Pediatric Pharmacology

Optimizing Vancomycin Use Through The Journal of Clinical Pharmacology

2019, 00(0) 1–9
2-Point AUC-Based Therapeutic Drug 
C 2019, The American College of

Clinical Pharmacology
DOI: 10.1002/jcph.1498
Monitoring in Pediatric Patients

Pintip Suchartlikitwong, MD1,2 , Suvaporn Anugulruengkitt, MD1,2 ,

Noppadol Wacharachaisurapol, B Pharm, MD3 , Watsamon Jantarabenjakul, MD1,2,4 ,
Jiratchaya Sophonphan, MSc5 , Tuangtip Theerawit, BSN1,2 , Tanittha Chatsuwan, PhD6 ,
Thitima Wattanavijitkul, PhD7 , and Thanyawee Puthanakit, MD1,2

Abstract
The 24-hour vancomycin area under the serum concentration-time curve (AUC24 ) divided by the minimum inhibitory concentration (MIC)
(AUC24 /MIC) is more closely related to patient outcomes than serum trough concentrations (Ctrough ). Two-point simplified equations for calculating
AUC based on serum peak concentrations (Cpeak ) and Ctrough , named equation A (EqA) and equation B (EqB), have recently been adopted into clinical
use for adult pediatric patients. We aimed to find the agreement between predicted AUC24 using the reference method (ref) relative to EqA and
EqB and the correlation between Ctrough and AUC24 . From June to December 2018, 43 pediatric patients with normal renal function, receiving 15
mg/kg of vancomycin intravenously every 6 hours, were enrolled. The pediatric patients’ median age was 2.2 years (range 0.1-15.3). At steady state,
vancomycin Cpeak and Ctrough were measured at 2 hours after infusion completion and within 30 minutes before the next dosing, respectively. AUC24
was estimated using ref, EqA, and EqB. From Bland-Altman analysis, the 2 AUC24 s estimated by ref and EqA showed less bias than those estimated by
ref and EqB (bias 1.3 and –72.1 mgh/L, respectively). Ctrough and AUC24 using either ref or EqA were correlated more closely (r2 = 0.94) than with
EqB (r2 = 0.86). Assuming a vancomycin MIC of 1 mg/L, an AUC24 400 mgh/L was targeted. Regardless of the method used, AUC24 400 mgh/L
was never seen with Ctrough <8 mg/L but was always seen with Ctrough >10 mg/L. In conclusion, EqA based on the 2 measured serum concentrations
was sufficiently accurate for AUC24 estimation. Ctrough >10 mg/L correlated highly to AUC24 400 mgh/L.

Keywords
Area under the serum concentration-time curve, Equation, Outcome, Pediatric, Trough concentration, Vancomycin

Vancomycin is used as a first-line antibiotic to treat is therefore recommended instead as a practical

healthcare-associated infections with methicillin-
resistant Staphylococcus aureus (MRSA) and
methicillin-resistant coagulase-negative staphyloco-
ccus.1,2 Its efficacy is closely related to the ratio of
24-hour area under the serum concentration-time
curve to the minimum inhibitory concentration
surrogate marker for vancomycin monitoring.5
1 Department of Pediatrics, Faculty of Medicine, Chulalongkorn
University, Bangkok, Thailand
2 Center of Excellence for Pediatric Infectious Diseases and Vaccines,

(AUC24 /MIC).3 An AUC24 /MIC of 400 has been
shown to predict better clinical and bacteriological
outcomes in adult pediatric patients with lower
respiratory tract MRSA infections.4,5 A recent study
of novel rabbit models of neonatal coagulase-negative
Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
3 Department of Pharmacology, Faculty of Medicine, Chulalongkorn
University, Bangkok, Thailand
4 Thai Red Cross Emerging Infectious Diseases Clinical Center, King
Chulalongkorn Memorial Hospital, Bangkok, Thailand
5 The HIV Netherlands Australia Thailand Research Collaboration

Staphlococcus central-line associated bloodstream (HIV-NAT), Bangkok, Thailand

infections demonstrated that an AUC24 /MIC >400
6 Department of Microbiology, Faculty of Medicine, Chulalongkorn

University, Bangkok, Thailand

was associated with maximal bacterial killing
and suppression of the emergence of vancomycin
resistance.6,7 However, determination of AUC involves
multiple blood samples and a linear-trapezoidal
formula or pharmacokinetic software that needs
further pharmacokinetic modeling, understanding, and
personnel training.8 These may contribute to limited
use of AUC-based vancomycin monitoring in routine
clinical practice. Serum trough concentration (Ctrough )
7 Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences,
Chulalongkorn University, Bangkok, Thailand
Submitted for publication 20 April 2019; accepted 1 July 2019.
Corresponding Author:
Pintip Suchartlikitwong, MD, Center of Excellence for Pediatric Infectious
Diseases and Vaccines, Department of Pediatrics, Faculty of Medicine,
Chulalongkorn University, 1873 Rama IV Road, Pathumwan, Bangkok,
10330 Thailand
Email: pintip.s@chula.ac.th
2 The Journal of Clinical Pharmacology / Vol 00 No 0 2019
Current vancomycin therapeutic guidelines recom-
mend a Ctrough of 15-20 mg/L for serious MRSA infec-
tions in adult pediatric patients, with the assumption
that it correlates with a target AUC24 /MIC 400 when
the MIC of the organism is 1 mg/L.9 However,
several published studies propose that this is not always
necessary for achieving a target AUC24 /MIC 400. A
study of vancomycin pharmacokinetics in 47 adults
reported that, using Bayesian modeling, 30% to 40%
of adults could achieve AUC24 400 mgh/L with
a Ctrough <10 mg/L.10 Additionally, several studies
report no association between clinical efficacy and van-
comycin Ctrough .11–13 In pediatric populations there have
been limited data to guide vancomycin monitoring,
and maintaining Ctrough >15 mg/L may be associated
with increased nephrotoxicity.14–16 Vancomycin AUC-
based monitoring may therefore be a more accurate
predictor of clinical efficacy and reduce unnecessary
vancomycin exposure. Nevertheless, findings of a recent
meta-analysis study suggested a vancomycin AUC24
threshold of 650 mgh/L was significantly associated
with reduced incidence of acute kidney injury (AKI).17
Targeting levels higher than this AUC24 cutoff could
result in an increased risk of nephrotoxicity.
Several different methods have been used to calculate
vancomycin AUC.18–21 Most of them rely on calcu-
lated AUCs, which are the quotient of the total daily
vancomycin dose and vancomycin clearance. However,
each method defines vancomycin clearance differently.
The 1-compartment model using first-order kinetics
is the most widely accepted model estimating van-
comycin clearance.22–24 In 2013, a large study among
702 pediatric patients proposed a model of vancomycin
clearance estimation using the 1-compartment model
kinetic equation as a reference for clearance estimate
comparison.19 Pai et al25 demonstrated an innovative
2-point equation-based approach for calculating the
vancomycin AUC based on serum peak concentrations
(Cpeak ) and Ctrough . They proposed 2 different simplified
formulas for AUC calculation that had high precision
and low bias compared with the Bayesian approach.25
The equation-based approach for vancomycin AUC
monitoring has been adopted into clinical practice
for adults. Its several advantages include reducing un-
necessary adjustments of the vancomycin dose26 and
improving clinical outcomes with less nephrotoxicity.8
However, data to support this approach in children
remain limited.
To monitor vancomycin AUC through 2-point sim-
plified pharmacokinetic equations in pediatrics, we pre-
sumed that the effect would be similar to that observed
in adults. The primary objectives of this study were
to assess the agreement between 2 methods of AUC
estimation in pediatrics and to find the correlation
between Ctrough and AUC24 derived from 3 specific
methods, the reference method (ref)19 and 2 simplified
2-point equations, named equation A (EqA) and equa-
tion B (EqB).25 The secondary objective was to evaluate
the impact of AUC-based vancomycin monitoring on
clinical outcomes of pediatric patients with MRSA and
methicillin-resistant coagulase-negative staphylococcus
infections.
Methods
This study was approved by the Institutional Review
Board of the Faculty of Medicine, Chulalongkorn
University, Bangkok, Thailand (IRB No. 234/61).
Written informed consent was obtained from par-
ents/guardians. Pediatric patients aged 7 years were
asked to provide written or verbal assent as appropriate.
Study Design and Patient Population
This was a prospective study performed at King
Chulalongkorn Memorial Hospital, a tertiary care
university hospital in Bangkok, Thailand. Inclusion
criteria were hospitalized pediatric patients aged 1
month to 18 years who had received vancomycin for
24 hours for suspected MRSA or methicillin-resistant
coagulase-negative Staphylococcus infections such as
bacteremia, pneumonia, osteomyelitis, or skin and
soft tissue infections. Prescription of vancomycin
was at the discretion of the pediatric patients’ own
physicians. Pediatric patients with renal impairment,
defined as elevated serum creatinine by age or on renal
replacement therapy, were excluded. According to our
hospital dosing protocol, vancomycin (Vancin-S; Siam
Pharmaceuticals, Bangkok, Thailand) was adminis-
tered as 15 mg/kg intravenously over 1-2 hours every 6
hours. After steady state had been attained, defined as
after administration of the fourth dose onward, Cpeak
(2 hours after infusion completion) and Ctrough (within
30 minutes before the next dosing) were obtained.
Analytical Assay
Vancomycin serum concentrations were quantified
at the Center for Medical Diagnostic Laboratories,
Faculty of Medicine, Chulalongkorn University, us-
ing a validated chemiluminescent microparticle im-
munoassay (ARCHITECTi2000SR, Abbott Laborato-
ries, Chicago, Illinois) with a coefficient of variation
ranging from 3.1% to 6.2%. The assay precision was
10% of the total coefficient of variation. The limit of
quantitation of the assay was 3.0 mg/L, and the assay
range was 3.0 to 100.0 mg/L.27
Staphylococcal Identification and Vancomycin MIC Testing
Species identification and antibiotic susceptibility pat-
terns of Staphylococcus spp were determined by the
VITEK 2XL automated system (bioMérieux, Durham,
North Carolina) with the VITEK 2GP and AST P592
Suchartlikitwong et al
cards, respectively. The VITEK 2XL utilized a com-
bination of oxacillin MIC and cefoxitin screen results
to detect MRSA. An oxacillin MIC of  4 mg/L
was deemed resistant.28 A S aureus isolate with either
positive cefoxitin screen or oxacillin resistance was
considered MRSA.28 Vancomycin MICs of MRSA and
methicillin-resistant coagulase-negative Staphylococcus
were further determined using the Etest (bioMérieux,
Durham, North Carolina). The predefined exponential
gradient of vancomycin on the Etest scale directly
quantifies to discrete MIC values such as 0.75, 1, 1.5,
2, 3, and 4 mg/L.
AUC-Based Vancomycin Monitoring
AUC24 was determined using the intermittent short
infusion, 1-compartment model with first-order
elimination19 as the reference method:
Vancomycin dose (mg/day)
AUC24 (mg · h/L) =
Clearance
 
Dose (mg) 1 − e−ktinf e−k(t−tinf )
Clearance (L/h) =  
Ct · tinf · 1 − e−kτ
where k is the elimination rate constant (hours−1 ),
Ct and t are the serum concentration/time pair after
starting the infusion, tinf is the infusion time (hours) and
τ is the dosing interval (hours).
The elimination rate constant is calculated by the
following equation:
 
C1
ln C2
k =
t2 − t1
where C1 is the Cpeak measured at time t1 and C2 is
the Ctrough measured at time t2 after the start of the
infusion.
The AUC24 was also estimated by 2 other methods,
simplified 2-point pharmacokinetic equations, named
equations A and B, referred to as equations 4 and 5 in
Pai et al.25
tinf·(Cmax +Cmin ) Cmax − Cmin
AUC0−τ = + (A)
2 k
 
C1 · ek(t1 ) − Cmin
AUC0−τ = (B)
k the Student t-test. Statistical significance was defined
where Cmax is the theoretical concentration at the end
of infusion and Cmin is the theoretical concentration
3
at the end of the dosing interval, which were back-
extrapolated and forward-extrapolated using the fol-
lowing equations:
Cmax = C1 xek·(t1 −tinf )
Cmin = C2 xe−k·(τ −t2 )
Under equations A and B, the AUC24 will be a func-
tion of the number of vancomycin doses administered
over 24 hours. For example, when vancomycin is given
every 6 hours, AUC24 = AUC0−τ × 4AUC24 = AUC0-τ
× 4.
An internally created calculator was installed in
Microsoft Office Excel 2016 (Redmond, Washington)
to assist with AUC calculations.
Data Collection
Pediatric patient clinical data, including demograph-
ics, underlying diseases, baseline serum creatinine,
source of infections triggering empirical initiation of
vancomycin therapy, and microbiological data were
recorded. To evaluate the clinical outcomes of pe-
diatric patients with MRSA and methicillin-resistant
coagulase-negative Staphylococcus infections, resolu-
tions of clinical signs and symptoms of acute staphylo-
coccal infection or achievement of hemoculture sterility
within 72 hours of vancomycin use were considered
treatment success. Follow-up serum creatinine dur-
ing and within 72 hours after stopping vancomycin
therapy were also recorded. AKI was defined as an
increase in serum creatinine concentrations 0.5 mg/dL
or a 50% increase from baseline on 2 consecutive
measurements.3 Administration of vancomycin includ-
ing specified time, daily dosage, infusion time, and
dosing interval was identified from pediatric patients’
nursing records.
Statistical Methods
Based on a predetermined α level of 0.05, 90% power,
the mean and SD of differences between natural loga-
rithm of calculated AUC24 obtained from the 2 meth-
ods, 2.5 and 0.17 mgh/L, a sample size of 40 subjects
is required. Assuming a dropout rate of 10%, the total
sample size is 45.
Bland-Altman analyses were performed to evalu-
ate the agreement between the 2 methods of AUC
estimation. The correlation between Ctrough and AUC
was analyzed using a Pearson correlation and linear
regression. Vancomycin Ctrough and AUC were com-
pared between patient groups stratified by age using
as P < .05. All statistical analyses were performed
using STATA software, version 15.1 (Stata Corp LLC,
College Station, Texas).
4 The Journal of Clinical Pharmacology / Vol 00 No 0 2019
Table 1. Characteristics of Pediatric Patients Who Received Van-
comycin Therapy and Vancomycin Monitoring (n = 43)
Characteristics
Demographic data
Age, y
Male sex, n (%)
Height, cm
Weight, kg
Baseline serum creatinine, mg/dL
Creatinine clearance,b mL/min per 1.73 m2
Underlying diseases, n (%)
Hematologic and oncologic diseases
Cardiac diseases
Gastrointestinal and hepatobiliary diseases
Surgery-related diseases
Others
Indications for vancomycin, n (%)
Central line–associated bloodstream infections
Skin and soft tissue infections
Ventilator-associated pneumonia
Central nervous system infections
Others
Therapeutic drug monitoring of vancomycin
Measured serum peak concentrations (C1 ), mg/L
Measured serum trough concentrations (C2 ), mg/L
Theoretical Cmax , mg/L
Theoretical Cmin , mg/L
Time between the end of infusion and blood
drawn for C1 , h
Time between blood drawn for C2 and the start of
next dose, h
AUC24 using the reference method, mgh/L
AUC24 indicates 24-hour steady-state vancomycin area under the serum
concentration-time curve; C1 , measured serum peak concentrations; C2 ,
measured serum trough concentrations; Cmax , theoretical concentration at
the end of infusion; Cmin , theoretical concentration at the end of the dosing
interval.
a
Data are median (range) unless otherwise stated.
b
Creatinine clearance is based on revised Schwartz equation.29
Results
Clinical Characteristics of Pediatric Patients and
Vancomycin Therapy
From June to December 2018, 127 children were
prescribed vancomycin. Forty-five eligible pediatric
patients who received intravenous vancomycin for 24
hours were consented to participate in the study. Two
pediatric patients were excluded; 1 due to renal failure
and 1 due to circulatory collapse. The remaining 43
pediatric patients were included in the analyses. Charac-
teristics of the pediatric patients and vancomycin moni-
toring are summarized in Table 1. Thirty-three pediatric
patients (77%) were <5 years of age. All pediatric pa-
tients had underlying medical conditions, the majority
having hematologic and oncologic diseases (35%).
Twenty-two pediatric patients (41%) were admitted to
the intensive care unit. Twenty-five pediatric patients
(58%) had suspected coagulase-negative Staphlococcus
central-line associated bloodstream infections when
vancomycin therapy was initiated. Among the sus-
pected coagulase-negative Staphlococcus central-line
Median (Range)a associated bloodstream infections cases, 13 pediatric
patients (52%) had confirmed positive hemocultures
drawn from indwelling central venous catheters.
2.2 (0.1-15.3)
26 (60) Twelve Gram-positive bacteria—8 methicillin-resistant
80 (45-172) coagulase-negative Staphylococcus, 2 methicillin-
10 (3-64) susceptible Staphylococcus aureus, 1 Streptococcus
0.3 (0.1-0.6) pneumoniae, 1 Bacillus cereus, and 1 Gram-negative
134 (69-277)
bacterium, Chryseobacterium sp—were identified.
15 (35) There was 1 case of surgical site infection in which
8 (19) MRSA was isolated from an open abdominal wound.
6 (14) The mean (SD) daily dose of vancomycin given to
5 (11) this patient group was 63 (11) mg/kg. Thirty-seven
9 (21)
pediatric patients (86%) had Cpeak and Ctrough collected
25 (58) after finishing the fourth to sixth dose. Blood samples
8 (19) of the remaining 6 pediatric patients were collected
3 (7) after completion of the seventh dose onward. Median
2 (5) duration of vancomycin therapy was 6 days (range 1-20
5 (11)
days), depending on the final diagnosis.
18.0 (6.1-34.0)
10.6 (2.8-23.8) Vancomycin Therapeutic Drug Monitoring
30.3 (11.7-47.3) The agreement between the 2 methods of AUC esti-
9.1 (2.2-22.5) mation is illustrated in Figure 1. According to Bland-
2.0 (1.5-2.5)
Altman analysis, the calculated AUC24 using the
0.5 (0-0.75) reference method reached higher agreement with the
AUC24 using EqA [bias 1.3 (95% CI –2.0, 4.6) mgh/L],
426 (168-782) whereas the mean difference between the AUC24 using
the reference method and EqB was –72.1 (95% CI –84.9,
59.2) mgh/L.
The vancomycin Ctrough values of <8, 8-10, >10
to <15, and 15 mg/L were found in 13 (30%), 8
(19%), 9 (21%), and 13 (30%) pediatric patients, re-
spectively. Using either the reference method or EqA,
the predicted AUC24 of <400, 400-650, and >650
mgh/L were observed in 17 (40%), 23 (53%), and 3
(7%) pediatric patients, respectively. The distribution of
Ctrough correlated with AUC24 estimation using EqA,
demonstrated in Figure 2. Correlation between Ctrough
and predicted AUC24 was significant with all of 3
methods for AUC determination (r2 ref = 0.94, P <
.001; r2 EqA = 0.94, P < .001; r2 EqB = 0.86, P <
.001). Regardless of method used, AUC24 400 mgh/L
was never seen in Ctrough < 8 mg/L but was always
seen in Ctrough > 10. In pediatric patients with Ctrough
8-10 mg/L, 50% had predicted AUC24  400 mgh/L
using either the reference method or EqA, whereas 88%
achieved that target AUC24 using EqB.
Subgroup Analysis of Pediatric Patients With Proven
Methicillin-Resistant Staphylococcal Infections
Nine pediatric patients were diagnosed with methicillin-
resistant staphylococcal infections: 1 MRSA and
8 methicillin-resistant coagulase-negative Staphylo-
coccus. Clinical information, microbiological data
Suchartlikitwong et al 5

Figure 1. Bland-Altman analyses of the differences between the 2 AUCs calculated using the reference method vs the simplified Equations A and B,
respectively. AUC indicates area under the plasma concentration–time curve; LOA, limits of agreement.

including vancomycin MICs, vancomycin Ctrough , and
calculated AUCs are shown in Table 2. Only 3 out of
9 pediatric patients developed infections with strains
with MICs  1 mg/L. Of these, all achieved the tar-
get AUC24 /MIC  400 (range 414-1094). Among the
remaining 6 pediatric patients whose organisms had
MICs > 1 mg/L, all but 1 reached AUC24 400 mgh/L
(range 414-646 mgh/L); however, none achieved the
target AUC24 /MIC  400.
For the patient with MRSA surgical site infection,
clinical improvement was documented, although pus
culture was not repeated. In our clinical settings
follow-up hemocultures are not routinely obtained
daily once a hemoculture is positive for pathogenic
bacteria. All 8 pediatric patients with methicillin-
resistant coagulase-negative Staphlococcus central-line
associated bloodstream infections showed sterility in
their first repeat hemocultures. Six of these 8 achieved
6 The Journal of Clinical Pharmacology / Vol 00 No 0 2019

Figure 2. Scatter plot displaying the AUC using Equation A and measured serum trough concentrations. Each black dot represents 1 patient. The
solid line displays the linear regression line described by the equation: AUC = 28.4 (Trough) + 125. The coefficient of determination (r2 ) is 0.94. AUC
indicates area under the plasma concentration–time curve.

Table 2. Vancomycin Ctrough , Predicted AUC24 /MIC, and Clinical Outcomes of 9 Pediatric Patients Who Had Methicillin-Resistant Staphylococcal
Infections

AUC24
Vancomycin by Ref Vancomycin Treatment Presence
Age Diagnosis Identified Organisms MIC (mg/L) (mgh/L) AUC24 /MIC Ctrough (mg/L) Outcomes of AKI

3y SSI S. aureus 1.5 414 276 11 Success No

9 mo CLABSIa S. hominis 0.5 547 1094 15 Success No
3 mo CLABSI S. capitis 1 486 486 10 Success No
11 mo CLABSIa S. hominis 1 414 414 13 Success No
10 mo CLABSI S. haemolyticus 1.5 426 284 12 Success No
3 mo CLABSI S. hominis 2 646 323 16 Success No
9 mo CLABSI S. epidermidis 2 576 288 15 Success Yes
3y CLABSI Coagulase-negative 2 465 233 10 Success No
Staphylococcus sp.
1 mo CLABSI S. epidermidis 2 208 104 3 Success No

AKI indicates acute kidney injury; AUC24 , 24-hour steady-state vancomycin area under the serum concentration-time curve; CLABSI, central line-associated
bloodstream infection; Ctrough , serum trough concentration; MIC, minimum inhibitory concentration; ref, the reference method; SSI, surgical site infection.
a
These 2 pediatric patients had central venous catheters removed.

hemoculture sterility within 72 hours of vancomycin
therapy. The remaining 2 showed clinical improvement
within 72 hours; however, as hemocultures were
not taken at this point, determination of sterility at
this time point was not possible. The duration of
vancomycin therapy ranged from 7 to 12 days.
Subgroup Analysis of Pediatric Patients With Acute
Kidney Injury
Four out of 43 pediatric patients developed AKI after
vancomycin was administered. The mean (SD) of base-
line serum creatinine and vancomycin doses were 0.25
(0.06) mg/dL and 62 (1.6) mg/(kg·day), respectively.
Median time from vancomycin initiation to AKI onset
was 4 days (range 2-5 days). Two pediatric patients
were diagnosed while staying in the intensive care
unit. All pediatric patients received 1 concomitant
nephrotoxic medication, including furosemide (100%)
and vasopressors (25%). Their median measured Ctrough
was 15.1 mg/L (range 7.6-16.0 mg/L). In regard to the
AUC threshold of vancomycin-associated AKI, none
of these pediatric patients reached the AUC24 cutpoint
of >650 mgh/L. Their calculated AUC24 ranged from
392 to 610 mgh/L (median 568 mgh/L). Duration of
vancomycin therapy varied between 2 and 9 days. AKI
was entirely reversible in all pediatric patients without
progressing to renal replacement therapy.
Discussion
We sought an accurate method for vancomycin AUC-
based monitoring that had more acceptability and
Suchartlikitwong et al
reproducibility in pediatric settings. Calculating the
AUC24 using 2-point simplified pharmacokinetic EqA
was more precise than using EqB. Regardless of the
method used, AUC24  400 mgh/L was never seen
in Ctrough < 8 mg/L but was always seen in Ctrough
> 10. A Ctrough 8-10 mg/L achieved the target AUC24
calculated by EqA in 50% of our pediatric patients. This
finding was consistent with a systematic review, demon-
strating that Ctrough 6-10 mg/L was likely sufficient to
achieve AUC24 /MIC  400 for hospitalized children.30
The AUC-based monitoring through 2-point simpli-
fied equations could reduce unnecessary vancomycin
dosage increments. In our study vancomycin was
prescribed for children who had suspected serious
methicillin-resistant staphylococcal infections. With
only Ctrough monitoring, 70% of pediatric patients were
expected to have their vancomycin dose increased when
their measured Ctrough was <15 mg/L. When calculated
AUC24  400 mgh/L was targeted instead of Ctrough , a
vancomycin dose adjustment would be required in only
40% of pediatric patients. This impact was similar to
a study in an adult population conducted at Syracuse
Upstate University Hospital, where pediatric patients
were transitioned from only vancomycin Ctrough mon-
itoring to a 2-point AUC estimation method. Hos-
pital pharmacists made dosing alterations for pedi-
atric patients treated with vancomycin for complicated
MRSA infections. When Ctrough was 10 to <15 mg/L,
vancomycin doses were increased in 71% of pediatric
patients in the Ctrough -based group and in 25% of
pediatric patients in the AUC-based group if they had
estimated AUC24 /MIC < 400.26
Some studies report a relationship between patient
age and vancomycin serum concentrations. Pediatric
patients <6 years of age tended to have a lower Ctrough
than older pediatric patients despite the same daily
dose and dosing interval.12,31 We evaluated patient age-
associated differences in both vancomycin Ctrough and
calculated AUC; however, no significant associations
were found. This was due to the limited number of
children aged above 5 years in our study.
In order to implement vancomycin AUC-based
monitoring in resource-limited settings, we propose a
2-step approach. First, a vancomycin Ctrough should
be obtained when steady state is attained. Measured
Ctrough > 10 mg/L usually corresponds to a target
AUC24  400 mgh/L, thereby making dose adjustment
unnecessary. When Ctrough is <8 mg/L, it is unlikely
to produce an AUC24  400 mgh/L; therefore, dose
adjustment could be done roughly in a linear fashion
in accordance with Ctrough and then Ctrough repeated
at the next steady state. Caution should be exercised
when Ctrough is very low because it will overpredict
the increase in vancomycin dose. When Ctrough is 8-
10 mg/L, the possibility of achieving the target AUC24
7
is 50%. Thus, we suggest obtaining paired Cpeak and
Ctrough of the next dose to calculate AUC using EqA,
especially in pediatric patients with serious infections.
In such cases, vancomycin dosing can be adjusted until
the target AUC24 is reached.
Of note, vancomycin-associated AKI is related to
higher vancomycin exposure as measured both directly
by Ctrough  15-20 mg/L14,32 and indirectly by calculated
AUC24 > 650 mgh/L.17 To avoid the side effect of renal
toxicity, vancomycin dosing should not be tailored
beyond these upper limits of the therapeutic range.
Regarding vancomycin-associated AKI, we could
not demonstrate whether a higher vancomycin expo-
sure had a direct impact on the risk of nephrotoxicity
in this study. Although there were 4 pediatric patients
who developed AKI after receiving vancomycin treat-
ment, toxicity occurred in the context of concurrent
use of nephrotoxic agents and critical illness, which
contributed to further renal impairment.
An important factor affecting AUC24 /MIC is the
MIC of a Staphylococcus isolate.33 In our study, 1
MRSA isolate was found to have a vancomycin MIC
of 1.5 mg/L. This is consistent with previous studies
in Thailand that reported MRSA strains with reduced
susceptibility to vancomycin and alarming rises in
vancomycin MIC creep rates.34–36 It is our concern
that a higher dose of vancomycin may be necessary
to meet a target AUC24 /MIC  400. However, risk
of nephrotoxicity should be considered when intensive
vancomycin dosing regimen is used.
This study had several strengths. Because of its
practicality, the 2-point simplified EqA for calculating
AUC is implementable for clinical practice. This study
was conducted in the context of a hospital antibiotic
stewardship program aiming to optimize vancomycin
use for hospital-acquired infections. Additionally, ow-
ing to this being a prospective study, it has allowed us to
determine exact time points at which vancomycin was
given and blood was drawn for vancomycin levels. This
contributed to the accuracy of AUC calculation by the
equation-based approach.
Our study also had some limitations. First, the sam-
ple size was calculated based on the primary end point
to find the differences between AUC values calculated
from the reference method and EqA and EqB. Twenty
percent of study pediatric patients had staphylococcal
infections, but only 1 had a MRSA infection. We there-
fore had too few pediatric patients to address whether
vancomycin AUC-based monitoring affected treatment
efficacy. Extrapolation of the target AUC24 /MIC  400
to methicillin-resistant coagulase-negative Staphylococ-
cus infection should be considered with caution. This
target ratio is largely derived from clinical studies of
pediatric patients with MRSA infections. However, an
experimental study in novel rabbit models of neonatal
8 The Journal of Clinical Pharmacology / Vol 00 No 0 2019
coagulase-negative Staphlococcus central-line associ-
ated bloodstream infections demonstrated a strong
relationship between the maximal bacterial killing and
AUC24 /MIC  400.6 Consequently, this study informs
the need for future studies in humans to explore the
relationship between patient outcomes and optimal
AUC24 /MIC of vancomycin dosing against methicillin-
resistant coagulase-negative Staphylococcus. Neverthe-
less, all cases of coagulase-negative Staphlococcus
central-line associated bloodstream infections in this
study were caused by methicillin-resistant coagulase-
negative Staphylococcus, which is a low-virulence bac-
terium. This may explain the successful treatment out-
comes seen in this study despite few pediatric patients
actually reaching the goal AUC24 /MIC  400.
Regarding the pharmacokinetic profile of the refer-
ence method for AUC determination, the AUC24 that
is calculated from the vancomycin daily dose divided
by the total body clearance is based on the concept of
steady state (Ratein = Rateout ) and does not depend
on body compartment assumptions. However, it is
worth mentioning that we estimated the vancomycin
clearance assuming a 1-compartment model with first-
order elimination. Our AUC24 may not reflect the true
AUC24 , which requires extensive blood sampling, but
this estimation method is more practical in our clinical
pediatric settings.
Last, this study utilized the Etest, which has been the
only available technique for vancomycin MIC detection
in our hospital to date. Due to the high molecu-
lar weight of vancomycin, it can be problematic for
the Etest and can result in limited diffusion on the
agar plate,37 thereby producing MIC values slightly
higher than those produced by the standard broth
microdilution method.28,38 The ratio of AUC24 /MIC
could therefore be undervalued by the overestimation
of MICs. This may explain why clinical success was
observed in the patient who had a MRSA surgical
site infection with MICs > 1 mg/L despite having an
AUC24 /MIC < 400.
Conclusions
To our knowledge, this is the first study to assess
vancomycin AUC-based monitoring through 2-point
simplified pharmacokinetic equations in hospitalized
Thai children. Vancomycin Ctrough levels of >10 mg/L
are sufficient to achieve desirable AUC24 /MIC  400,
assuming MICs of 1 mg/L for the treatment of
methicillin-resistant staphylococcal infections in chil-
dren. When Ctrough < 8 mg/L, the AUC24 should be
estimated using the equation-based approach to guide
vancomycin dose adjustment. This study confirms the
reliability of another existing approach for vancomycin
AUC-based monitoring that is suitable for clinical use
in pediatric patients.
Conflicts of Interest
The authors declare no conflicts of interest with respect to the
research, authorship, and publication of this article.
Funding
This study was supported by the Ratchadapiseksompotch
Fund, Faculty of Medicine, Chulalongkorn University, Grant
Number RA61/087.
Acknowledgments
We acknowledge the following study team who contributed
to this project: Dr Chotirat Nakaranurack, PhD, and the
pharmacy staff at Department of Pharmacy Practice, Faculty
of Pharmaceutical Sciences, Chulalongkorn University, for
sharing their expertise on vancomycin pharmacokinetics;
Orawan Anunsittichai, RN, Jesdaporn Srisamer, RN, and
Pathomchai Amornrattanapaijit for data collection and doc-
ument management; and Sumanee Nilgate, MSc, and the
microbiology staff for providing microbiological information.
Data Sharing
The data used in these analyses are sharable under a commit-
ment to use the data only for research purposes and not to
identify any individual participant.
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