Cmin (mg/L) 37 (26) 66 (32) t½ (h) 2.5 (1.5) 7.5 (4.2)a AUC0–6 (mg·h/L) 532 (204) 1258 (701) CL (L/h) 6 (2) 2 (3)a Vss (L) 27.0 (6) 23.9 (12) Extraction ratio (%) 58 (5) NA Parameter With SLED-f, median (IQR) Without SLED-f, median (IQR) Cmax (mg/L) 197 (34) 197 (115) Cmin (mg/L) 37 (26) 66 (32) t½ (h) 2.5 (1.5) 7.5 (4.2)a AUC0–6 (mg·h/L) 532 (204) 1258 (701) CL (L/h) 6 (2) 2 (3)a Vss (L) 27.0 (6) 23.9 (12) Extraction ratio (%) 58 (5) NA AUC0–6, AUC from 0 to 6 h; NA, not applicable. a Statistically significant difference compared with PK observed during SLED-f (P < 0.05, Mann–Whitney U-test). Table 2. Piperacillin PK with and without SLED-f in critically ill patients Parameter With SLED-f, median (IQR) Without SLED-f, median (IQR) Cmax (mg/L) 197 (34) 197 (115) Cmin (mg/L) 37 (26) 66 (32) t½ (h) 2.5 (1.5) 7.5 (4.2)a AUC0–6 (mg·h/L) 532 (204) 1258 (701) CL (L/h) 6 (2) 2 (3)a Vss (L) 27.0 (6) 23.9 (12) Extraction ratio (%) 58 (5) NA Parameter With SLED-f, median (IQR) Without SLED-f, median (IQR) Cmax (mg/L) 197 (34) 197 (115) Cmin (mg/L) 37 (26) 66 (32) t½ (h) 2.5 (1.5) 7.5 (4.2)a AUC0–6 (mg·h/L) 532 (204) 1258 (701) CL (L/h) 6 (2) 2 (3)a Vss (L) 27.0 (6) 23.9 (12) Extraction ratio (%) 58 (5) NA AUC0–6, AUC from 0 to 6 h; NA, not applicable. a Statistically significant difference compared with PK observed during SLED-f (P < 0.05, Mann–Whitney U-test). Table 3. PK parameters of piperacillin in critically ill patients receiving SLED-f compared with other RRTs and other patient cohorts Healthy volunteers,8 mean (COV) Severe sepsis with CLCR >50 mL/min,11 median (range) Haemodialysis,12 mean (SD) CVVHF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,14 mean (SD) This study, mean (SD) Membrane type 1.1–1.6 m2 (cuprophan) PS 0.7 m2 PS 0.7 m2 PS 0.7 m2 AN69 PS 1.4 m2 Qb (mL/min) 329.2 (83.8) 100 100 100 150 200 Quf (L/h) RF NA 0.8 post 0.8 post 0.8 post 0.08–0.2 0.4 pre Qd (L/h) 32.7 (7.1) NA 1 2 1.5 12 t½ off (h) 2.8 (2) NA NA NA NA 7 (4) t½ RRT (h) 1.3 (0.4) 7.7 (2.3) 6.7 (1.9) 6.1 (2) 4.3 (1.2) 2 (1) V (L) 12.3 (7) 25 (19–34) 18.7 (1.2) 43.2 49 48.23 20 (5) 27 CLoff (mL/min) NA NA 74.9 (34) NA NA NA NA 34 (50) CLRRT (mL/min) NA NA 92.4 (30) 64.8 (20.5) 84.3 (28) 91.3 (35.1) 22 (5) 100 (34) CLtot (mL/min) 242 (8) 285 (240–343) NR NR NR NR 47 (26) NR Urine status polyuria polyuria anuric anuric anuric anuric anuric anuric Dose (g/g) 4/0.5 4/0.5 4 4/0.5 4/0.5 4/0.5 4/0.5 4/0.5 Duration (h) NA NA 3.5 continuous continuous continuous continuous 6 AUC0–24 (mg·h/L) 278 (to infinity) NR 576.2 (319) NR NR NR NR 532 (204)a Healthy volunteers,8 mean (COV) Severe sepsis with CLCR >50 mL/min,11 median (range) Haemodialysis,12 mean (SD) CVVHF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,14 mean (SD) This study, mean (SD) Membrane type 1.1–1.6 m2 (cuprophan) PS 0.7 m2 PS 0.7 m2 PS 0.7 m2 AN69 PS 1.4 m2 Qb (mL/min) 329.2 (83.8) 100 100 100 150 200 Quf (L/h) RF NA 0.8 post 0.8 post 0.8 post 0.08–0.2 0.4 pre Qd (L/h) 32.7 (7.1) NA 1 2 1.5 12 t½ off (h) 2.8 (2) NA NA NA NA 7 (4) t½ RRT (h) 1.3 (0.4) 7.7 (2.3) 6.7 (1.9) 6.1 (2) 4.3 (1.2) 2 (1) V (L) 12.3 (7) 25 (19–34) 18.7 (1.2) 43.2 49 48.23 20 (5) 27 CLoff (mL/min) NA NA 74.9 (34) NA NA NA NA 34 (50) CLRRT (mL/min) NA NA 92.4 (30) 64.8 (20.5) 84.3 (28) 91.3 (35.1) 22 (5) 100 (34) CLtot (mL/min) 242 (8) 285 (240–343) NR NR NR NR 47 (26) NR Urine status polyuria polyuria anuric anuric anuric anuric anuric anuric Dose (g/g) 4/0.5 4/0.5 4 4/0.5 4/0.5 4/0.5 4/0.5 4/0.5 Duration (h) NA NA 3.5 continuous continuous continuous continuous 6 AUC0–24 (mg·h/L) 278 (to infinity) NR 576.2 (319) NR NR NR NR 532 (204)a COV, coefficient of variation; CVVHF, continuous veno-venous haemofiltration; PS, polysulphone; AN, acrylonitrile; Qb, blood flow rate; Quf, ultrafiltration rate; RF, replacement fluid; Qd, dialysis flow rate; t½ RRT, t½ during RRT; CLRRT, CL during RRT; CLoff, CL without RRT; CLtot, total clearance; t½ off, half-life without RRT; NA, not applicable; NR, not reported. a AUC0–6. Table 3. PK parameters of piperacillin in critically ill patients receiving SLED-f compared with other RRTs and other patient cohorts Healthy volunteers,8 mean (COV) Severe sepsis with CLCR >50 mL/min,11 median (range) Haemodialysis,12 mean (SD) CVVHF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,14 mean (SD) This study, mean (SD) Membrane type 1.1–1.6 m2 (cuprophan) PS 0.7 m2 PS 0.7 m2 PS 0.7 m2 AN69 PS 1.4 m2 Qb (mL/min) 329.2 (83.8) 100 100 100 150 200 Quf (L/h) RF NA 0.8 post 0.8 post 0.8 post 0.08–0.2 0.4 pre Qd (L/h) 32.7 (7.1) NA 1 2 1.5 12 t½ off (h) 2.8 (2) NA NA NA NA 7 (4) t½ RRT (h) 1.3 (0.4) 7.7 (2.3) 6.7 (1.9) 6.1 (2) 4.3 (1.2) 2 (1) V (L) 12.3 (7) 25 (19–34) 18.7 (1.2) 43.2 49 48.23 20 (5) 27 CLoff (mL/min) NA NA 74.9 (34) NA NA NA NA 34 (50) CLRRT (mL/min) NA NA 92.4 (30) 64.8 (20.5) 84.3 (28) 91.3 (35.1) 22 (5) 100 (34) CLtot (mL/min) 242 (8) 285 (240–343) NR NR NR NR 47 (26) NR Urine status polyuria polyuria anuric anuric anuric anuric anuric anuric Dose (g/g) 4/0.5 4/0.5 4 4/0.5 4/0.5 4/0.5 4/0.5 4/0.5 Duration (h) NA NA 3.5 continuous continuous continuous continuous 6 AUC0–24 (mg·h/L) 278 (to infinity) NR 576.2 (319) NR NR NR NR 532 (204)a Healthy volunteers,8 mean (COV) Severe sepsis with CLCR >50 mL/min,11 median (range) Haemodialysis,12 mean (SD) CVVHF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,14 mean (SD) This study, mean (SD) Membrane type 1.1–1.6 m2 (cuprophan) PS 0.7 m2 PS 0.7 m2 PS 0.7 m2 AN69 PS 1.4 m2 Qb (mL/min) 329.2 (83.8) 100 100 100 150 200 Quf (L/h) RF NA 0.8 post 0.8 post 0.8 post 0.08–0.2 0.4 pre Qd (L/h) 32.7 (7.1) NA 1 2 1.5 12 t½ off (h) 2.8 (2) NA NA NA NA 7 (4) t½ RRT (h) 1.3 (0.4) 7.7 (2.3) 6.7 (1.9) 6.1 (2) 4.3 (1.2) 2 (1) V (L) 12.3 (7) 25 (19–34) 18.7 (1.2) 43.2 49 48.23 20 (5) 27 CLoff (mL/min) NA NA 74.9 (34) NA NA NA NA 34 (50) CLRRT (mL/min) NA NA 92.4 (30) 64.8 (20.5) 84.3 (28) 91.3 (35.1) 22 (5) 100 (34) CLtot (mL/min) 242 (8) 285 (240–343) NR NR NR NR 47 (26) NR Urine status polyuria polyuria anuric anuric anuric anuric anuric anuric Dose (g/g) 4/0.5 4/0.5 4 4/0.5 4/0.5 4/0.5 4/0.5 4/0.5 Duration (h) NA NA 3.5 continuous continuous continuous continuous 6 AUC0–24 (mg·h/L) 278 (to infinity) NR 576.2 (319) NR NR NR NR 532 (204)a COV, coefficient of variation; CVVHF, continuous veno-venous haemofiltration; PS, polysulphone; AN, acrylonitrile; Qb, blood flow rate; Quf, ultrafiltration rate; RF, replacement fluid; Qd, dialysis flow rate; t½ RRT, t½ during RRT; CLRRT, CL during RRT; CLoff, CL without RRT; CLtot, total clearance; t½ off, half-life without RRT; NA, not applicable; NR, not reported. a AUC0–6. Discussion To the best of our knowledge, this is the first report of piperacillin PK during SLED-f in critically ill patients. Piperacillin is widely used in critically ill patients and yet information on the effect of SLED-f on its dosing requirements is lacking. Although limited data are available from IHD studies in end-stage renal disease patients,12,15 these cannot be directly extrapolated to SLED-f, particularly in the context of critical illness owing 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 amount of removal by the filter and CL could differ from that of IHD. It was reported that ∼30%–45% of the administered piperacillin dose was eliminated during one IHD session (3.5 h) in patients with end-stage renal disease12,15 compared with 58% observed in our study (Table 2). The longer treatment time (3.5 versus 6 h), possibly higher-efficiency dialyser and additional component of filtration (effluent) rate could explain the higher piperacillin removal observed in this study. A statistically significant correlation was observed between effluent flow rate and piperacillin total CL during CRRTs in a regression analysis of published PK data.16 This suggests that the dose recommended for IHD and other RRT techniques could lead to suboptimal dosing in patients receiving SLED-f. CL during RRT, t½ and AUC obtained from this study were comparable with those reported in the post-dilution mode of continuous veno-venous haemodiafiltration (CVVHDF) studies (Table 3).8,11–14 This demonstrates that although the drug CL per unit of time is greater during SLED-f, the shorter duration of therapy means that drug CL over 24 h is comparable for both modalities. Importantly, this study cannot provide definitive dosing guidance owing to small patient numbers, but we hypothesize that piperacillin could be dosed as in patients receiving CVVHDF (every 8 h).17 However, it should be noted that, as in CRRT, piperacillin CL in patients receiving SLED-f will neither be constant nor predictable because of higher CL during SLED-f and potentially impaired CL when not receiving SLED-f. Therefore, it is important to pay attention to residual renal function, which could increase the total CL of piperacillin along with the CL observed during SLED-f and the duration of SLED-f. Knowledge of these issues can help procure appropriate doses and timing of these doses relative to use of SLED-f. Another important factor to consider is that some ICUs use SLED-f for up to 12 h or potentially in a continuous mode, in which the amount of piperacillin eliminated by SLED-f treatment will be higher than reported in this study. Accordingly, in such circumstances alternative dose/dosing strategies would be required. The observed mean Vss was higher than reported in healthy volunteers (27 versus 15 L), but similar to that reported in patients with severe sepsis (27 versus 25 L) (Table 3). Observed t½, CL and AUC without SLED-f were more than double the values observed during SLED-f, consistent with the fraction of piperacillin (58%) cleared during SLED-f. The observed median Cmin was higher than the EUCAST clinical breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa (16 mg/L).18 However, it should be noted that there were considerable inter-individual differences with observed Cmin, with two of the six patients achieving a Cmin <16 mg/L towards the end of the 6 h duration of the SLED-f (measured Cmin was 13 and 5 mg/L in these two patients). Based on the observed Cmin and amount of piperacillin removed by SLED-f (58%), a maintenance dose of at least 4 g every 12 h with at least a 2 g replacement dose post-SLED-f or 4 g every 8 h would be a reasonable approach to piperacillin dosing in ICU patients with anuria and sepsis receiving SLED-f with a duration similar to the current study until these are validated using a relatively larger sample size supplemented by population PK analysis and associated dosing simulations. In centres where SLED-f is used for longer than in this study (6 h) or used continuously with settings similar to those used in this study, alternative dosing strategies, i.e. extended infusion/continuous infusion and/or therapeutic drug monitoring, would be required to avoid sub-optimal concentrations during SLED-f. Acknowledgements We would like to acknowledge the help of the medical and nursing staff of the ICU of The Queen Elizabeth Hospital, Adelaide. Funding This study was supported by internal funding. 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Crit Care Med 2014 ; 42 : 1640 – 50 . Google Scholar CrossRef Search ADS PubMed 17 Varghese JM , Jarrett P , Boots RJ et al. Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration . Int J Antimicrob Agents 2014 ; 43 : 343 – 8 . Google Scholar CrossRef Search ADS PubMed 18 EUCAST . Clinical Breakpoints. http://www.eucast.org/clinical_breakpoints. © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Pharmacokinetics of piperacillin in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration

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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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10.1093/jac/dky057
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Abstract

Abstract Background Piperacillin is a β-lactam penicillin antibiotic commonly used for the empirical therapy of sepsis and other hospital-acquired infections. However, knowledge regarding the effect of sustained low-efficiency diafiltration (SLED-f), a technique increasingly being used in ICUs, on piperacillin pharmacokinetics (PK) and dosing in critically ill patients is lacking. Objectives To describe the PK of piperacillin during SLED-f and compare the results with those reported for other forms of renal replacement therapies. Methods Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f in one session and from an arterial catheter during sampling without SLED-f. Piperacillin concentrations were measured using a validated chromatography method. Non-compartmental PK analysis of the data was performed. Results The median clearance and area under the concentration–time curve during SLED-f were 6 L/h and 532 mg·h/L, respectively. Fifty-eight percent of piperacillin was cleared by a single SLED-f session (6 h) compared with previous reports of 30%–45% clearance by a 3.5 h intermittent haemodialysis session. Clearance, half-life and area under the concentration–time curve during SLED-f obtained from this study were comparable with those reported in the post-dilution mode of continuous veno-venous haemodiafiltration studies. Conclusions As it can be challenging to accurately predict when SLED-f will be initiated in the critically ill, a maintenance dose of at least 4 g every 12 h with at least a 2 g replacement dose post-SLED-f would be a practical approach to piperacillin dosing in ICU patients with anuria receiving SLED-f with a duration similar to the current study. Introduction Infection and related sepsis/septic shock are the most common causes of acute kidney injury (AKI) in ICU patients. It is associated with a high (up to 60%) in-hospital mortality. The mortality associated with the combination of sepsis and AKI is significantly higher compared with AKI alone.1,2 Therefore, as with all other interventional measures, an early and appropriate antibiotic regimen is important for improving patient outcomes. Renal replacement therapy (RRT) is an integral part of the management of AKI in critically ill patients. Although continuous RRT (CRRT) is commonly employed, hybrid techniques, including sustained low-efficiency dialysis/diafiltration (SLED/SLED-f), also known as slow low-efficiency dialysis and extended daily dialysis/diafiltration (EDD/EDD-f), are being used because of their practical advantages and cost savings over CRRT with similar haemodynamic stability and no difference in mortality.3,4 SLED-f was developed as an intermediate mode of therapy between CRRT and intermittent haemodialysis (IHD). SLED-f is typically used for only 6–12 h per day, although rarely some units employ it as a continuous modality.4 However, these advantages present a new set of challenges for drug dosing owing to variations in CL during and after SLED-f because of its intermittent nature. Drug dosing studies have been conducted on <20% of the currently used drugs in CRRT and <1% of the hybrid techniques.4–6 This is further complicated by the pathophysiological changes and related pharmacokinetic (PK) and pharmacodynamic (PD) variation in critically ill patients.7 Piperacillin is a β-lactam penicillin antibiotic commonly used for the empirical therapy of sepsis and other hospital-acquired infections in critically ill patients. Renal elimination of piperacillin accounts for ∼50%–60% of the dose administered and involves glomerular filtration and tubular secretion.8 Although dosing requirements for piperacillin/tazobactam have been relatively well established in CRRTs, the dosages required to attain the PD targets during SLED-f have not been established.9 The objective of the study was to describe the PK of piperacillin during SLED-f and compare the results with those reported in other forms of RRT. Methods Ethics Ethics approval was granted by the Institutional Human Research Ethics Committee (HREC/12/TQEHLMH/44/AM01) and University of South Australia, Adelaide Human Ethics Committee (0000031129). This was a prospective, open-labelled PK study conducted at the ICU of The Queen Elizabeth Hospital (Adelaide, Australia). Critically ill patients who met the following criteria were enrolled after obtaining written informed consent either from the patient or the patient’s legally authorized representative: (i) receiving piperacillin in combination with tazobactam; (ii) age ≥18 years; (iii) present in ICU and undergoing/planning to undergo SLED-f; (iv) arterial line in situ or planned insertion; and (v) indwelling urinary catheter in situ or planned insertion. Patients who met one or both of the following criteria were excluded: (i) known or suspected allergy to penicillin agents; and (ii) pregnancy. Piperacillin/tazobactam administration and sample collection Piperacillin in combination with tazobactam was initiated at the discretion of the treating physician based on the clinical requirement. Piperacillin (4 g) was administered in combination with tazobactam as an intravenous infusion over 30 min. Sampling occurred during two dosing intervals: one during SLED-f and another without SLED-f. Piperacillin/tazobactam was administered 30 min prior to initiation of SLED-f when sampling with SLED-f. Blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter during sampling without SLED-f. Blood samples were collected before initiation of the infusion and at 30, 60, 120, 180, 240, 300 and 360 min post-commencement of the infusion. Ultrafiltration samples could not be collected owing to use of an online water inlet and outlet system common to SLED-f circuitry. SLED-f was performed in all patients using a 4008S haemodialysis machine (Fresenius Medical Care, Bad Homburg, Germany) with an AV600S polysulphone ultra-flux filter (1.4 m2 surface area, Fresenius Medical Care, Bad Homburg, Germany). A standardized prescription consisted of haemodiafiltration with a target duration of 6–8 h (with 12 L/h blood and dialysate flow and 4 L/h pre-dilution). Data on the precise times for SLED-f commencement and cessation, owing to blood clotting on the filter or the end of treatment, were recorded. Plasma concentrations of piperacillin were analysed with a previously validated HPLC system with an electrospray mass spectrometer detector (LC/MS–MS) (AB Sciex Pty Ltd API3200; Shimadzu HPLC, Kyoto, Japan).10 PK and statistical analysis Non-compartmental PK analysis of the data was performed. Cmax and Tmax after drug administration were obtained directly by visual examination of concentration–time data. The terminal Kel was estimated from the slope of the terminal exponential phase of the logarithmic plasma concentration–time profile, and t½ was determined as 0.693/Kel. CL was determined as dose/plasma AUC0–∞. The amount of piperacillin removed owing to SLED-f was estimated from concentrations before (Cin) and directly after (Cout) the SLED-f filter: (Qin·Cin − Qout·Cout)/Cin, where plasma flows in (Qin) and out (Qout) of the dialyser were estimated using the blood flow, haematocrit and ultrafiltration rate. The Mann–Whitney U-test was used to compare the PK parameters with and without SLED-f using GraphPad Prism version 7.00 for Windows (GraphPad Software, La Jolla, CA, USA; www.graphpad.com) and P < 0.05 was considered to be statistically significant. Results Six AKI patients with anuria (urine output <100 mL) and sepsis were recruited. Sampling occurred in six patients during SLED-f and in five patients without SLED-f. In all patients sampling occurred at least 2 days after treatment initiation with piperacillin/tazobactam. All six patients received SLED-f for 6 h with a total fluid removal of 2.08 ± 0.92 L. The total effluent flow achieved in this study was 16.36 ± 0.18 L/h. The cumulative fluid balance was positive (6.30 ± 3.90 L). All patients received 12 hourly piperacillin dosing except one who received 24 hourly piperacillin. Tables 1 and 2 describe the demographic and clinical characteristics of the subjects and the PK parameter estimates for piperacillin with and without SLED-f, respectively. A statistically significant difference (P < 0.05) was observed for CL and t½ with and without SLED-f. We compared the PK parameters observed in this study against the published data for piperacillin in other RRTs (Table 3).8,11–14 Fifty-eight percent of piperacillin was cleared by SLED-f during the 6 h treatment. Table 1. Demographic and clinical characteristics of critically ill patients receiving SLED-f and piperacillin Number of patients 6 Dose (mg) 4000 Age (years), median (IQR) 58 (12) Weight (kg), median (IQR) 80 (25) Male/female, n/n 4/2 APACHE II score, median (IQR) 34 (10) SOFA score, median (IQR) 9 (2.7) Invasive ventilation, n (%) 6 (100) Vasopressor/inotropic supporta, n (%) 3 (50) Number of patients 6 Dose (mg) 4000 Age (years), median (IQR) 58 (12) Weight (kg), median (IQR) 80 (25) Male/female, n/n 4/2 APACHE II score, median (IQR) 34 (10) SOFA score, median (IQR) 9 (2.7) Invasive ventilation, n (%) 6 (100) Vasopressor/inotropic supporta, n (%) 3 (50) a Received one of the following to maintain clinician-targeted mean arterial pressure: noradrenaline, adrenaline, dopamine, vasopressin or dobutamine. Table 1. Demographic and clinical characteristics of critically ill patients receiving SLED-f and piperacillin Number of patients 6 Dose (mg) 4000 Age (years), median (IQR) 58 (12) Weight (kg), median (IQR) 80 (25) Male/female, n/n 4/2 APACHE II score, median (IQR) 34 (10) SOFA score, median (IQR) 9 (2.7) Invasive ventilation, n (%) 6 (100) Vasopressor/inotropic supporta, n (%) 3 (50) Number of patients 6 Dose (mg) 4000 Age (years), median (IQR) 58 (12) Weight (kg), median (IQR) 80 (25) Male/female, n/n 4/2 APACHE II score, median (IQR) 34 (10) SOFA score, median (IQR) 9 (2.7) Invasive ventilation, n (%) 6 (100) Vasopressor/inotropic supporta, n (%) 3 (50) a Received one of the following to maintain clinician-targeted mean arterial pressure: noradrenaline, adrenaline, dopamine, vasopressin or dobutamine. Table 2. Piperacillin PK with and without SLED-f in critically ill patients Parameter With SLED-f, median (IQR) Without SLED-f, median (IQR) Cmax (mg/L) 197 (34) 197 (115) Cmin (mg/L) 37 (26) 66 (32) t½ (h) 2.5 (1.5) 7.5 (4.2)a AUC0–6 (mg·h/L) 532 (204) 1258 (701) CL (L/h) 6 (2) 2 (3)a Vss (L) 27.0 (6) 23.9 (12) Extraction ratio (%) 58 (5) NA Parameter With SLED-f, median (IQR) Without SLED-f, median (IQR) Cmax (mg/L) 197 (34) 197 (115) Cmin (mg/L) 37 (26) 66 (32) t½ (h) 2.5 (1.5) 7.5 (4.2)a AUC0–6 (mg·h/L) 532 (204) 1258 (701) CL (L/h) 6 (2) 2 (3)a Vss (L) 27.0 (6) 23.9 (12) Extraction ratio (%) 58 (5) NA AUC0–6, AUC from 0 to 6 h; NA, not applicable. a Statistically significant difference compared with PK observed during SLED-f (P < 0.05, Mann–Whitney U-test). Table 2. Piperacillin PK with and without SLED-f in critically ill patients Parameter With SLED-f, median (IQR) Without SLED-f, median (IQR) Cmax (mg/L) 197 (34) 197 (115) Cmin (mg/L) 37 (26) 66 (32) t½ (h) 2.5 (1.5) 7.5 (4.2)a AUC0–6 (mg·h/L) 532 (204) 1258 (701) CL (L/h) 6 (2) 2 (3)a Vss (L) 27.0 (6) 23.9 (12) Extraction ratio (%) 58 (5) NA Parameter With SLED-f, median (IQR) Without SLED-f, median (IQR) Cmax (mg/L) 197 (34) 197 (115) Cmin (mg/L) 37 (26) 66 (32) t½ (h) 2.5 (1.5) 7.5 (4.2)a AUC0–6 (mg·h/L) 532 (204) 1258 (701) CL (L/h) 6 (2) 2 (3)a Vss (L) 27.0 (6) 23.9 (12) Extraction ratio (%) 58 (5) NA AUC0–6, AUC from 0 to 6 h; NA, not applicable. a Statistically significant difference compared with PK observed during SLED-f (P < 0.05, Mann–Whitney U-test). Table 3. PK parameters of piperacillin in critically ill patients receiving SLED-f compared with other RRTs and other patient cohorts Healthy volunteers,8 mean (COV) Severe sepsis with CLCR >50 mL/min,11 median (range) Haemodialysis,12 mean (SD) CVVHF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,14 mean (SD) This study, mean (SD) Membrane type 1.1–1.6 m2 (cuprophan) PS 0.7 m2 PS 0.7 m2 PS 0.7 m2 AN69 PS 1.4 m2 Qb (mL/min) 329.2 (83.8) 100 100 100 150 200 Quf (L/h) RF NA 0.8 post 0.8 post 0.8 post 0.08–0.2 0.4 pre Qd (L/h) 32.7 (7.1) NA 1 2 1.5 12 t½ off (h) 2.8 (2) NA NA NA NA 7 (4) t½ RRT (h) 1.3 (0.4) 7.7 (2.3) 6.7 (1.9) 6.1 (2) 4.3 (1.2) 2 (1) V (L) 12.3 (7) 25 (19–34) 18.7 (1.2) 43.2 49 48.23 20 (5) 27 CLoff (mL/min) NA NA 74.9 (34) NA NA NA NA 34 (50) CLRRT (mL/min) NA NA 92.4 (30) 64.8 (20.5) 84.3 (28) 91.3 (35.1) 22 (5) 100 (34) CLtot (mL/min) 242 (8) 285 (240–343) NR NR NR NR 47 (26) NR Urine status polyuria polyuria anuric anuric anuric anuric anuric anuric Dose (g/g) 4/0.5 4/0.5 4 4/0.5 4/0.5 4/0.5 4/0.5 4/0.5 Duration (h) NA NA 3.5 continuous continuous continuous continuous 6 AUC0–24 (mg·h/L) 278 (to infinity) NR 576.2 (319) NR NR NR NR 532 (204)a Healthy volunteers,8 mean (COV) Severe sepsis with CLCR >50 mL/min,11 median (range) Haemodialysis,12 mean (SD) CVVHF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,14 mean (SD) This study, mean (SD) Membrane type 1.1–1.6 m2 (cuprophan) PS 0.7 m2 PS 0.7 m2 PS 0.7 m2 AN69 PS 1.4 m2 Qb (mL/min) 329.2 (83.8) 100 100 100 150 200 Quf (L/h) RF NA 0.8 post 0.8 post 0.8 post 0.08–0.2 0.4 pre Qd (L/h) 32.7 (7.1) NA 1 2 1.5 12 t½ off (h) 2.8 (2) NA NA NA NA 7 (4) t½ RRT (h) 1.3 (0.4) 7.7 (2.3) 6.7 (1.9) 6.1 (2) 4.3 (1.2) 2 (1) V (L) 12.3 (7) 25 (19–34) 18.7 (1.2) 43.2 49 48.23 20 (5) 27 CLoff (mL/min) NA NA 74.9 (34) NA NA NA NA 34 (50) CLRRT (mL/min) NA NA 92.4 (30) 64.8 (20.5) 84.3 (28) 91.3 (35.1) 22 (5) 100 (34) CLtot (mL/min) 242 (8) 285 (240–343) NR NR NR NR 47 (26) NR Urine status polyuria polyuria anuric anuric anuric anuric anuric anuric Dose (g/g) 4/0.5 4/0.5 4 4/0.5 4/0.5 4/0.5 4/0.5 4/0.5 Duration (h) NA NA 3.5 continuous continuous continuous continuous 6 AUC0–24 (mg·h/L) 278 (to infinity) NR 576.2 (319) NR NR NR NR 532 (204)a COV, coefficient of variation; CVVHF, continuous veno-venous haemofiltration; PS, polysulphone; AN, acrylonitrile; Qb, blood flow rate; Quf, ultrafiltration rate; RF, replacement fluid; Qd, dialysis flow rate; t½ RRT, t½ during RRT; CLRRT, CL during RRT; CLoff, CL without RRT; CLtot, total clearance; t½ off, half-life without RRT; NA, not applicable; NR, not reported. a AUC0–6. Table 3. PK parameters of piperacillin in critically ill patients receiving SLED-f compared with other RRTs and other patient cohorts Healthy volunteers,8 mean (COV) Severe sepsis with CLCR >50 mL/min,11 median (range) Haemodialysis,12 mean (SD) CVVHF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,14 mean (SD) This study, mean (SD) Membrane type 1.1–1.6 m2 (cuprophan) PS 0.7 m2 PS 0.7 m2 PS 0.7 m2 AN69 PS 1.4 m2 Qb (mL/min) 329.2 (83.8) 100 100 100 150 200 Quf (L/h) RF NA 0.8 post 0.8 post 0.8 post 0.08–0.2 0.4 pre Qd (L/h) 32.7 (7.1) NA 1 2 1.5 12 t½ off (h) 2.8 (2) NA NA NA NA 7 (4) t½ RRT (h) 1.3 (0.4) 7.7 (2.3) 6.7 (1.9) 6.1 (2) 4.3 (1.2) 2 (1) V (L) 12.3 (7) 25 (19–34) 18.7 (1.2) 43.2 49 48.23 20 (5) 27 CLoff (mL/min) NA NA 74.9 (34) NA NA NA NA 34 (50) CLRRT (mL/min) NA NA 92.4 (30) 64.8 (20.5) 84.3 (28) 91.3 (35.1) 22 (5) 100 (34) CLtot (mL/min) 242 (8) 285 (240–343) NR NR NR NR 47 (26) NR Urine status polyuria polyuria anuric anuric anuric anuric anuric anuric Dose (g/g) 4/0.5 4/0.5 4 4/0.5 4/0.5 4/0.5 4/0.5 4/0.5 Duration (h) NA NA 3.5 continuous continuous continuous continuous 6 AUC0–24 (mg·h/L) 278 (to infinity) NR 576.2 (319) NR NR NR NR 532 (204)a Healthy volunteers,8 mean (COV) Severe sepsis with CLCR >50 mL/min,11 median (range) Haemodialysis,12 mean (SD) CVVHF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,13 mean (SD) CVVHDF,14 mean (SD) This study, mean (SD) Membrane type 1.1–1.6 m2 (cuprophan) PS 0.7 m2 PS 0.7 m2 PS 0.7 m2 AN69 PS 1.4 m2 Qb (mL/min) 329.2 (83.8) 100 100 100 150 200 Quf (L/h) RF NA 0.8 post 0.8 post 0.8 post 0.08–0.2 0.4 pre Qd (L/h) 32.7 (7.1) NA 1 2 1.5 12 t½ off (h) 2.8 (2) NA NA NA NA 7 (4) t½ RRT (h) 1.3 (0.4) 7.7 (2.3) 6.7 (1.9) 6.1 (2) 4.3 (1.2) 2 (1) V (L) 12.3 (7) 25 (19–34) 18.7 (1.2) 43.2 49 48.23 20 (5) 27 CLoff (mL/min) NA NA 74.9 (34) NA NA NA NA 34 (50) CLRRT (mL/min) NA NA 92.4 (30) 64.8 (20.5) 84.3 (28) 91.3 (35.1) 22 (5) 100 (34) CLtot (mL/min) 242 (8) 285 (240–343) NR NR NR NR 47 (26) NR Urine status polyuria polyuria anuric anuric anuric anuric anuric anuric Dose (g/g) 4/0.5 4/0.5 4 4/0.5 4/0.5 4/0.5 4/0.5 4/0.5 Duration (h) NA NA 3.5 continuous continuous continuous continuous 6 AUC0–24 (mg·h/L) 278 (to infinity) NR 576.2 (319) NR NR NR NR 532 (204)a COV, coefficient of variation; CVVHF, continuous veno-venous haemofiltration; PS, polysulphone; AN, acrylonitrile; Qb, blood flow rate; Quf, ultrafiltration rate; RF, replacement fluid; Qd, dialysis flow rate; t½ RRT, t½ during RRT; CLRRT, CL during RRT; CLoff, CL without RRT; CLtot, total clearance; t½ off, half-life without RRT; NA, not applicable; NR, not reported. a AUC0–6. Discussion To the best of our knowledge, this is the first report of piperacillin PK during SLED-f in critically ill patients. Piperacillin is widely used in critically ill patients and yet information on the effect of SLED-f on its dosing requirements is lacking. Although limited data are available from IHD studies in end-stage renal disease patients,12,15 these cannot be directly extrapolated to SLED-f, particularly in the context of critical illness owing 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 amount of removal by the filter and CL could differ from that of IHD. It was reported that ∼30%–45% of the administered piperacillin dose was eliminated during one IHD session (3.5 h) in patients with end-stage renal disease12,15 compared with 58% observed in our study (Table 2). The longer treatment time (3.5 versus 6 h), possibly higher-efficiency dialyser and additional component of filtration (effluent) rate could explain the higher piperacillin removal observed in this study. A statistically significant correlation was observed between effluent flow rate and piperacillin total CL during CRRTs in a regression analysis of published PK data.16 This suggests that the dose recommended for IHD and other RRT techniques could lead to suboptimal dosing in patients receiving SLED-f. CL during RRT, t½ and AUC obtained from this study were comparable with those reported in the post-dilution mode of continuous veno-venous haemodiafiltration (CVVHDF) studies (Table 3).8,11–14 This demonstrates that although the drug CL per unit of time is greater during SLED-f, the shorter duration of therapy means that drug CL over 24 h is comparable for both modalities. Importantly, this study cannot provide definitive dosing guidance owing to small patient numbers, but we hypothesize that piperacillin could be dosed as in patients receiving CVVHDF (every 8 h).17 However, it should be noted that, as in CRRT, piperacillin CL in patients receiving SLED-f will neither be constant nor predictable because of higher CL during SLED-f and potentially impaired CL when not receiving SLED-f. Therefore, it is important to pay attention to residual renal function, which could increase the total CL of piperacillin along with the CL observed during SLED-f and the duration of SLED-f. Knowledge of these issues can help procure appropriate doses and timing of these doses relative to use of SLED-f. Another important factor to consider is that some ICUs use SLED-f for up to 12 h or potentially in a continuous mode, in which the amount of piperacillin eliminated by SLED-f treatment will be higher than reported in this study. Accordingly, in such circumstances alternative dose/dosing strategies would be required. The observed mean Vss was higher than reported in healthy volunteers (27 versus 15 L), but similar to that reported in patients with severe sepsis (27 versus 25 L) (Table 3). Observed t½, CL and AUC without SLED-f were more than double the values observed during SLED-f, consistent with the fraction of piperacillin (58%) cleared during SLED-f. The observed median Cmin was higher than the EUCAST clinical breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa (16 mg/L).18 However, it should be noted that there were considerable inter-individual differences with observed Cmin, with two of the six patients achieving a Cmin <16 mg/L towards the end of the 6 h duration of the SLED-f (measured Cmin was 13 and 5 mg/L in these two patients). Based on the observed Cmin and amount of piperacillin removed by SLED-f (58%), a maintenance dose of at least 4 g every 12 h with at least a 2 g replacement dose post-SLED-f or 4 g every 8 h would be a reasonable approach to piperacillin dosing in ICU patients with anuria and sepsis receiving SLED-f with a duration similar to the current study until these are validated using a relatively larger sample size supplemented by population PK analysis and associated dosing simulations. In centres where SLED-f is used for longer than in this study (6 h) or used continuously with settings similar to those used in this study, alternative dosing strategies, i.e. extended infusion/continuous infusion and/or therapeutic drug monitoring, would be required to avoid sub-optimal concentrations during SLED-f. Acknowledgements We would like to acknowledge the help of the medical and nursing staff of the ICU of The Queen Elizabeth Hospital, Adelaide. Funding This study was supported by internal funding. Transparency declarations None to declare. References 1 Hoste EA , Bagshaw SM , Bellomo R et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study . Intensive Care Med 2015 ; 41 : 1411 – 23 . Google Scholar CrossRef Search ADS PubMed 2 Moore EM , Bellomo R , Nichol AD. The meaning of acute kidney injury and its relevance to intensive care and anaesthesia . Anaesth Intensive Care 2012 ; 40 : 929 – 48 . Google Scholar PubMed 3 Ronco C , Ricci Z , De Backer D et al. Renal replacement therapy in acute kidney injury: controversy and consensus . Crit Care 2015 ; 19 : 146. Google Scholar CrossRef Search ADS PubMed 4 Bogard KN , Peterson NT , Plumb TJ et al. Antibiotic dosing during sustained low-efficiency dialysis: special considerations in adult critically ill patients . Crit Care Med 2011 ; 39 : 560 – 70 . Google Scholar CrossRef Search ADS PubMed 5 Mueller BA , Smoyer WE. Challenges in developing evidence-based drug dosing guidelines for adults and children receiving renal replacement therapy . Clin Pharmacol Ther 2009 ; 86 : 479 – 82 . Google Scholar CrossRef Search ADS PubMed 6 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 . Google Scholar CrossRef Search ADS PubMed 7 Roberts JA , Abdul-Aziz MH , Lipman J et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions . Lancet Infect Dis 2014 ; 14 : 498 – 509 . Google Scholar CrossRef Search ADS PubMed 8 Sorgel F , Kinzig M. Pharmacokinetic characteristics of piperacillin/tazobactam . Intensive Care Med 1994 ; 20 Suppl 3: S14 – 20 . Google Scholar CrossRef Search ADS PubMed 9 Hayashi Y , Roberts JA , Paterson DL et al. Pharmacokinetic evaluation of piperacillin-tazobactam . Expert Opin Drug Metab Toxicol 2010 ; 6 : 1017 – 31 . Google Scholar CrossRef Search ADS PubMed 10 Sime FB , Roberts MS , Roberts JA et al. Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies . J Chromatogr B Analyt Technol Biomed Life Sci 2014 ; 960 : 134 – 44 . Google Scholar CrossRef Search ADS PubMed 11 Roberts JA , Kirkpatrick CM , Roberts MS et al. First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis . Int J Antimicrob Agents 2010 ; 35 : 156 – 63 . Google Scholar CrossRef Search ADS PubMed 12 Heim-Duthoy KL , Halstenson CE , Abraham PA et al. The effect of hemodialysis on piperacillin pharmacokinetics . Int J Clin Pharmacol Ther Toxicol 1986 ; 24 : 680 – 4 . Google Scholar PubMed 13 Valtonen M , Tiula E , Takkunen O et al. 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 . Google Scholar CrossRef Search ADS PubMed 14 Mueller SC , Majcher-Peszynska J , Hickstein H et al. Pharmacokinetics of piperacillin-tazobactam in anuric intensive care patients during continuous venovenous hemodialysis . Antimicrob Agents Chemother 2002 ; 46 : 1557 – 60 . Google Scholar CrossRef Search ADS PubMed 15 Johnson CA , Halstenson CE , Kelloway JS et al. Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease . Clin Pharmacol Ther 1992 ; 51 : 32 – 41 . Google Scholar CrossRef Search ADS PubMed 16 Jamal JA , Udy AA , Lipman J et al. The impact of variation in renal replacement therapy settings on piperacillin, meropenem, and vancomycin drug clearance in the critically ill: an analysis of published literature and dosing regimens* . Crit Care Med 2014 ; 42 : 1640 – 50 . Google Scholar CrossRef Search ADS PubMed 17 Varghese JM , Jarrett P , Boots RJ et al. Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration . Int J Antimicrob Agents 2014 ; 43 : 343 – 8 . Google Scholar CrossRef Search ADS PubMed 18 EUCAST . Clinical Breakpoints. http://www.eucast.org/clinical_breakpoints. © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 1, 2018

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