ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1988, p. 848-852 Vol. 32, No.

6
0066-4804/88/060848-05$02.00/0
Copyright C 1988, American Society for Microbiology

Vancomycin Pharmacokinetics in Patients with Various Degrees of

Renal Function
KEITH A. RODVOLD,1* ROBERT A. BLUM,' JAMES H. FISCHER,' HUMPHREY Z. ZOKUFA,23
JOHN C. ROTSCHAFER,2'3 KENT B. CROSSLEY,2'4 AND LOUISE J. RIFES
College of Pharmacy' and College of Medicine,5 University of Illinois at Chicago, Chicago, Illinois 60612;
St. Paul-Ramsey Medical Center, St. Paul, Minnesota 551012; and College of Pharmacy3 and College of Medicine,4
University of Minnesota, Minneapolis, Minnesota 55455
Received 26 October 1987/Accepted 8 March 1988

The influence of age, protein binding, and renal function on the pharmacokinetics of intravenous vancomycin
was evaluated in 37 adult patients with various degrees of renal function. Patients were categorized into three
groups based on measured creatinine clearance (CLCR): groups 1, 2, and 3 had 24-h CLCRs of >70, 40 to 70,
and 10 to 39 ml/min per 1.73 M2, respectively. After 1 h of intravenous infusion, concentrations of vancomycin
in serum declined in a biexponential manner in all patients. Diminished renal function in groups 2 and 3 was
accompanied by a lower total body vancomycin clearance (CL) (52.6 and 31.3, respectively, versus 98.4 ml/min
per 1.73 m2) and a lower renal vancomycin clearance (CLR) (48.2 and 19.8, respectively, versus 88.0 ml/min
per 1.73 i2) than in group 1. No significant differences in apparent distribution volume of the central
compartment or apparent distribution volume at steady state were observed. Mean serum protein binding of
vancomycin was 30% and was not significantly affected by renal function. Stepwise multiple linear regression
analysis revealed that CLCR was the strongest predictor of vancomycin CL (r = 0.77, P < 0.001) and
vancomycin CLR (r = 0.87, P < 0.001). Age did not significantly improve these correlations once CLCR was
included. The relationship of vancomycin CL and CLCR was utilized to develop the following equation to dose
vancomycin in the majority of renally impaired patients: dose (milligrams per kilogram per 24 h) = 0.227CLcR
+ 5.67, where CLCR is standardized to milliliters per minute per 70 kg. The practical dosing intervals that the
calculated dose can be divided into and administered include 8, 12, 24, and 48 h based on the CLCR of the
patient.

The use of vancomycin has increased in recent years
owing to the increasing incidence of infections caused by
methicillin-resistant strains of both Staphylococcus aureus
and Staphylococcus epidermidis (2, 5, 30). This renewed
interest has dramatically increased the utilization of vanco-
mycin and stimulated the examination of pharmacokinetic
characteristics to determine appropriate dosage guidelines
(16, 20, 22, 24, 28).
The pharmacokinetics of vancomycin are complex, requir-
ing at least a two-or three-compartment model for a mathe-
matically accurate description of the serum concentration-
time curve (8, 14, 15, 21, 28). Recent findings in healthy
subjects with normal renal function have suggested that age,
protein binding, and renal tubular secretion influence the
disposition of vancomycin in humans (8, 15; T. A. Golper, L.
Elzinga, H. Noonan, J. Anderson, D. N. Gilbert, and W. M.
Bennett, Program Abstr. 26th Intersci. Conf. Antimicrob.
Agents Chemother., abstr. no. 1260, 1986). The clinical
pharmacokinetics of vancomycin have been evaluated in
patients with various degress of renal function (1, 7, 17-20,
24, 28). Most of these studies involved nonspecific bioassay
procedures, various models for pharmacokinetic data anal-
ysis and/or a limited number of patients with measured
creatinine clearance (CLCR), therefore necessitating caution
in interpretation of the data and their application.
The purposes of this investigation were to characterize the
pharmacokinetics of vancomycin in patients with various
degrees of renal function and to evaluate the influence of
*
Corresponding author.
848
age, protein binding, and renal function on vancomycin
distribution and elimination.
MATERIALS AND METHODS
Thirty-seven adult patients (26 men and 11 women) rang-
ing in age from 26 to 87 years were enrolled into the study
after informed consent was obtained. The study protocol
was approved by the Institution Review Boards at the
University of Illinois at Chicago (21 patients) and St. Paul-
Ramsey Medical Center (16 patients). Complete history and
physical examination, urinalysis, and chemistry studies were
performed before the administration of intravenous vanco-
mycin (Vancocin; Eli Lilly & Co., Indianapolis, Ind.). None
of the patients had known hypersensitivity to vancomycin,
and all patients had been started on vancomycin by their
attending physicians for treatment of presumed or docu-
mented gram-positive infections.
The initial doses of vancomycin prescribed by the attend-
ing physicians ranged from 350 to 1,400 mg (6.2 to 20 mg/kg
of total body weight). All doses were administered over a
minimum of 1 h as a continuous intravenous infusion. The
pharmacokinetic study described below was carried out
within the first 48 h of vancomycin therapy over a minimum
dosage interval of 12 h.
Blood samples were serially collected before infusion, at
the end of the infusion, and at 0.25, 0.50, 0.75, 1, 1.5, 3, 5, 7,
and 11 h after the end of the infusion. Additional blood
samples were obtained at 17 and 23 h for patients receiving
vancomycin every 24 h. A 24-h urine collection, in timed
aliquots of 0 to 12 h and 12 to 24 h, was begun with the start
of the vancomycin infusion for determining CLCR and van-
VOL. 32, 1988
TABLE 1. Demographic characteristics for 37 patients according to renal functiona
Group (n) Age (yr) Wt (kg)
1 (10) 46.3 ± 11.6 86.4 ± 19.7
2 (14) 49.5 ± 14.3 73.7 ± 24.2
3 (13) 61.6 ± 18.4' 68.8 + 15.5
" Values expressed as mean ± SD. SCR, Serum creatinine.
b
All groups are significantly different from each other (P < 0.05).
'
Significantly different from groups 1 and 2 (P < 0.05).
d Significantly different from group 1 (P < 0.01).
comycin renal clearance (CLR). Serum and urine samples
were stored at -70°C until analysis.
Serum and urine samples for each patient were allowed to
thaw at room temperature and were analyzed on the same
day. The determination of 24-h CLCR was made on each
patient with the two 12-h urine collections and two determi-
nations of levels of creatinine in serum made at the start of
each 12-h urine collection. Vancomycin concentrations in
serum and urine were determined by fluorescence polariza-
tion immunoassay (TDx; Abbott Laboratories, Diagnostic
Div., Irving, Tex.) (29).
Vancomycin concentration in the urine samples was de-
termined by a modification of the serum vancomycin assay.
Urine samples were initially diluted 1:17 with distilled water
and then analyzed by the same assay procedure as the serum
samples. Urine samples containing a vancomycin concentra-
tion of .200 mg/liter were assayed with a 1:5 dilution with
distilled water. Three control samples prepared in blank
urine at concentrations of 200, 500, and 1,000 mg/liter were
analyzed with each assay. Mean (± standard deviation [SD])
measured concentrations for the control samples from six
replicates assayed over a 3-month period were 211.2 + 7.2,
516.9 + 23.2, and 980.9 ± 55.6 mg/liter. The intraassay and
interassay coefficients of variation for replicate control sam-
ples (n = 6) were less than 4.0 and 6.0%, respectively.
Vancomycin binding to serum proteins was determined for
each patient by ultrafiltration of a blood sample obtained
within the first 3 h after vancomycin administration (26). A
1-ml amount of serum was placed in a micropartition system
(MPS-1; Amicon Corp., Danvers, Mass.) and centrifuged in
an angle head rotor at 2,000 x g for 20 min at 25°C. The
percentage of unbound vancomycin was expressed as the
ratio of vancomycin concentration in the ultrafiltrate to that
in serum. The vancomycin concentration in the ultrafiltrate
was determined by the serum vancomycin assay described
above. The coefficients of variation for replicate (n = 6)
analysis of serum control samples at total concentrations of
10 and 30 mg/liter were 9.4 and 4.1%, respectively, for the
above ultrafiltration procedure. Adsorption of vancomycin
to the ultrafiltration device was assessed after replicate (n =
5) ultrafiltration of a control sample of serum ultrafiltrate
with a vancomycin concentration of 23.9 mg/liter. Minimal
vancomycin adsorption was observed with a mean (±SD)
recovery of 96.8 ± 1.7%.
Initial estimates of pharmacokinetic parameters were ob-
tained by stripping the serum concentration-time data with
RSTRIP (11). These initial estimates were then used to
generate a best fit of the data by using both two- and
three-compartment open infusion models by nonlinear iter-
ative least-squares regression with PCNONLIN (32). A
model-discriminating F-ratio test (3) and the difference (re-
sidual) between measured and computer-fitted concentra-
tions of vancomycin were used to choose the appropriate
VANCOMYCIN PHARMACOKINETICS 849
CLCR (mi/min Albumin Dose
SCR (mg/dl) per 1m7 i Albumin (mg/kg)
1.1 ± 0.5 93.4 ± 28.3b 2.6 ± 0.5 10.5 ± 3.7
1.4 ± 0.6 51.0 ± 8.3" 2.6 ± 0.7 11.6 ± 4.7
2.1 ± 1.Od 23.9 ± 8.2b 2.4 ± 0.6 11.0 ± 3.3
pharmacokinetic model. These data were best described by
using a weighting factor of 1/y2.
The area under the serum concentration-time curve
(AUC) was calculated by the trapezoidal rule and standard
extrapolation techniques with the terminal elimination rate
constant (13). For patients studied on doses other than the
first dose (n = 19), the area contribution from previous doses
was calculated by dividing the predose serum concentration
by the terminal elimination rate constant. The AUC for the
study dose was then corrected by subtracting this area.
The apparent distribution volume of the central compart-
ment (V1), distribution volume at steady-state (Vss), distri-
bution half-life (t1/2a), elimination half-life (01/20), and total
body vancomycin clearance (CL) were calculated by stan-
dard compartmental pharmacokinetic equations (13). Van-
comycin CLR was determined by dividing the amount of
vancomycin excreted in the urine for the 12- or 24-h period
after drug administration by the AUC for the same 12- or
24-h period. Total body vancomycin CL (CLunbound), renal
vancomycin clearance (CLR-unbound), and apparent steady-
state volume of distribution (VSS Ufb0Ufd) based on unbound
concentrations were obtained by dividing the reported phar-
macokinetic parameter by the free fraction in serum.
Patients were categorized into three groups based on
measured CLCR. Groups 1, 2, and 3 had endogenous 24-h
CLCRs of >70, 40 to 70, and 10 to 39 ml/min per 1.73 m2,
respectively. The clinical characteristics of the renal func-
tion groups were compared by chi-square analysis. Overall
differences in patient characteristics and pharmacokinetic
parameters across the three renal function groups were
determined by analysis of variance. When significant differ-
ences were found, Duncan's multiple range test was used to
identify differences between individual renal groups. The
effect of patient-specific clinical and biochemical variables
on vancomycin clearance (CL, CLR) were evaluated by
simple linear regression and forward stepwise multiple re-
gression analysis. Vancomycin clearance parameters and
CLCR were analyzed by using raw values and values stan-
dardized to 1.73-M2 body surface area (10). Statistical signif-
icance was defined as P < 0.05. All analysis of data was
performed with a statistical software package (Statistical
Analysis System; SAS Institute, Inc., Cary, N.C.) (31). All
data are expressed as mean ± SD.
RESULTS
The demographic characteristics of the 37 patients studied
are listed in Table 1. The patients with moderate renal
impairment (group 3) were significantly older than patients
with normal renal function (group 1) and mild renal impair-
ment (group 2). There were no significant differences in the
number of patients between groups who had infections of the
heart and lung (n = 17), bloodstream (n = 25), skin and soft
 ~
850 RODVOLD ET AL. ANTIMICROB. AGENTS CHEMOTHER.

tissue (n = 11), or abdominal cavity (n = 6). There was,

however, a higher incidence of bloodstream infections in
patients with mild renal impairment (n = 12), which often
required aminoglycosides (chi-square analysis, P = 0.07) to
'IC sbe "D
started concurrently at the initiation of vancomycin
+1 +1 +1 therapy. Overall, there were no significant differences in the
r
ooo c vancomycin pharmacokinetic parameters between patients
'.2= oR0> oreceiving or not receiving concomitant aminoglycoside ther-
< < < apy.
After 1 h of infusion, vancomycin concentrations in serum
i.E a+1+1+
+1 +1 +1
declined in a biexponential manner in all patients. The mean
pharmacokinetic parameters for the three renal function
806Oo a;
£6 ofgroups are shown in Table 2. Diminished renal function in
groups 2 and 3 was accompanied by a lower mean vanco-
oo
1%0 00 mycin CL (52.6 and 31.3, respectively, versus 98.4 ml/min
per 1.73 i2) and a lower mean vancomycin CLR (48.2 and
o; .8 ^ +I +I +I 19.8, respectively, versus 88.0 ml/min per 1.73 m2) than in
CoIR
. 0coOo t O

~
group 1. No significant differences in apparent V1 and Vss
were observed among the three groups.
The mean percentage of protein binding in serum for
, Go 0 t vancomycin was 30.3 ± 7.4%. The mean serum albumin
:: : = 8 tl+1 +1+1+1 concentrations were low in all three renal function groups,
o u>> as r- ranging from 1.3 to 4.1 g/dl (mean ± SD = 2.6 ± 0.6 g/dl).
;v;wMean ~wCLunbouCL tCLRUfbOUfd were 83.3 and 71.0 ml/min
per 1.73 m2, respectively, whereas mean Vs-unbOund was 0.84
o|liter/kg. The ratio of CLRRunbund/CLCR averaged 1.33 (range
U E R +1 +1+1 Vancomycin CL and CLR, whether expressed as uncor-
o6
00 eq~ ^rected values (milliliters/minute) or standardized to body
surface area, were significantly (P < 0.05) related to CLCR,
total body weight, body surface area, and serum creatinine
0o 0o o
0 level. Additionally, uncorrected vancomycin CLR correlated
with lean body weight (9) (r = 0.37, P < 0.05), and
>% oc0 0 vancomycin CLR standardized to body surface area corre-
SE0 lated to age (r = -0.33, P < 0.05). Age was significantly
C X ooo related with CLCR (r = -0.35, P < 0.05). Stepwise multiple
> linear regression analysis revealed CLCR as the only predic-
o _ mo o5 tor of vancomycin CL (r = 0.77, P < 0.001; Fig. 1) and
.oo o o vancomycin CLR (r = 0.87, P < 0.001; Fig. 2). Similar
4) w .correlations
N were observed between CLCR and CLunboun d (r
O = 000 = 0.80, P < 0.001, y = 1.21x + 19.4) and between CLcR and
+1 +1 °V CLR-unbound (r = 0.88, P < 0.001, y = 1.39x - 2.4). There
.
. was no significant relationship between the apparent total
and unbound volume of distribution parameters (V1 or VsS)
and CLCR or age.
> ^ +l +l +l
o E 160
IO

140
0~~~~~~ 120
NsNsN 1 /
| = |+I +I +I n 0 tc.1
C
+ 100

|
Q
| tScO2 m 3
|1 |1 t+t1> I-. 40

_ _ q t Q 20-
0 - *-

><
| o^e | o t °' - ' 0 20 40 60 80 100 1i0 140 160
Creatinine Clearance
FIG. 1. Correlation between vancomycin CL (milliliters per
minute per 1.73 m2) and CLCR (milliliters per minute per 1.73 m2).
The linear regression was as follows: y = 0.79x + 15.7 (r = 0.77; P
< 0.001).
VOL. 32, 1988
160 -
140 0 CLCR (ml/min per
120
a,C) E
100
L_ E 80
E 10-19
60 -
a-)
0) 40
20 40 60 80 100 120
20 - terminant of therapeutic vancomycin dosage regimens is
n C
20 40 60 so 1 00 1 20
Creatinine Clearance
(ml/mn/1 .73m2)
FIG. 2. Correlation between vancomycin CLR and CLCR. The
linear regression was as follows: y = 0.90x + 1.55 (r = 0.87; P <
0.001).
DISCUSSION
The results of this study demonstrate that large differences
in vancomycin clearance are due to differences in renal
function. Vancomycin CL for the 37 patients averaged 57.5
ml/min per 1.73 m2 (range, 14.6 to 138 ml/min per 1.73 m2)
and exhibited a high degree of correlation with CLCR (Fig.
1). Vancomycin CLR accounted for 85% of CL, indicating
renal excretion to be the predominant route. The slope of the
regression line for CLR-unbound versus CLCR was signifi-
cantly different from a slope of 1.0 (slope = 1.39; P < 0.05)
indicating that the renal elimination of vancomycin includes
net tubular secretion. Our data support observations in
human volunteers (Golper et al., 26th ICAAC) and in a
rabbit model (25) indicating that substantial tubular secretion
of vancomycin does occur.
The presence of measurable vancomycin in the bile and
stools after intravenous administration supports the exist-
ence of extrarenal routes of elimination (12). The y-intercept
in this study is significantly (P < 0.05) different from zero for
the relationship between CL and CLCR (Fig. 1) and suggests
that more than renal excretion accounts for vancomycin CL.
A similar relationship between vancomycin CL and CLCR
was noted by Rotschafer et al. (28) in a pharmacokinetic
study of 28 patients with serious staphylococcal infections.
In agreement with the conclusions of Narang et al. (Clin.
Pharmacol. Ther. 37:216 [abstr. IV-A]) and in contrast to
those of Brown et al. (4), no significant correlations were
demonstrated between liver function tests and vancomycin
CL among our patients with various degrees of renal func-
tion. Our data suggest that some nonrenal clearance of
vancomycin may occur; however, dosage adjustment in
patients with hepatic impairment does not appear to be
necessary.
Stepwise multiple linear regression analysis of liver and
renal function tests and other patient-specific variables was
performed. CLCR was the strongest predictor of vancomycin
CL (r2 = 0.59) and vancomycin CLR (r2 = 0.76). Although
age appears to correlate (r = -0.33) with vancomycin CLR,
age did not significantly improve these correlations once
CLCR was included. Similar results were reported by Cutler
et al. (8) for a group of young and elderly male volunteers.
Multiple linear regression analysis of their data revealed that
age and CLCR accounted for 60% of variance in
however, CLCR accounted for 85% of this explained vari-
ance. We conclude that age does not contribute additional
information in predicting vancomycin CL.
VANCOMYCIN PHARMACOKINETICS 851
TABLE 3. Dosing intervals of vancomycin as a function of CLCR
Dosage interval
70 kg) (h)
>65 8
40-65 12
20-39 24
48
140 Clinical implications. The primary pharmacokinetic de-
vancomycin CL. Since vancomycin CL was decreased in
1 40
patients with renal impairment, dosage guidelines for van-
comycin in patients with various degrees of renal function
were constructed based on providing similar maximum con-
centration values by extending the dosing interval and
decreasing the daily dose. These guidelines were determined
by multiple-dose simulated kinetics with equations for a
standard two-compartment 1-h infusion model (13) and the
pharmacokinetic parameters of each patient. The actual
maintenance dose needed in each patient to achieve an
average steady-state concentration (Css) of 15 mg/liter was
determined from the calculated vancomycin CL of the
patient by using the following relationship: dose (milligrams
per 24 h) = CL (liters per hour) x Css, (milligrams per liter).
Simulations were then performed with this dose for each
patient to determine the dosage interval that produced a
trough and peak concentration of vancomycin in serum of 5
to 10 mg/liter and 30 to 40 mg/liter, respectively. Concentra-
tions in serum at the end of the infusion were defined as peak
concentrations (27).
Since the relationship of vancomycin CL and CLCR is
linear in patients with various degrees of impaired renal
function, CLCR can be used to determine the appropriate
daily dose of vancomycin for such patients. The dose may be
calculated by the following equation: dose (milligrams per
kilogram per 24 h) = 0.227CLCR + 5.67, where CLCR is
standardized to milliliters per minute per 70 kg. CLCR
corrected to milliliters per minute per 70 kg was utilized
since height data are not uniformly available for conversion
of clearances to 1.73-M2 body surface area. To use these
dosage guidelines, one must measure or calculate CLCR. If
CLCR cannot be measured directly, it can be estimated (6) by
using the patient's age, sex, and serum creatinine (SCR) as
follows: CLCR-maleS (milliliters per minute per 70 kg) = (140
- age)/SCR; CLCR-females (milliliters per minute per 70 kg) =
0. 8SCLCR-males.
The degree of change in the dosing interval was calculated
by using the relationship between vancomycin CL and CLCR.
Table 3 lists the practical dosing intervals that the above
calculated dose can be divided into and administered in the
majority of renally impaired patients. Calculated doses
should be administered by intravenous infusion of at least 1
h to minimize infusion-related toxicity (23).
These initial dosage guidelines are only approximations
based on the pharmacokinetic properties of vancomycin
observed in our patient populations. Although a highly
significant relationship exists between vancomycin CL and
CLCR, CLCR explains only 59% of the variance (r2) in
vancomycin CL. Measuring concentrations in serum and
individualizing dosage regimens is essential to optimize
vancomycin therapy.
CLR;
ACKNOWLEDGMENTS
This study was supported in part by a grant from Eli Lilly & Co.,
Indianapolis, Ind.
852 RODVOLD ET AL.
We greatly appreciate the technical assistance of Sharon Anto-
siak.
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