Nephrol Dial Transplant (2002) 17: 1649–1654
Original Article
CAHP-210 dialyzer influence on intra-dialytic vancomycin removalz Aroonrut Lucksiri1, Meri K. Scott1, Bruce A. Mueller1,§, Richard J. Hamburger2 and Kevin M. Sowinski1 1
Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, Indianapolis, USA and 2Department of Medicine, School of Medicine, Indiana University, Indianapolis, USA
Abstract Background. Vancomycin is often administered during the last hour of haemodialysis because it was not removed significantly by older hemodialyzers. However, newer higher permeability hemodialyzers remove vancomycin, although the amount removed varies considerably between dialyzers. The purpose of this study was to determine the apparent amount of vancomycin removed during the last hour of haemodialysis with a CAHP-210 hemodialyzer. Methods. Eight subjects with end-stage renal disease (ESRD) received i.v. vancomycin 15 mgukg after their regular haemodialysis session ended. Serum samples for the determination of vancomycin concentrations were obtained serially for 44 h. After a 3-week washout, the study was repeated with the vancomycin infused during the last hour of their regular haemodialysis session using a CAHP-210 hemodialyzer. Vancomycin concentrations were determined by the Enzyme Multiplied Immunoassay Technique. Differential equations describing a two-compartment open infusion model were fitted to the serum concentration vs time data and pharmacokinetic parameters and apparent vancomycin removal was estimated. Results. The median age and weight of the subjects were 52 years (range 37–71) and 75.6 kg (range 37.6–89.8), respectively. The apparent vancomycin intra-dialytic removal was 0.24 (range 0.07–0.35), which was statistically significantly different from zero. Conclusions. Vancomycin administered during the last hour of CAHP-210 dialysis results in 24% less vancomycin exposure than when administered post-haemodialysis. This intra-dialytic drug loss
Correspondence and offprint requests to: Kevin M. Sowinski, Purdue University, Department of Pharmacy Practice, D711 Myers Building, WHS, 1001 West 10th Street, Indianapolis, IN, 46202-2879, USA. Email:
[email protected] Present address: §College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. z Presented in part at the Annual Meeting of the American College of Clinical Pharmacy, Los Angeles, CA, November 1999. #
should be accounted for when dosing vancomycin in this manner. Keywords: antibiotics; biocompatible membrane; cellulose acetate; cellulose acetate high performance210; cross-over study; drug removal; end-stage renal disease; glycopeptide; haemodialysis; hemodialyzer; human; pharmacokinetics; prospective study; vancomycin
Introduction US Renal Data System data indicates that in the US from 1997 to 1999, infection accounted for 14% of all deaths among haemodialysis patients [1]. Gram-positive organisms (e.g. Staphylococcus aureus, Enterococcus species, and Streptococcus species) accounted for more than half (52.3%) of all reported bacterial infectious cases in haemodialysis patients and S. aureus was the most common causative microorganism [2,3]. Vancomycin is commonly used for the treatment of susceptible Gram-positive infections in patients with end-stage renal disease (ESRD). It is a glycopeptide antibiotic with a molecular weight of 1449 Da. The drug was often administered during the last hour of haemodialysis preventing patients from having to remain in the haemodialysis unit for an extended period of time following completion of their haemodialysis therapy. The dialytic clearance (ClD) of vancomycin by conventional membranes (range 0–15 mlumin) [4–7] is minimal because of the combination of the drug’s high molecular weight and the membrane’s limited permeability [8]. Studies have shown that the percentage of vancomycin removed by various types of these low permeability cellulosic hemodialyzers (e.g. Cuprophan, CU) ranges from 4.0 to 6.9% [4–7]. Therefore, supplemental vancomycin dosing following haemodialysis with these dialyzers was not required and intra-dialytic administration was an attractive and practical dosing strategy.
2002 European Renal Association–European Dialysis and Transplant Association
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The removal of vancomycin during intra-dialytic administration has been studied with high-permeable, modified cellulosic hemodialyzers including cellulose acetate (CA) and cellulose triacetate (CT) hemodialyzers [4,5,8]. Scott et al. [8] observed that the mean of 12.8% (range 0–25%) of the administered dose was removed by the CA-210 hemodialyzer, where as 26.3% (range 16–44%) of vancomycin was removed by the CT-190 hemodialyzer when vancomycin was given during the last hour of haemodialysis. Desoi et al. [4] reported that 22% of vancomycin was removed when the drug was given during the last 30 min of haemodialysis and for 30 min after haemodialysis. When vancomycin was given during the last hour of a haemodialysis session in a study conducted by Bastani et al. [5], a mean"SD of 13.6"1.3 vancomycin was removed by the CA dialyzer (Cordis Dow 4000) [5]. Thus, with these two studies taken together, CT hemodialyzers removed twice the vancomycin that was removed by the CA hemodialyzers. The authors suggested no need for dosing adjustments due to dialytic removal when the CA hemodialyzer is used. However, when the CT hemodialyzer is used they recommended either administering an additional amount of vancomycin to account for dialytic loss or administering the drug after haemodialysis is completed. When high-flux, synthetic membranes are used, the removal of vancomycin has been shown to be markedly enhanced [4–7,9–11]. The fraction of vancomycin removed by highly permeable polysulfone (PS) dialyzers ranges from approximately 30 to 55% depending on the PS dialyzer used and the study conducted [4–7,9–11]. Polyacrylonitrile (AN-69) hemodialyzer use also results in 25–40% vancomycin removal [4–6]. The CA high performance-210 (CAHP-210) hemodialyzer is a relatively new type of CA hemodialyzer. In vitro ultrafiltration coefficients (10 vs 13 mluhummHg, CA-210 vs CAHP-210, respectively) and vitamin B12 clearances (77 vs 105 mlumin, CA-210 vs CAHP-210, respectively) suggest that the CAHP210 hemodialyzer may provide enhanced solute removal as compared with other CA hemodialyzers [8,12]. The lack of information of the CAHP-210 hemodialyzer’s influence on vancomycin removal made the use of this hemodialyzer in haemodialysis patients who required vancomycin treatment difficult. The purpose of this study was to determine the influence of the CAHP-210 hemodialyzer on the apparent removal of vancomycin when administered during the last hour of haemodialysis.
A. Lucksiri et al.
Nine subjects from the Outpatient Haemodialysis Unit at Indiana University Hospital, Indiana University Medical Center in Indianapolis, Indiana were enrolled into the study. They were considered for inclusion if they were at least 18 years of age, received maintenance haemodialysis thrice weekly for the treatment of ESRD, and had no acute intercurrent illness. Subjects were excluded if they had a history of vancomycin allergy, received vancomycin within 3 weeks prior to study initiation, or if their dry body weight was not within 30% of their ideal body weight using standard equations. The study protocol was approved by the Indiana University Purdue University Indianapolis Institutional Review Board. All subjects provided written informed consent before participating. The study was performed at the adult Outpatient Haemodialysis Unit, Indiana University Hospital, Indiana University Medical Center. The haemodialysis treatment time, blood flow rate, dialysate flow rate, and ultrafiltration rate were the same as that normally prescribed to maintain adequate haemodialysis for each subject and were not changed for the purposes of this study. The study dialyzer was a CA high-performance (CAHP210) dialyzer (Baxter Healthcare Co. McGaw Park, IL) with the surface area of 2.1 m2 and membrane thickness of 15 m. All dialyzers used in this study were new (non-reprocessed) and rinsed with 2 l of normal saline prior to use. Vancomycin (15 mgukg of the usual post-dialysis body weight) was administered in both study arms. Vancomycin hydrochloride (Abbott Laboratories, North Chicago, IL) was reconstituted with sterile water for injection to a concentration of 50 mguml as recommended by the manufacturer. The appropriate volume of vancomycin solution for each subject was added into a 100 ml bag of 0.9% sodium chloride for injection. This solution was then administered over 1 h as an i.v. infusion after a haemodialysis session and during the last hour of haemodialysis session in control and treatment arms, respectively.
Control arm Following completion of a regularly scheduled haemodialysis treatment with the subject’s normally used hemodialyzer, vancomycin (15 mgukg as described above) was administered intravenously as a 1 h i.v. infusion through the venous port of the subject’s haemodialysis access. Venous blood samples, for determination of vancomycin serum concentrations, were obtained immediately before and 0.5, 1, 1.5, 2, 3, 5, 24, and approximately 44 h after the infusion started from the arterial port of the subject’s haemodialysis access. Normal saline was used to maintain patency of the venous access. The 24-h blood sample was obtained by direct venipuncture on the following day. The 44-h blood sample was obtained from the arterial port of the subject’s haemodialysis access immediately prior to the next haemodialysis session. After the completion of the control arm, there was at least a 3-week washout period before the initiation of the treatment arm.
Patients and methods
Treatment arm
This study utilized a prospective, controlled, crossover design. Each subject participated in two study arms; study arm one served as the control and study arm two served as the treatment arm. Each study arm took 3 consecutive days to complete and required a 3-week washout period between study arms.
Each subject underwent a haemodialysis treatment with a new CAHP-210 dialyzer. One hour before the end of the haemodialysis treatment, vancomycin 15 mgukg was administered as a 1-h i.v. infusion through the medication port on the venous haemodialysis tubing (post-dialyzer port).
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Blood samples were obtained as described in the control arm. Haemodialysis ended as the 1-h sample was obtained and the vancomycin infusion ended. Blood samples were collected into non-heparinized evacuated blood collection tubes, centrifuged, and the serum was separated and stored frozen (708C) until analysed. Vancomycin serum concentration was determined in duplicate by Enzyme Multiplied Immunoassay Technique (EMIT1; Syva Co., Dade Behring Inc., Cupertino, CA) using a method that has been described previously [13,14]. Linear calibration curves were obtained for vancomycin over the concentration range of 5–50 mgul. Samples with concentrations above this range were diluted and re-assayed. The within-day and between-day coefficients of variation for replicate control samples were less than 7% at 15 and 40 mgul. Differential equations describing a two-compartment open infusion pharmacokinetic model were fitted to each individual subject’s vancomycin serum concentration vs time data by iterative non-linear weighted least squares regression analysis using ADAPT II computer software [15]. Equations (1)–(6) were used in this process to determine the pharmacokinetic parameters apparent per cent vancomycin removal when administered intra-dialytically. The initial estimates for pharmacokinetic parameters used in the two-compartment model were obtained by literature review [4,16]. dX1 udts(Cldist uVp Þ ðX2 Þ ðCldist uVc Þ ðX1 Þ ðCls uVc Þ ðX1 ÞqðR01 Þ
ð1Þ
dX2 udts(Cldist uVc Þ ðX1 Þ ðCldist uVp ÞðX2 Þ
ð2Þ
Y (1)sX1 uVc
(3)
dX3 udts(Cldist uVp Þ ðX4 Þ ðCldist uVc Þ ðX3 Þ ðCls uVc Þ ðX3 ÞqðR02 Þ
ð4Þ
dX4 udts(Cldist uVc Þ ðX3 Þ ðCldist uVp Þ ðX4 Þ
ð5Þ
Y (2)s(1 AR)3X3 uVc
(6)
where, X1 and X2 are the amount of vancomycin in the central and peripheral compartments, respectively, when the drug was administered after a haemodialysis session (control arm); X3 and X4 are the amount of vancomycin in the central and peripheral compartments, respectively, when the drug was administered during the last hour of haemodialysis with a CAHP-210 dialyzer (treatment arm); Cldist and Cls are the distribution and systemic clearances, respectively; Vc and Vp are the volumes of distribution of the central and peripheral compartments, respectively; R01 and R02 are the vancomycin i.v. infusion rates in control and treatment arms, respectively; Y(1) and Y(2) are ADAPT output equations describing the estimated vancomycin serum concentrations during control and treatment arms, respectively; AR is the apparent vancomycin removal during haemodialysis with the CAHP-210 hemodialyzer. The control and treatment arms were fitted simultaneously. Volumes of distribution were assumed to be constant during the entire study period. Systemic clearance of vancomycin was assumed to occur from the central compartment only. The pharmacokinetic parameter estimates obtained by this model were: Vc, Vp, Cldist, Cls, and AR. Based upon the fitted pharmacokinetic parameters obtained by this model, apparent volume of distribution at steady-state (Vss) was calculated as the sum of Vc and Vp and
terminal elimination rate constant (ke) and terminal elimination half-life (t1u2b) were calculated by standard equations [17]. The per cent of apparent vancomycin removal when administered during the haemodialysis session was calculated as AR 3 100%. Statistical comparisons of demographic characteristics and between study arms were performed using the Wilcoxon Signed Rank test. All statistical analyses were performed using StatView1 for Windows (version 4.5, SAS Institute, Cary, NC). Overall differences were considered statistically significant at P-0.05. Data are presented as median (range) unless otherwise noted.
Results Eight subjects (two females, six males) successfully completed the two-arm study. No adverse effects were documented in the study. One female subject did not complete the study due to the development of diarrhoea unrelated to the study. Table 1 lists the subjects’ demographic data. Subjects’ body weights were not significantly different between the two study arms (Ps0.78). The haemodialysis characteristics and haematocrit values of each subject are listed in Table 2. There was no statistically significant difference between the haematocrit values in the two study arms (Ps0.26). All subjects had been undergoing thrice weekly haemodialysis for a median of 54 months (range 14–87 months) before participation and had no measurable renal function. Blood and dialysate flow rates for each subject were kept the same in both study arms. Individual pharmacokinetic model fits in both the treatment and control arms, in two representative subjects of vancomycin serum concentrations vs time, are shown in Figure 1. In all subjects taken together, 42% of the fitted data points were within 5% of the observed data points, 73% were within 10%, 91% were within 15%, 98% were within 20%, and all data points were within 25%. Thus, there was a good agreement between the observed and model-derived serum concentrations. Table 1. Subject demographics Subject
1 2 3 4 5 6 7 8 Median
Sex
Male Male Female Male Female Male Male Male NuA
Age (years)
55 39 71 56 37 48 68 47 52
Post-haemodialysis body weight (kg) Control arm
Treatment arm
74.7 80.9 37.6 80.3 61.2 89.8 76.7 65.4 75.7a
74.2 80.0 39.4 81.8 61.4 84.2 77.0 64.4 75.6a
a Ps0.78 (Wilcoxon Signed Rank test) comparing a subject’s post-dialysis body weight between study arms.
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Fig. 1. Individual pharmacokinetic model fits of vancomycin serum concentrations vs time in two representative subjects. The open squares and closed squares represent observed data points for the control and treatment arms, respectively. The solid lines represent the fitted lines to the data. Table 2. Subject haemodialysis parameters and haematocrit values Subject
1 2 3 4 5 6 7 8 Median a
Time on dialysis (months)
47 52 56 83 19 14 80 87 54
Blood flow rate (mlumin)
400 400 400 400 400 430 400 450 400
Dialysate flow rate (mlumin)
600 800 600 600 600 600 600 600 600
Duration (h)
4.0 4.0 3.5 4.0 3.5 3.5 4.0 4.0 4.0
Ps0.26 (Wilcoxon Signed Rank test) comparing haematocrit (%) of each subject between study arms.
Haematocrit (per cent) Control arm
Treatment arm
31.4 42.6 34.2 47.1 35.0 40.6 36.6 32.4 35.8a
36.0 40.6 31.6 39.6 35.3 39.3 37.2 29.2 36.6a
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Fig. 2. Model-derived mean"SD vancomycin serum concentrations vs time in the control (h) and treatment (j) arms, respectively. Table 3. Individual and median vancomycin pharmacokinetic parameter estimates Cls t1u2b Apparent Subject Vp (l) Vc (l) Vss (l) Cldist (mlumin) (mlumin) (h) removal (%) 1 2 3 4 5 6 7 8 Median
29.0 27.2 19.9 23.0 16.4 28.0 32.0 32.4 27.6
9.5 6.5 4.7 6.6 4.5 7.7 9.7 9.5 7.1
38.4 33.7 24.7 29.5 20.8 35.6 41.6 41.9 34.7
267.0 223.7 149.1 170.3 145.9 206.5 234.7 465.7 215.1
11.6 7.9 6.7 8.0 5.8 8.9 11.1 7.1 7.95
39.3 50.5 43.7 43.9 42.8 47.5 44.5 68.6 44.2
7.1 22.4 27.2 34.8 29.0 9.1 27.2 5.1 24.8
Individual and median pharmacokinetic parameter estimates for vancomycin are listed in Table 3, which are similar to those observed in previously published literature. Linear regression analysis revealed no statistically significant relationship between either Cls or Vss and subjects’ post-dialysis body weight (data not shown). Median (range) apparent vancomycin removal when administered during haemodialysis with a CAHP-210 dialyzer was 24.8% (range 7.0–34.8%), which was significantly different from zero (P-value s0.04). Mean"SD model-derived vancomycin serum concentration vs time profiles for control and treatment arms are illustrated in Figure 2. The median estimated vancomycin serum concentration at 44 h after vancomycin administration (control) and at 44 h after intradialytic vancomycin administration (treatment) were 15.9 (range 10.6–20.4) and 14.0 mgul (range 7.7–16.0), respectively (Ps0.04).
Discussion The CAHP-210 hemodialyzer was designed to improve middle molecule removal as compared with other CA
hemodialyzers. The results from the current study revealed 24.8% (median) less exposure to vancomycin when the dose was administered during haemodialysis as compared with when administered after haemodialysis. Our data are consistent with enhanced vancomycin removal with this CA dialyzer as compared with other dialyzers. Apparent vancomycin removal observed in the current study (i.e. 24.8%) is approximately twice that reported previously for CA hemodialyzers (13.6 [5] and 12.8% [8]). In addition, the apparent vancomycin removal in this study is similar to a previous study in our laboratory with a CT hemodialyzer, in which the apparent of per cent vancomycin removal by the CT-190 was 26.3% [8]. Given the lower exposure to vancomycin we observed when the dose is administered during the last hour of haemodialysis, administration of 15 mgukg during the last hour of haemodialysis still provides subsequent pre-dialysis (2-day inter-dialytic period) median vancomycin serum concentrations of 14.0 mlul (range 7.7–16.0). Based on these concentrations, all subjects had vancomycin concentrations above the NCCLS breakpoint (4 mgul) [18] of susceptible organisms during the entire inter-dialytic period. However, with longer intra-dialytic periods (i.e. 72 h) and substantial variability in individual apparent vancomycin removal, higher doses anduor individualized dosing regimens guided by serum concentration monitoring may be required. Several issues related to vancomycin removal in this study require comment. Two of our subjects had negative apparent vancomycin removal values, indicating the serum concentration vs time profiles were nearly the same in both study arms. This finding suggests that vancomycin was not removed when administered during haemodialysis in these two subjects. There are previous studies in the literature, which have observed similar phenomenon [8]. Variability in dosage form content, intra-individual variability in pharmacokinetics or unknown technical errors may contribute to this result. The ability to generalize our findings to other ESRD patients receiving haemodialysis and vancomycin requires comment. First, all hemodialyzers used in this study were new (non-reprocessed). Depending on the solute, dialyzer reprocessing may result in changes in cellulosic hemodialyzer permeability [13,14]. Therefore, the effects of reprocessing should be considered when estimating vancomycin removal by reused CAHP-210 dialyzers. Secondly, because of limited sample size and with the inclusion and exclusion subject selection criteria used in our study, caution should be used when the results from this study are applied to other ESRD patients. For example, in patients with post-dialysis body weights not within 70–130% of their ideal body weight, the fraction of vancomycin removed by haemodialysis may be different. In summary, the i.v. administration of vancomycin (15 mgukg) during the last hour of haemodialysis by the CAHP-210 hemodialyzer results in a statistically
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significant apparent removal of vancomycin as compared with vancomycin administration after haemodialysis However, serum vancomycin concentrations were maintained above the breakpoint of susceptible organisms until the following haemodialysis session approximately 48 h later. Thus, our data suggest that vancomycin dosage adjustment may not be required when it is administered during the last hour of haemodialysis. However, due to the large variability in vancomycin removal by this dialyzer, serum concentration monitoring to individualize therapy may be warranted.
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6. 7. 8. 9.
10. Acknowledgements. The authors wish to thank Marie Stransky, Christine Gassensmith, and the staff at the adult Outpatient Hemodialysis and Peritoneal Dialysis Units at University Hospital, Indiana University Medical Center for their assistance. This study was supported in part by grants from The National Kidney Foundation of Indiana, Inc. and Baxter Health Care Co., McGaw Park, IL.
11. 12. 13.
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Received for publication: 28.1.02 Accepted in revised form: 15.5.02
