Pharmacokinetics of Vancomycin in Extremely Obese

Patients with Suspected or Confirmed Staphylococcus

aureus Infections
Eyob D. Adane,1,* Michael Herald,1 and Firas Koura2
1
Department of Pharmacy, Hazard Appalachian Regional Medical Center, Hazard, Kentucky; 2Kentucky Lung
Clinic, PSC, Appalachian Regional Healthcare, Hazard, Kentucky

STUDY OBJECTIVE To estimate vancomycin pharmacokinetic parameters and dosing requirements in a

cohort of extremely obese patients.
DESIGN Prospective pharmacokinetic study.
SETTING Acute care community teaching hospital.
PATIENTS Thirty-one extremely obese (body mass index [BMI] ≥ 40 kg/m2) men and women who were
receiving vancomycin for at least 3 days for suspected or confirmed Staphylococcus aureus infections.
MEASUREMENTS AND MAIN RESULTS Population pharmacokinetic parameters were used to determine
vancomycin doses that target trough concentrations of 10–20 lg/ml. Three serum vancomycin con-
centrations (peak, trough, and midpoint) were measured at steady state for each patient. A 24-hour
urine collection was performed to determine creatinine clearance (Clcr). A one-compartment intra-
venous infusion model was fit to the serum vancomycin concentrations by using nonlinear mixed-
effects modeling. Covariates that affect the volume of distribution and clearance of vancomycin were
explored. Patients had a median weight of 147.9 kg, BMI of 49.5 kg/m2, and a Cockcroft-Gault Clcr
of 124.8 ml/minute/1.73 m2. Patients received a median vancomycin dose of 4000 mg/day that pro-
vided a median 24-hour area under the concentration-time curve (AUC) of 582.9 (interquartile
range 513.8–726.2) mg
hour/L. The population mean volume of distribution was 0.51 L/kg, and
clearance was 6.54 L/hour. Simulations indicated that 4000–5000 mg/day of vancomycin pro-
vided ≥ 93% probability 24-hour AUC/minimum inhibitory concentration (MIC) ratio of ≥ 400 for
an MIC of 1 lg/ml.
CONCLUSION Total body weight and Clcr influenced volume of distribution and vancomycin clearance,
respectively. Vancomycin can be initiated in extremely obese patients at dosages determined based
on renal function and pharmacokinetic parameter estimates from this study. Vancomycin serum
concentrations should be monitored to ascertain attainment within the therapeutic range.
KEY WORDS pharmacokinetics, vancomycin, peak, trough, obesity, NONMEM.
(Pharmacotherapy 2015;35(2):127–139) doi: 10.1002/phar.1531

Vancomycin is a tricyclic glycopeptide antibi- staphylococcal and enterococcal infections.1 Its

otic that is useful in the treatment of serious
This work was supported by the Appalachian Regional
Healthcare Medical Center, Hazard, KY, USA.
*Address for correspondence: Eyob D. Adane, Depart-
ment of Pharmacy Practice, The Raabe College of Phar-
macy, Ohio Northern University, 525 S. Main Street, Ada,
OH 45810; e-mail: e-adane@onu.edu.
Ó 2015 Pharmacotherapy Publications, Inc.
pharmacokinetic profile has been described by
one-, two-, or three-compartment models,2–4
although the one-compartment model offers sim-
plicity in clinical practice. Despite its hydrophi-
licity, vancomycin is widely distributed, with a
volume of distribution ranging between 0.4 and
1 L/kg of total body weight.2, 5, 6 After intrave-
nous administration, renal elimination accounts
for 80–90% of vancomycin clearance,2, 4, 7
128 PHARMACOTHERAPY Volume 35, Number 2, 2015
necessitating dosage adjustment for decreased
renal function. The drug is < 50% protein
bound.8 Vancomycin exerts a time-dependent
antibacterial effect,9 and its clinical response is a
function of the 24-hour area under the concen-
tration-time curve to minimum inhibitory con-
centration (AUC:MIC) ratio.10
A consensus review of the American Society
of Health-System Pharmacists (ASHP), the Infec-
tious Diseases Society of America (IDSA), and
the Society of Infectious Diseases Pharmacists
(SIDP) recommends maintaining vancomycin
trough concentrations > 10 lg/ml to avoid
Staphylococcus aureus resistance and between 15
and 20 lg/ml in complicated infections such as
bacteremia, endocarditis, and osteomyelitis.10
The consensus review also states that doses for
obese patients are based on total body weight
and are adjusted based on serum vancomycin
concentrations to achieve therapeutic levels.
Similarly, the guideline for the treatment of
methicillin-resistant Staphylococcus aureus
(MRSA) infections in adults and children recom-
mends a vancomycin dosage of 15–20 mg/kg
every 8–12 hours without exceeding 2000 mg of
vancomycin/dose.11 Obese patients would, how-
ever, typically require doses > 2000 mg/dose
because of the initial weight-based dosing. To
our knowledge, the performance of this dosing
regimen has not been evaluated in extremely
obese patients.
Available literature indicates associations
between obesity and increased risk of infection
and poor outcome following established infec-
tion.12, 13 According to the Centers for Disease
Control and Prevention, obesity has increased
over the past 20 years.14 U.S. data in 2010 indi-
cate that 35.7% of adults and ~17% of children
and adolescents between the ages of 2 and
19 years are obese.14 The World Health Organi-
zation (WHO) classifies obesity based on body
mass index (BMI) into obesity class I (BMI
30.0–34.9 kg/m2), obesity class II (BMI 35.0–
39.9 kg/m2), and obesity class III/extreme obes-
ity (BMI ≥ 40.0 kg/m2).15 Clinically, the initial
vancomycin dose is estimated from nomo-
grams7, 16 or calculated from population
pharmacokinetic parameter estimates.17 Subse-
quently, therapeutic monitoring is performed to
optimize its efficacy and minimize nephrotoxi-
city. Vancomycin doses > 4000 mg/day,
weight > 101 kg, creatinine clearance
(Clcr) < 86.6 ml/minute, and intensive care unit
residence were found to be related to an
increased likelihood of nephrotoxicity.18, 19 The
increase in nephrotoxicity in patients
weighing > 101 kg was attributed to the large
volume of distribution that results in a more
intensive vancomycin exposure profile.19 The
risk of nephrotoxicity increases when vancomy-
cin is used in combination with aminoglyco-
sides20 and with the intensity of vancomycin
daily dose,21 number of vancomycin doses
received, and use of vancomycin
doses > 2000 mg.22 Despite extensive studies on
vancomycin pharmacokinetics in nonobese
patients, few such studies and dosing guidelines
exist for extremely obese patients. Earlier studies
reported > 2-fold increase in vancomycin clear-
ance in extremely obese patients and recom-
mended higher vancomycin doses at more
frequent intervals.5, 23 Our institutional practice,
however, indicates that currently available dosing
regimens often fall short of achieving recom-
mended therapeutic levels in extremely obese
patients.
Thus the objective of this study was to esti-
mate the vancomycin pharmacokinetic parame-
ters and dosing requirements in a cohort of
extremely obese patients.
Methods
Study Design, Setting, and Patient Population
This prospective pharmacokinetic study was
conducted at a 322-bed acute care community
teaching hospital (Appalachian Regional Health-
care Medical Center, Hazard, KY) and was
granted institutional review board (IRB)
approval by the hospital system. Extremely
obese adult patients (BMI ≥ 40 kg/m2) with sus-
pected or confirmed Staphylococcus aureus infec-
tion and requiring treatment with vancomycin
for ≥ 3 days according to the treating clinician’s
judgment were recruited for the study. All
patients participating in the study provided IRB-
approved written informed consent. Inclusion
criteria were age ≥ 18 years and Clcr ≥ 30 ml/
minute/1.73 m2. Exclusion criteria were history
of vancomycin allergy or intolerance, adminis-
tration of < 4 doses of vancomycin, pregnancy,
and meningitis.
Creatinine Clearance and Glomerular Filtration
Rate Calculation, and Vancomycin Dosing
To determine initial vancomycin doses and to
monitor and prevent nephrotoxicity, we calcu-
lated Clcr with the Cockcroft-Gault equation,24
 VANCOMYCIN IN EXTREMELY OBESE PATIENTS Adane et al.
using total body weight (TBW) standardized to
body surface area (BSA).25 We also determined
Cockcroft-Gault Clcr using ideal body weight
(IBW), adjusted body weight (ABW = IBW + 0.4
[TBW  IBW]), and lean body weight.26, 27 The
Clcr and glomerular filtration rate were also esti-
mated by using the Salazar Corcoran28 and the
four-variable Modification of Diet in Renal Dis-
ease Study (MDRD 4) equations,29 respectively.
Vancomycin was discontinued or the dosage
adjusted if Scr (serum creatinine) concentration
rose by > 1.5 times the baseline values over 2
consecutive days or if vancomycin trough con-
centrations were > 20 lg/ml according to the
treating clinician’s judgment.
Population pharmacokinetic parameters were
used to determine vancomycin doses that target
trough concentrations of 10–20 lg/ml as
described in the literature7 and according to
standard hospital practice and relatively recent
guidelines.10, 30 Patients typically received 15
mg/kg doses that were infused over 1 hour
if ≤ 2000 mg and > 2 hours if > 2000 mg.
According to institutional practice, the maxi-
mum dose was capped at 2500 mg every
12 hours to minimize adverse events. Peak and
trough vancomycin concentrations were esti-
mated as follows:
  ðR Þð1  ekt ÞekT
in
Peak concentration Css pk ¼ ; A one-compartment model has been shown
kVð1  eks Þ
ð1Þ

after the distribution phase.23 Therefore, due
kT0
tr ¼ Cpk  e
Trough concentration Css ; ð2Þ
ss
where Rin = rate of infusion (dose/t), t = length
  T = time between end of infusion
of infusion,
pk
and Ctr , V = volume of distribution, k = rate
of elimination, s = dosing interval, and
T0 = s  (t + T).
Vancomycin Serum Concentration Measurement
Vancomycin serum concentrations were mea-
sured at steady state, typically after the fourth
dose. The peak concentration was measured
within 1 hour after end of the vancomycin infu-
sion, whereas the trough concentration was mea-
sured within 30 minutes before the next dose
and the random concentration measured approx-
imately midway between the peak and trough
concentrations. Additional concentrations were
measured according to the treating clinician’s
judgment. Concentrations were determined at
the Appalachian Regional Healthcare Medical
129
Center Clinical Laboratory by using a commer-
cial kit (VANC Flex Reagent Cartridge, Siemens
Healthcare Diagnostics Ltd., Newark, DE). The
method uses a particle-enhanced turbidimetric
inhibition immunoassay on a Dimension clinical
chemistry system analyzer (Siemens Healthcare
Diagnostics Ltd.). Assay sensitivity is 0.8 lg/ml,
and assay range is 0.0–50.0 lg/ml. Within-run
coefficient of variation is 5% at a concentration
of 4.59 lg/ml and 20% at a concentration of
30.0 lg/ml.
A 24-Hour Urine Collection for Determination
of Creatinine Clearance
The urine of patients receiving vancomycin
was collected for 24 hours to determine Clcr as
follows:
Clr ðml=minÞ ¼ Vurine ðmlÞ=1440 min
 Ucr ðmg=dlÞ=Scr ðmg=dlÞ; ð3Þ
where Vurine is urine volume (in milliliters) col-
lected over 24 hours, and Ucr and Scr are urine
and serum creatinine concentrations, respec-
tively.
Nonlinear Mixed-Effects Modeling of
Vancomycin Population Pharmacokinetics
to adequately describe vancomycin pharmaco-
kinetics when concentrations are measured
to its simplicity and ease of clinical applicabil-
ity, a one-compartment intravenous infusion
model was fit to the serum vancomycin con-
centrations by using NONMEM 7.3 (ADVAN1
TRANS2 FOCE INTER) (Icon Development
Solutions, Hanover, MD),31 using Wings for
NONMEM (N. Holford, Auckland, New Zea-
land).32
The base model is represented as follows:
V ¼ THETA (1)  EXP (ETA (1)); ð4Þ
Cl ¼ THETA (2)  EXP (ETA (2)); ð5Þ
where V is volume of distribution, Cl is clear-
ance of vancomycin, and ETA (1) and ETA (2)
are between-subject variabilities (BSV) in volume
of distribution and clearance, respectively. BSV
and within-subject variabilities were modeled by
using exponential and proportional error mod-
els, respectively. Individual pharmacokinetic
parameters were determined by using the POST
130 PHARMACOTHERAPY Volume 35, Number 2, 2015

HOC option in NONMEM. To explore covari- Table 1. Demographic and Clinical Characteristics of the
ates influencing the pharmacokinetics of vanco- 31 Study Patients
mycin in the patient population, plots of Characteristic Data
individual parameter estimates and BSV in the No. of patients
parameter estimates versus possible covariates Male 19 (61.3)
were made. The following covariates were Female 12 (38.7)
explored for their effects on volume of distribu- Age, yrs 43.0 (38.5–53.0)
Weight, kg
tion: age, weight, sex, height, BMI, and BSA. TBW 147.9 (142.8–178.3)
Because of the predominantly renal elimination IBW 71.9 (57.4–78.8)
of vancomycin and the correlation of age, ABW 104.2 (92.4–114.3)
weight, and sex with Clcr, we decided to test LBW 82.4 (62.9–89.4)
Clcr as a covariate on vancomycin clearance. A Height, cm 175.3 (165.6–184.2)
Body surface area, m2 2.6 (2.4–2.8)
covariate was retained in the model if the objec- Body mass index, kg/m2 49.5 (44.3–54.8)
tive function value (OFV) decreased by 3.84 Creatinine clearance
and/or if its inclusion decreased the BSV and/or Cockcroft-Gault equation using 124.8 (106.0–133.9)
improved precision of parameter estimates. To TBW, ml/min/1.73 m2a
assess performance of the final model, 1000 sim- Cockcroft-Gault equation using 207.1 (157.0–229.8)
TBWb
ulations were performed using the SIM option in 24-hr urine creatinine clearance 83.5 (69.5–121.9)
NONMEM. Similarly, 500 simulations were per- Salazar-Corcoran equation 154.4 (117.9–165.5)
formed using the final model for a set of patients Cockcroft-Gault equation using 147.1 (108.8–155.4)
weighing between 110 and 280 kg at 10-kg ABW
increments and Clcr between 77 and 147 ml/ Cockcroft-Gault equation using 106.9 (74.5–119.0)
LBW
minute/1.73 m2 at 10-ml/minute/1.73 m2 incre- Cockcroft-Gault equation using 81.8 (69.6–107.8)
ments. The range of weights and Clcr reflects the IBW
range observed in the study patients. The simu- GFR, MDRD 4 equation, 86.7 (73.4–95.9)
lations determined 24-hour AUCs, steady-state ml/min/1.73 m2
trough concentrations, elimination rate con- Vancomycin dose, mg/day 4000 (3625–4375)
Vancomycin 24-hr AUC, mg
hr/L 582.9 (513.8–726.2)
stants, and half-lives following the administra- Concomitant drugs
tion of four vancomycin doses ranging from Piperacillin-tazobactam 16 (51.6)
1500–5000 mg/day. Simulation outputs from Cefepime 5 (16.1)
NONMEM were processed with R3.0.1.33 Cefepime + polymyxin B 1 (3.2)
Meropenem 2 (6.5)
Diuretics 20 (64)
Results NSAIDs 10 (32)
ACEIs or ARBS 18 (58)
Thirty-one extremely obese WHO class III Data are no. (%) of patients or median (interquartile range).
patients with a median BMI of 49.5 kg/m2 con- ABW = adjusted body weight; ACEIs = angiotensin-converting
enzyme inhibitors; ARBs = angiotensin II receptor blockers;
sented to participate in the study between Janu- AUC = area under the concentration-time curve; GFR = glomeru-
ary 2012 and August 2013. Table 1 shows the lar filtration rate; IBW = ideal body weight; LBW = lean body
patient demographics and clinical characteris- weight; MDRD 4 = four-variable Modification of Diet in Renal Dis-
ease Study; NSAIDs = nonsteroidal antiinflammatory drugs;
tics. Men accounted for 61% of the study par- TBW = total body weight.
ticipants. The median weight of the study a
Serum creatinine concentration measurements < 1 were rounded
participants was 147.9 kg, which was 2-fold to 1.
b
Measured serum creatinine concentration was used, and creatinine
higher than the median IBW. Patients had a clearance was not adjusted to body surface area.
median age of 43 years and received a median
vancomycin dose of 4000 mg/day, resulting in
median 24-hour AUCs that were all above in both cases by their medical providers and
400 mg
hour/L (Tables 1 and 2). Two patients according to the study protocol. In addition to
had increases > 1.5 times their baseline Scr and vancomycin, study patients were taking other
were not included in the pharmacokinetic medications that are renally eliminated and/or
analysis. One of the patients was a 38-year-old could alter renal function during or around the
woman weighing 189.2 kg (BMI 69.4 kg/m2); study period. The list of concomitant drugs
the other was a 41-year-old woman weighing taken by all the study patients is shown in
127.1 kg (BMI 42.6 kg/m2). Both patients were Table 1. A 24-hour Ucr was available for 13
receiving vancomycin 2000 mg intravenously patients. In general, patients had good renal
every 12 hours. Vancomycin was discontinued function, with a median estimated Clcr of
 VANCOMYCIN IN EXTREMELY OBESE PATIENTS Adane et al.
Table 2. Median 24-Hour AUCs Achieved with Various Daily Doses of Vancomycin
Vancomycin Median weight,
daily dose, mg kg, %IBW
2000 147.9 (282%)
3000 116.1 (182%)
3500 143.5 (206%)
4000 149.7 (205%)
4500 147.0 (226%)
5000 193.7 (236%)
AUC
a
= area under the concentration-time curve; IBW = ideal body weight; IQR = interquartile range.
AUCs were calculated from the ratio of 24-hour vancomycin dose and vancomycin clearance.
124.8 ml/minute/1.73 m2 and a measured 24-
hour Ucr of 83.5 ml/minute.
Nonlinear Mixed-Effects Modeling of
Vancomycin Population Pharmacokinetics
A total of 93 serum vancomycin concentra-
tions were obtained from the 29 study patients.
The concentrations were fit to a one-compart-
ment intravenous infusion model. Exploratory
data analysis was performed with pharmacoki-
netic parameter estimates and potential covari-
ates. The models tested, the pharmacokinetic
parameter values, and the changes in OFV are
presented in Table 3. Among covariates that
were tested on volume of distribution, TBW and
ABW each decreased the OFV by 3.3 points.
Although a decrease in OFV of 3.84 is consid-
ered significant, including either TBW or ABW
as a covariate on volume of distribution
decreased the error estimates (Table 3). TBW
was then included in the model due to simplic-
ity of use in clinical settings. Having included
TBW as a covariate on volume of distribution,
Clcr estimated with the Cockcroft-Gault equation
and glomerular filtration rate estimated with the
MDRD 4 equation were tested as a covariate on
vancomycin clearance. The results indicated that
the nonrenal component of vancomycin clear-
ance is close to zero. Cockcroft-Gault Clcr using
TBW and centered on the median Clcr (125 ml/
min/1.73 m2) (model 13 in Table 3) resulted in
the largest drop in OFV (DOFV = 14). There-
fore, the final model included TBW on volume
of distribution and Cockcroft-Gault Clcr on
vancomycin clearance.
Model performance was also assessed with
plots of population predictions versus measured
concentrations, individual predictions versus
measured concentrations, and population predic-
tions with residuals (Figure 1). Scatter plots of
final model estimates of volume of distribution
versus TBW and ABW demonstrate better corre-
131
Creatinine clearance, Median 24-hour AUC,
ml/min/1.73 m2 mg
hr/La (IQR)
77.1 403.3
85.7–143.7 628.1 (580.9–735.7)
82–95.6 1101.6 (822.2–1381.1)
95–151.6 547.1 (513.8–659.5)
103–144.2 881.7 (633.8–812.5)
113.1–194.3 767.1 (633.8–812.5)
lation of volume of distribution with TBW than
with ABW (Figure 2). Similarly, Figure 3 dem-
onstrates better correlation between vancomycin
clearance (Cl) and BSA-adjusted Cockcroft-Gault
Clcr with Scr concentration values below 1
rounded to 1. The results of 1000 simulations
run using the final model indicated that 97% of
measured concentrations were within the 2.5–
97.5 percentile of simulated concentrations,
indicating that the model adequately described
the data.
As shown in Table 3, volume of distribution
of vancomycin in this patient population is
0.51 L/kg TBW or 0.76 L/kg ABW, whereas
clearance of vancomycin in a patient with a Clcr
of 125 ml/minute/1.73 m2 is 6.54 L/hour.
Although both TBW and ABW provide similar
changes in OFV, the scatter plots of volume of
distribution versus TBW and ABW (Figure 2), as
well as the simplicity of use, support the use of
TBW for the estimation of volume of distribu-
tion. The rate of elimination (k) could be deter-
mined from the ratio of clearance and volume of
distribution (k=Cl/V). In a typical patient in this
study, weighing 147.9 kg and having a Clcr of
125 ml/minute/1.73 m2, rate of elimination and
half-life are estimated to be 0.087 and ~8 hours,
respectively. A plot of the relationship between
simulated rate of elimination, half-life, weight,
and Clcr is shown in Figure 4. The figure indi-
cates that rate of elimination increases and half-
life decreases with increases in BSA-standardized
Clcr. However, in patients with similar BSA-stan-
dardized Clcr but differing weights, rate of elimi-
nation will be smaller and the half-life longer in
the larger patient.
Table 4 shows simulated 24-hour vancomycin
AUCs at various daily doses and Clcr, whereas
Figure 5 shows the percentage of doses providing
a 24-hour AUC:MIC ratio of ≥ 400 for an MIC
value of 1 lg/ml. Table 4 indicates that vancomy-
cin doses must at least be 2750 mg/day to provide
median 24-hour AUCs of ≥ 400 mg
hour/L in
 132

Table 3. Pharmacokinetic Parameter Estimates of Vancomycin and Changes in Objective Function Value of the Base Model and Select Covariate Models
Between-subject variability
(RSE%) Residual variability
Model no. Covariate model OFV DOFV V (RSE%) Cl (RSE%) ΩV (%) ΩCl (%) (RSE%)
1 Base model 459.83 – 80.7 (10.3) 6.19 (6.5) 25.1 (35.5) 34.9 (21.0) 19.4 (19.0)
2 V = h1*ABW 456.54 3.30 0.76 (9.4) 6.19 (6.5) 24.7 (33.1) 35.4 (20.0) 18.8 (19.2)
3 V = h1*ABW0.15 458.7 1.1 0.97 (9.4) 6.19 (6.6) 25.8 (34.2) 35.5 (20.0) 19 (19.3)
4 V = h1*HT 458.78 1.05 0.46 (9.7) 6.19 (6.6) 24.8 (34.6) 35.2 (20.5) 19.2 (19.1)
5 V = h1*IBW 460.53 0.70 1.16 (9.7) 6.18 (6.6) 27.1 (35.5) 35.6 (19.9) 19.1 (19.5)
6 V = h1*LBW 461.68 1.84 1.04 (9.6) 6.18 (6.6) 29.1 (30.8) 35.5 (20.1) 19 (19.3)
7 V = h1* TBW 456.50 3.33 0.51 (9.4) 6.20 (6.5) 23.9 (32.2) 35.2 (20.2) 18.9 (18.9)
8 V = h1*ABW 453.44 3.10 0.76 (9.5) 7.06 (6.0) 24.3 (34.2) 33.3 (16.3) 18.9 (19.4)
Cl = h2*(ClcrABW/147)
9 V = h1*TBW 453.03 3.48 0.52 (9.4) 6.86 (6.0) 23.7 (32.7) 32.9 (18.0) 19 (19.1)
Cl = h2*(ClcrSC/154)
10 V = h1*ABW 453.06 3.47 0.76 (9.5) 6.85 (6.0) 24.3 (34) 33 (17.9) 18.9 (19.5)
Cl = h2*(ClcrSC/154)
11 V = h1*TBW 455.14 1.36 0.52 (9.6) 6.96 (6.2) 23.8 (33.4) 34.2 (13.8) 19 (19.4)
Cl = h2*(ClcrLBW/107)
12 V = h1*TBW 453.97 2.53 0.52 (9.5) 6.74 (6.1) 23.6 (33.4) 33.5 (16.9) 19 (19.3)
Cl = h2* (ClcrTBWunadj./207)a
13 V = h1* TBW 442.38 14.12 0.51 (9.2) 6.54 (4.9) 23.9 (30.9) 26.7 (18.5) 18.9 (18.9)
Cl = h2*(ClcrTBW/125)
ABW = adjusted body weight, kg; ABW0.15 = IBW + 0.15*(TBW  IBW); Cl = clearance; Clcr = creatinine clearance estimated by using the Salazar Corcoran equation (ClcrSC) or the Cock-
croft-Gault equation with ABW (ClcrABW), IBW (ClcrIBW), LBW (ClcrLBW), unadjusted TBW (ClcrTBWunadj), and TBW (ClcrTBW); HT = height, cm; IBW = ideal body weight, kg; LBW = lean body
weight, kg; OFV = objective function value; RSE% = percent relative standard error; ΩV = between-subject variability in V; ΩCl = between-subject variability in Cl; TBW = total body weight,
PHARMACOTHERAPY Volume 35, Number 2, 2015

kg; V = volume of distribution.

a
Measured serum creatinine concentration was used and was not standardized to body surface area.
 VANCOMYCIN IN EXTREMELY OBESE PATIENTS Adane et al. 133

Figure 1. Model diagnostics of the final vancomycin population model. Panels A and B show population-predicted and
individual-predicted vancomycin serum concentrations versus predicted concentrations, respectively. Panels C and D show
residuals and weighted residuals versus predicted concentrations, respectively. The line of identity is indicated as a dotted
line. The plots show that the model was able to describe the observed data.

patients with Clcr above 125 ml/minute/1.73 m2
(i.e., the median Clcr in the study population). As
depicted in Figure 5, the probability of achieving
this target was < 10% for vancomycin
doses < 2000 mg/day (Figure 5A) and 55.1% at
2750 mg/day (Figure 5B) but increased to > 93%
at doses of ≥ 4000 mg/day (Figure 5C, D).
Discussion
Vancomycin exerts time-dependent bacterial
killing in susceptible organisms.34 The 24-hour
AUC:MIC ratio is the pharmacodynamic parame-
ter predictive of its clinical efficacy.10, 11 In
patients receiving vancomycin for S. aureus–
associated lower respiratory tract infections,
clinical success correlated with AUC:MIC
ratios > 315, whereas microbiologic response
correlated with AUC:MIC ratios > 866.35 Vanco-
mycin doses achieving a 24-hour AUC/MIC
ratio < 211 were associated with a > 4-fold
increase in attributable mortality in patients with
complicated MRSA bacteremia and infective
endocarditis.36 Clinical practice guidelines state
that a 24-hour AUC:MIC ratio ≥ 400 is needed
for clinical effectiveness and that monitoring
vancomycin trough concentration is the most
accurate and practical method to guide vanco-
mycin dosing.10, 11 Although no association has
been clearly established between trough concen-
tration and clinical response, a vancomycin
trough of 15–20 lg/ml is needed to achieve a
24-hour AUC:MIC of 400 for an MIC ≤1 lg/
ml.10, 11
Further complicating treatment outcomes with
vancomycin is the decrease in susceptibility of
MRSA strains due to an increase in vancomycin
MICs, also known as the “MIC creep.”37 In
patients with MRSA bloodstream infections, a
2.4-fold increase in treatment failure was noted
with vancomycin MICs ≥ 1.5 lg/ml compared
with MICs ≤ 1.0 lg/ml.38 Vancomycin is typi-
cally administered at doses of 15–20 mg/kg
based on actual body weight and at dosing inter-
vals determined by renal function while not
exceeding 2000 mg/dose.10, 11 However, in
extremely obese patients, the calculated dose
usually exceeds 2000 mg/dose, especially if load-
ing doses of 20–25 mg/kg are used.10, 11 One
study reported a higher incidence of nephrotoxi-
134 PHARMACOTHERAPY Volume 35, Number 2, 2015

Figure 2. Scatter plots of volume of distribution (V) of vancomycin and weight in extremely obese patients. Panels A and C
show the correlation of V with total body weight (TBW) and adjusted body weight (ABW), respectively. The slopes of the
scatter plots were significantly different from 0 (p<0.05). The slopes of TBW-normalized V (V/TBW) versus TBW (panel B)
and ABW-normalized V (V/ABW) versus ABW (panel D) were not significantly different from zero. The plots show that V is
better correlated with TBW (correlation coefficient r = 0.81) than with ABW (r = 0.70).

Figure 3. Scatter plot of vancomycin clearance and Cockcroft-Gault creatinine clearance (Clcr) adjusted to body surface area
(panel A) and not adjusted to body surface area (panel B). Vancomycin clearance was better correlated with body surface
area–adjusted Clcr (r = 0.61).

city with vancomycin trough concentrations of
15–20 lg/ml.39 Similarly, a meta-analysis in
2013 indicated that the odds of nephrotoxicity
were 2.67 times higher when vancomycin
troughs were ≥ 15 lg/ml.40
In this study we determined the pharmacoki-
netics of vancomycin in extremely obese
patients. The measurement of peak, trough, and
midpoint concentrations allowed the reliable
estimation of vancomycin volume of distribution
 VANCOMYCIN IN EXTREMELY OBESE PATIENTS Adane et al. 135

Figure 4. The relationship between weight and Clcr (creatinine clearance) with simulated rate of elimination (panel A) and
half-life (t1/2; panel B) plotted as median and interquartile range data. The plots indicate that rate of elimination increases
and t1/2 decreases with increases in Clcr, but for patients with similar Clcr and differing weights, increase in weight
contributes to a decrease in rate of elimination and an increase in t1/2.

and clearance. The utility of available nomo-
grams and/or population-based pharmacokinetic
equations to determine initial and maintenance
vancomycin doses is limited because the meth-
ods were intended to achieve troughs of
5–10 lg/ml.7, 16, 41 One group of authors com-
pared the performance of common methods
used to dose vancomycin and found no method
adequate to replace therapeutic monitoring.42
Another limitation is that initial doses are often
determined by estimating rate of elimination (k)
based on Clcr (k = 0.00083*Clcr + 0.0044) and
using an average volume of distribution of
0.7 L/kg.7 The rate of elimination, however,
depends not only on clearance but also on vol-
ume of distribution (k = Cl/V). With increase in
weight, both clearance and volume of distribu-
tion are expected to increase, albeit to different
extents. Our study incorporates the estimation
of rate of elimination from Clcr and volume of
distribution, and it attempts to address the need
for a dosing method in this special population.
Parameter estimates were 0.51 L/kg TBW for
volume of distribution and 6.54 L/hour for
clearance in a typical extremely obese patient
(TBW 148 kg, Clcr 125 ml/min/1.73 m2). The
selection of TBW and Clcr as covariates on vol-
ume of distribution and vancomycin clearance,
respectively, is consistent with the available lit-
erature.43
In nonobese patients, some values reported for
clearance include Clcr 9 0.689 + 3.66 (ml/min),7
Clcr 9 0.79 + 15.7 (ml/min),2 and Clcr 9 0.048
(L/hr).41 Similarly, values reported for volume of
distribution in nonobese patients include 0.72–
0.9 L/kg,7 0.5–0.64 L/kg,2 and 0.706 L/kg.41 In a
study involving six morbidly obese patients
receiving vancomycin (mean TBW 165.7 kg,
mean BMI 56 kg/m2), one study reported a mean
steady-state volume of distribution of 43 L
(0.26 L/kg) and a mean clearance of 10.5 L/
hour.5 In a subsequent study involving 24 mor-
bidly obese (mean TBW 165 kg, IBW 63 kg) and
normal-weight patients (mean TBW 68 kg, IBW
60 kg), volume of distribution and clearance
were 0.32 L/kg TBW and 11.8 L/hours, respec-
tively, in the morbidly obese group.23 Vancomy-
cin half-life was 3.3 hours in the morbidly obese
patients and 7.2 hours in the normal-weight
patients. The authors concluded that differences
in volume of distribution were not significantly
different and attributed the short half-life in the
morbidly obese patients to the increase in clear-
ance. Our study indicates that this may not
always be the case because rate of elimination is
a function of volume of distribution and clear-
ance, both of which increase with weight.
Another study assessed the performance of a
revised vancomycin dosing protocol (10 mg/kg
every 12 hrs or 15 mg/kg every 24 hrs) with a
protocol consistent with the guideline recom-
mendation of the ASHP/IDSA/SIDP consensus
panel (15 mg/kg every 8–12 hrs)10 in obese
patients with a Clcr ≥ 60 ml/minute.44 Seventy-
four patients in the revised protocol (mean
weight 129 kg, mean BMI 44 kg/m2) received an
average maintenance dose of 19 mg/kg/day in
contrast to 64 patients in the original protocol
(mean weight 117 kg, mean BMI 39 kg/m2) who
received an average maintenance dose of 34 mg/
kg/day. The original protocol resulted in lower
percentage of within-target troughs (36% in the
 136

Table 4. Simulated 24-Hour Median AUCs Achieved with Various Daily Doses of Vancomycin and Creatinine Clearances in the Morbidly Obese Study Patientsa
Median 24-hour AUC, mg
hr/L
(IQR)
Vancomycin Creatinine clearance, ml/min/1.73 m2
daily dose(mg)b 77 87 97 107 117 127 137 147
1250 308.1 274.0 248.0 222.6 204.7 187.8 174.7 162.3
(257.6–370.0) (228.3–329.9) (205.9–298.6) (186.0–267.1) (170.9–245.7) (156.3–224.4) (144.5–210.0) (135.8–195.0)
1500 375.1 328.8 295.7 267.3 243.7 226.0 210.0 195.9
(311.4–448.1) (274.7–395.7) (247.1–357.4) (222.1–321.5) (203.5–294.6) (188.2–271.0) (174.7–251.7) (162.9–235.9)
1750 436.1 385.9 345.5 311.8 287.7 264.4 243.3 228.2
(363.2–525.1) (319.7–462.5) (288.1–414.1) (258.3–376.9) (240.2–344.4) (220.0–317.0) (203.3–291.7) (190.2–274.5)
2000 496.6 439.7 394.6 358.1 326.5 299.4 279.6 258.5
(415.2–595.2) (366.0–531.1) (327.8–473.8) (298.8–427.5) (270.7–391.9) (249.7–359.7) (233.4–334.6) (214.9–311.3)
2250 560.8 493.6 446.7 400.6 366.1 337.6 314.5 291.3
(467.2–671.6) (411.5–594.2) (370.6–534.5) (334.6–480.0) (306.3–439.8) (281.4–404.2) (261.2–377.5) (243.2–350.7)
2500 621.6 548.0 489.9 445.4 408.3 377.4 350.8 324.6
(517.2–747.6) (457.6–658.5) (412.5–591.0) (370.5–534.4) (338.1–490.9) (314.8–449.4) (291.0–419.7) (270.3–391.1)
2750 681.7 600.4 541.3 489.6 452.4 414.5 385.3 356.9
(569.0–818.0) (502.8–723.0) (450.1–647.2) (408.2–587.5) (374.9–542.9) (344.7–497.7) (319.6–460.5) (297.0–428.54)
3000 740.3 659.8 596.2 536.2 488.4 452.2 420.7 389.1
(620.5–891.7) (549. 793.6) (496.5–715.0) (445.9–641.7) (408.0–587.4) (375.9–544.6) (351.3–506.3) (323.9–466.0)
3500 869.0 769.4 690.6 626.7 571.4 523.9 489.3 452.3
(553.8–1184.1) (480.5–1058.4) (435.1–946.1) (401.5–852.0) (359.4–783.4) (331.4–716.4) (312.2–666.3) (283.6–621.0)
3750 930.7 825.8 739.4 673.9 615.3 561.8 521.6 489.4
(773.3–1117.3) (684.2–987.8) (612.6–881.6) (561.6–809.4) (512.5–738.8) (469.6–674.8) (431.0–629.3) (406.6–587.7)
4000 996.9 877.6 794.2 712.2 650.8 600.2 559.2 517.8
(830.5–1194.0) (731.5–1056.4) (658.8–950.3) (594.8–853.4) (544.5–781.9) (500.3–718.6) (464.4–671.2) (432.4–623.4)
4500 1118.9 986.5 881.9 801.7 735.0 679.3 631.4 584.2
(931.0–1345.7) (823.8–1185.2) (742.4–1063.8) (666.9–962.0) (608.7–883.6) (566.6–809.0) (523.9–755.5) (486.6–704.1)
5000 1239.4 1091.6 984.1 890.1 822.5 753.6 700.5 649.0
PHARMACOTHERAPY Volume 35, Number 2, 2015

(1034.6–1487.3) (914.1–1314.5) (818.3–1176.7) (742.2–1068.2) (681.7–987.1) (626.7–905.0) (581.0–837.2) (540.1–779.2)

AUC = area under the concentration-time curve; IQR = interquartile range.
a
Patients weighed between 110 and 280 kg and had creatinine clearances between 77 and 147 ml/min/1.73 m2.
b
Total daily doses were given as single
(1250–3000 mg) and/or divided doses
(1500–5000 mg) at 8-, 12-, and 24-hr intervals.
 VANCOMYCIN IN EXTREMELY OBESE PATIENTS Adane et al. 137

Figure 5. Vancomycin doses and percentage of simulated area under the concentration-time curve to minimum inhibitory
concentration (AUC:MIC) ratios ≥ 400 for an MIC of 1 lg/ml at various Clcr (creatinine clearance) values. Simulations were
performed for patient weights ranging from 110 to 280 kg at 10-kg increments and Clcr ranging from 77 to 147 at 10-ml/
minute/1.73 m2 increments. The ranges of values reflect the minimum and maximum values for weight and Clcr in the study
patients. Panels A–D show that patients with lower Clcr achieve AUC:MIC ratios ≥ 400 at lower doses than patients with
higher Clcr.

original vs 59% in the revised protocol) and a
higher percentage of above-target troughs (55%
the original vs 18% in the revised protocol). The
overall incidence of nephrotoxicity was 2.9% and
did not significantly differ between the protocols.
The findings of the study illustrated the limita-
tion of available dosing regimens in obese
patients and highlighted the need for a dosing
regimen specific for this population. A 2013
review article on AUC versus peak-trough–based
dosing of vancomycin proposed two levels of
dosing: high-dose regimens targeting troughs
between 15 and 20 lg/ml and moderate-dose
regimens targeting troughs between 10 and
15 lg/ml.45 The regimens are derived from 24-
hour AUC:MIC ratio and vancomycin clearance
(Cl) as follows:
AUC24 hr
Dose (mg/day) ¼ Cl(L/hr)  : ð6Þ
MIC
The authors argued that lower doses of vanco-
mycin could provide an AUC:MIC ratio ≥ 400
using the AUC-based dosing method, which can
be tailored to high troughs by shortening dosing
intervals. Although the dosing chart proposed by
the authors needs to be clinically validated, it
presents a valid and simplified approach to dos-
ing vancomycin. Our results indicated that the
median vancomycin dose administered in the
patient population provided median 24-hour
AUCs above 400 mg
hour/L. Similarly, the simu-
lations we performed indicated that vancomycin
doses of 4000–5000 mg/day provide ≥ 93%
probability of AUC:MIC ratios ≥ 400 for an MIC
of 1 lg/ml. However, depending on the dosing
interval, doses that provide troughs of 10–20 lg/
ml may provide AUCs < 400 mg
hour/L. Con-
versely, doses that provide AUCs ≥ 400 mg

hour/L may provide troughs < 10 lg/ml or >
20 lg/ml. Thus dosing based on the AUC:MIC
ratio only is limited because of MIC creep and
the plus or minus one well variability of MICs
reported by automated antimicrobial susceptibil-
ity testing methodologies. Therefore, it is essen-
138 PHARMACOTHERAPY Volume 35, Number 2, 2015
tial to select doses based on renal function that
provide troughs of 10–20 lg/ml and maintain an
AUC:MIC ratio ≥ 400. Such doses are likely to
minimize development of S. aureus resistance,46
ensure adequate penetration in tissues such as
the lung with a reported tissue-to-plasma ratio
of 0.24–0.41,47 and minimize potential nephro-
toxicity.
In our study, we determined the clearance
and volume of distribution of vancomycin. The
clearance estimate can be used to determine
the daily vancomycin dose in the AUC-based
dosing by multiplying clearance by the desired
AUC:MIC ratio. In addition, rate of elimination
and volume of distribution estimates can con-
currently be used to design peak-trough–based
dosing regimens that achieve troughs > 10 lg/
ml. Vancomycin trough levels should be mea-
sured to ascertain achievement of therapeutic
trough levels as recommended in the guide-
lines.10, 11 Our study is limited by the rela-
tively small sample size, the narrow range of
covariates, and the young patient demographics
and patients with good renal function. The for-
mer limitation is compensated for by the mea-
surement of at least three vancomycin
concentrations per patient, allowing reliable
estimation of pharmacokinetic parameters. We
have not studied adolescent morbidly obese
patients, which would limit the use of these
pharmacokinetic parameter estimates in the
adolescent population. Further studies should
investigate vancomycin pharmacokinetics in
this population and in extremely obese adult
patients with Clcr <30 ml/minute/1.73 m2. Our
inability to obtain 24-hour Ucr in all patients is
another limitation. Further studies in a larger
patient cohort of extremely obese patients
could incorporate 24-hour Ucr and urine
vancomycin concentration measurements to
quantify the renal clearance of vancomycin. We
will use the findings of this study to dose
vancomycin in extremely obese patients at our
institution and prospectively evaluate the
achievement of therapeutic troughs and reduc-
tion of nephrotoxicity.
Conclusion
In this cohort of extremely obese patients who
received vancomycin to treat S. aureus infec-
tions, total body weight and Clcr influenced vol-
ume of distribution and vancomycin clearance,
respectively. Vancomycin can be initiated in
extremely obese patients at dosages determined
based on renal function and pharmacokinetic
parameter estimates from this study. Vancomy-
cin serum concentrations should be monitored
to ascertain attainment within the therapeutic
range.
Acknowledgments
The authors would like to acknowledge Helen Her-
ald, Director of Pharmacy, and the pharmacists,
nurses, and clinicians at Hazard Appalachian Regional
Medical Center for their assistance with the study.
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