Markedly increased clearance of vancomycin during hemodialysis using polysulfone dialyzers

Kidney International, Vol. 35 (/989), pp. /409—1412

Markedly increased clearance of vancomycin during hemodialysis using polysulfone dialyzers DIANE M. LANESE, PATRICIA S. ALFREY, and BRUCE A. M0LIT0RIs Department of Medicine and Division of Nephrologv, Veterans Administration Medical Center, Denver, Colorado, USA

Clearance of a drug during hemodialysis is affected by drug (post-dialyzers) extraction values based on total plasma vancospecific, membrane specific and dialysis specific factors [I, 21. mycin levels. At least five clearance determinations (hourly) Drug specific properties determining dialysability include its throughout the four-hour dialysis session were used to calculate volume of distribution (Vd), protein binding and molecular vancomycin clearance for an individual patient. The formula to weight. Dialyzer membrane specific factors include surface calculate plasma vancomycin clearance was QB (100%-hematoarea, permeability and adherence of the drug to the membrane. crit %) (A-V/A), where A and V refer to arterial and venous Finally, blood flow and dialysate flow also influence drug plasma vancomycin concentrations, respectively. Ultrafiltration rates were not included in this calculation. The intradialytic clearance. Vancomycin is commonly used in patients for the treatment half-life of vancomycin (t 1/2) was calculated using standard, of gram + infections. More than 90% of the drug is excreted by first-order kinetic equations based on decay curves with at least the kidneys; however, in the presence of renal failure significant five arterial serum vancomycin levels collected over the four dosage adjustments are required. The half life of vancomycin is hour dialysis. Data, expressed as the mean standard deviaquite prolonged in ESRD (200 hours) as compared to those with tion, were analyzed using the Student's t-test unless otherwise normal renal function (6 to 8 hours) [3—9]. Typically, vancomy- noted. P values less than <0.05 were considered significant and cm is not appreciably removed by the cuprophane or cellulose were reported as either <0.05 or <0.01. acetate membranes used in conventional hemodialysis. HowResults ever, with the introduction of the newer, more permeable membranes, such as the polysulfone dialyzers, the pharmacoFigure IA shows the change in plasma vancomycin concenkinetics of vancomycin removal during hemodialysis may be tration in each patient studied during a four hour hemodialysis increased since vancomycin has a small Vd (0.47 to 0.84 liter! using the Travenol model 12.11. The cuprophane dialyzer kg), minimal protein binding [3, 5, 9] and a relatively low resulted in a minimal decrease in plasma vancomycin concenmolecular weight (1500 daltons) [31. The purpose of the present tration (20.2 5.7 vs. 18.8 5.0) during four hours of study was therefore, to determine whether polysulfone mem- hemodialysis. However, the Fresenius polysulfone F-80 branes increased the clearance of vancomycin. dialyzer affected a marked reduction in plasma vancomycin concentration in each patient studied during a four hour dialysis Methods 1.9, P < 0.01), as shown in Figure lB. (15.7 3.9 vs. 8.0 Six male patients on chronic hemodialysis were studied in a The disappearance of plasma vancomycin during hemodialypaired fashion with each patient being studied on each dialyzer sis with different dialyzers was then quantitated by calculating membrane and, therefore, serving as his own control. All the percent removed, the intradialytic t 1/2, and the clearance of patients were dialyzed on a Fresenius A 2008C hemodialysis vancomycin. These data are shown in Table I. Vancomycin machine. Unless otherwise stated, the dialysis prescription was removal increased from 6.9% using the cuprophane dialyzer to held constant for all patients with respect to a blood flow rate of 49,5% using the polysulfone F-80 dialyzer. Within the polysul250 mI/mm with a bicarbonate dialysate (ph 7.2) flow rate of 500 fone series there was a linear relationship between surface area mI/mm. Vancomycin clearance was determined for the Trave- of the dialyzer and the amount of vancomycin removed (r = nol 12.11 cuprophane (surface area 0.8 m2) and the Fresenius 0.94, N = 10, P < 0.01). Using the cuprophane dialyzer the polysulfone F-40, F-60, F-80 dialyzers with surface areas of intradialytic t 1/2 of vancomycin was 35.1 11.2 hours, while 0.65, 1.2 and 1.9 m2, respectively. all the polysulfone dialyzers showed a markedly reduced intradialytic t 1/2. For the polysulfone dialyzers there was an inverse Analytical procedures relationship between the surface area of the dialyzer and the Plasma vancomycin levels were determined using the Abbott intradialytic t 1/2 of vancomycin (r = 0.74, P < 0.05). Figure 2. shows the effect of a surface area upon plasma TDx TM drug assay system as we have previously reported [4]. Initial plasma vancomycin levels were not statistically different vancomycin clearance during hemodialysis with the polysulfone membrane dialyzer series. The clearance of vancomycin when cuprophane or polysulfone dialyzers were studied (20.0 5.5 vs. 18.3 4.3 gIml). Plasma vancomycin clearances were was markedly enhanced with increased dialyzer surface area (r calculated using simultaneous arterial (pre-dialyzer) and venous = 0.95, P < 0.01). The clearance of vancomycin using the F-40 1409

Lanese el al: Increased vanco,n vein clearance

1410

A

B

25 S .E

20

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15

.

0

.

-

E

—

2•1) 10

5 0

2

1

4

3

0

2

1

Time, hours

3

Fig. 1. The change in plasma vancomycin levels during hemodialysis with the Tra venal /2./I cuprophane (A) and Fresenius polysulfone F'-80 dialyzers (B). Individual

symbols represent the same patient dialyzed on the two different membranes.

Table 1. Effect of different dialyzers on the clearance and intradialytic t 1/2 of plasma vancomycin

Membrane

m2

Cuprophane Polysulfone F-40 Polysulfone F-60 Polysulfone F-80

0.80 0.65

Vancomycin clearance mI/inin"

Vancomycin removal

Surface area

%

1.20 1.90

Intradialytic t 1/2 hoursc

6.9

1.0

9.6

25.8 35.8

6.0 3.0 0.5

44.7

6.7

35.1 11.8

73.0 85.2

5.0 7.0

6.7 4.5

49.5

2.9C

11.2

5.6 1.0 0.1

U Vancomycin removal was calculated using arterial pre-dialysis and post-dialysis plasma levels immediately prior to and following a 4 hour dialysis session. QB and QD were 250 and 500 mI/mm, respectively. 'The data represent the mean so. N = 4 for the cuprophane and F-80 and 3 for the F-40 and F-60 dialyzers. C The mntradialytic t 1/2 of vancomycin was determined during the entire 4 hours of hemodialysis and based on 5 arterial levels.

(Fig. 3) increased linearly over the range of QB studied from 83.7 5.5 to 104.9 8.8 mI/mm. A highly significant correlation was also noted between Q and vancomycin clçarance (P <

0

0.01).

C

a a

Discussion

60

Vancomycin is an effective and widely used antibiotic for the treatment of gram positive infections in dialysis patients. This is

C C., >,

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0U C

in part due to its ease of administration (I g i.v. every 7 to 10 days). Vancomycin, however, is somewhat unique in that it has

40

a

>

a small Vd and has a relatively small molecular weight allowing 20 .5

1

1.5

2

Surface area, m2

FIg. 2. The effect of suiface area on plasma vaneom.vein clearance. individual data points are shown for three patients each dialyzed using

an F-40, F-60 and F-80 Fresenius polysulfone dialyzer. Linear regression revealed a correlation of 0.95, P < 0.01.

its unhindered filtration across the glomerulus. Its clearance during hemodialysis, therefore, is primarily a function of the permeability of the dialysis membrane and the extent of its binding to serum proteins. The protein binding of vancomycin has been reported in Iwo studies (9, II] and has ranged between 10 and 55 percent. Our data is suggestive of low protein binding as the clearance of vancomycin is 61 percent of Q at a flow rate of 130 mI/mm. This high percent clearance would be unlikely to

occur if vancomycin was highly protein bound unless it was (0.65 m2) was 44.7 6.7 mI/mm, while that of the F-SO (1.9 m2) increased to 85.2 7.0 mI/mm (Table I). Both these clearance

values are significantly greater (P < 0.01) than that obtained with the Travenol cuprophane dialyzer (9.6 2.9 mI/mm). Finally, to determine the effect of QB and plasma flow rate (Q) on plasma vancomycin clearance with the F-80 dialyzer, QB was varied from 200 to 400 mI/mm. Vancomycin clearance

bound to small molecular weight proteins which are also cleared

during high flux hemodialysis. Cellulose acetate and cuprophane membranes, because of there limited permeability, do not result in effective removal of vancomycin (3—9]. Polysulfone

membranes, on the other hand, have markedly improved permeability characteristics. The ultrafiltration coefficient of the F-80 dialyzer is 55 mI/hr mm Hg compared with the Travenol

Lanese et a!: Increased 'ancomvcin clearance

1411

A 120

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.5

100

.5 .

90

f

8 t3

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80 70 100

200

300

400

Q, mUm/n 100

200

400

300

500

Q, mi/mm

B 125

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0 C

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0 75

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yintercept = 60.2 0.15 slope =0.91 r

100

150

200

250 Op. mi/rn in

12.11 which is only 3.0 mI/hr mm Hg. This results in more rapid

clearance of "middle molecules". In the present study we demonstrate that the polysulfone dialyzers affect the significant removal of vancomycin as compared to cuprophane dialyzers. Enhanced removal was documented by the increased clearance of vancomycin, the de-

300

Fig. 3. The effect of Q8 and Q,, on plasma vanco,n vein clearance using the F-80 dialyzer. Vancomycin clearances were determined in three patients at QB of 200, 300 and 400 ml! mm. (A) The effect of QB or vancomycin clearance. Data points represent the mean I SD of triplicate determinations in individual patients. Linear regression revealed a correlation of 0.99. P < 0.01. The insert (lower right) shows data for individual patients designated by different symbols for each patient. (B) The effect of Q on vancomycin clearance. Each symbol represents the mean of three determinations in each patient at one Q. The correlation value of 0.91, N = 9, is highly significant P < 0.01.

These data have important clinical implications. First, the standard regiment of vancomycin administration every 7 to 10

days, has to be altered when the patient is dialyzed using polysulfone dialyzers, so as to maintain therapeutic serum

levels. Secondly, the polysulfone membrane used, the QB and the duration of dialysis will determine how much vancomycin is creased intradialytic t 1/2 of vancomycin as well as the required post-dialysis. For example, it seems reasonable to decrement in serum vancomycin levels during the hemodialysis administer a post-dialysis vancomycin supplement of about session. We also showed that within the polysulfone dialyzers, 50% of the usual loading dose when a patient is dialyzing on the increasing the surface area enhances vancomycin clearance and polysulfone F-80 dialyzer for four hours, given the intradialytic 1/2 for vancomycin is four hours. decreases the intradialytic t 1/2. Finally, as QB or Qincrease so does vancomycin clearance with the F-80 dialyzer. The relaIn an attempt to provide a clinically applicable means of tionship between vancomycin clearance and Q. instead of QB' estimating vancomycin removal, we examined the relationship is probably preferable as vancomycin does not distribute into between a dialyzer's B1, clearance and its degree of vancomyerythrocytes. Since patient's hematocrits may vary from 15 to cm removal. For the four dialyzers we studied there was an 50 percent expressing the data in terms of Q removes the excellent linear relationship between B12 clearance and vancovariability in clearance induced by widely varying hematocrit mycin removal (Fig. 4. r = 0.99, P < 0.01). Whether this values. relationship holds for all dialyzers remains to be determined.

1412

Lanese et al: Increased vanco,nvcin clearance

60

.

50 C C, >,

E

00 40 C CD

> E

30

CD CD

C CD CD

Fig. 4. The correlation between the percent

20

decrease in plasma vancomycin levels and the B,2 clearance of individual dialyzers. Filled

yintercept = —5.9 = 0.36 slope

0 CD

10

0

0

20

40

60

80

100

rvalue

= 0.99

120

140

160

B,2 clearance, mI/mm

However, recent data from Bastani et at [121, for cellulose

acetate and polyacrylonitrile dialyzers were in close agreement with the linear regression equation generated by our data (Fig.

symbols are from the present study and the linear regression equation is based on those 4 data points. The open symbols represent data on cellulose acetate (Cordis Dow 4000) and polyacrylonitrile (Hospal 2400S AN 695) dialyzers taken from Bastani et al [(2]. For all data points QB and the time of hemodialysis were 250 mI/mm and 4 hours, respectively.

Reprint requests to Bruce A. Molitoris, M.D., Department of Medicine I/IC, VA Medical Center, /055 Clermont Street, Denver, Colorado 80220, USA.

4, open symbols). To this relationship one can then add equations to factor for variable Q and the duration of dialysis, resulting in the following equation to estimate the removal of vancomycin, where % vancomycin removal

I. KELLER F, WILMS H, OFFERMAN G, MOLZAHN M: Effect of

(1Post-dialysis level <

\

plasma protein binding volume of distribution and molecular weight on the fraction of drugs eliminated by hemodialysis. Clin Nephro!

Pre-dialysis level /

= (0.36 Cl, — 6) [1 + (QB

References

— 250) (0.001)]

(time(hr))

= (0.09 CIB. — 1.5) (0.75 + 0.001 QB) (time (hr)) and CIB, = manufacturers reported B1, clearance

19:201—205, 1983

2. MAHER J: Principles of dialysis and dialysis of drugs. Am J Med 62: 475—481, 1977 3. BENNET W, ARONOFF G, MORRISON G, GOLPER T, PULLIAM J,

M, SINGER 1: Drug prescribing in renal failure: Dosing guidelines for adults. Am J Kid Dis 3:155—181, 1983 4. EYKYN S. PHILLIPS I, EVANS J: Vancomycin for staphylococcal shunt site infections in patients on regular hemodialysis. Br MedJ WOLFSON

3:80—82, 1970

Using the percent of vancomycin removed one can then more accurately calculate a replacement dose. These data, however, are based on data derived using the polysulfone F40-80 dialyzers. Whether they hold for all dialyzers remains to be shown. In summary, use of the highly permeable polysulfone membrane necessitates supplemental vancomycin administration following each dialysis session to maintain therapeutic vancomycin plasma levels. The amount of supplementation will be dependent upon the duration of dialysis, dialysate flow rate, blood flow rate and polysulfone dialyzer utilized. In addition, other drugs with relatively small Vd, minimal protein binding and a molecular weight in the range of 1,000 to 12,000 daltons may also require supplementation following dialysis with highly permeable membranes. Acknowledgments We thank Priscilla Mendez for her secretarial support. This work was supported in part by a grant from the Fresenius Company, USA. B.A. Molitoris is a V.A. Clinical Investigator.

5. BENNET W: Drug management in patients on dialysis. Drug and Renal Disease, edited by D. AZARNOFF, New York, Churchill Livingstone, 1986, pp. 66—75 6. FEKETY R: Vancomycin. Med C/in North Am 66:175—181, 1982 7. MATZKE GR, MCGARY RW, HALSTEVSON CE, KEANE WF: Phar-

macokinetics of vancomycin in patients with various degree of

renal function. Antimicrob Agents Chemother 25:433-437, 1984 8. CUNHA BA, QUINTILIAI R, DEGLIN JM, IZAND MV, NIGHTINGALE CH: Pharmacokinetics of vancomycin in anuria. Rev Infect Dis 3: 5269—5272. 1981 9. LINDHOLM DD, MURRAY

iS: Persistence of vancomycin in the

blood during renal failure and its treatment by hemodialysis. N EngI J Med 274: 1047—1051, 1966 10. SEDMAN A, MOLIT0RIS B, NAKATA L, GAL I: Therapeutic drug monitoring in patients with chronic renal failure: Evaluation of the Abbott TDxTM drug assay system. Am J Nephrol 6:132—134, 1986 II. KROGSTAD Di, MOELLERINO RC, GREENBLATT Di: Single-dose kinetics of intravenous vancomycin. J Clin Pharmacol 20:197—201, 1980 12. BASTANI B, SPYKER DA, MINOCHA A, CUMMINGS R, WESTERVELT FB JR: In vivo comparison of three different hemodialysis mem-

branes for vancomycin clearance: Cuprophan, cellulose acetate and polyacrylonitrile. Dial Transplant 17:527—543, 1988