Predictive Performance of Bayesian

Vancomycin Monitoring in the Critically Ill*

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Sujita W. Narayan, BPharm,

OBJECTIVES: It is recommended that therapeutic monitoring of van- MPharmPrac, PhD1
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 10/31/2023

comycin should be guided by 24-hour area under the curve concentra- Yann Thoma, PhD2
tion. This can be done via Bayesian models in dose-optimization software.
Philip G. Drennan, MB ChB3
However, before these models can be incorporated into clinical practice
in the critically ill, their predictive performance needs to be evaluated. This Hannah Yejin Kim, BPharm, PhD1,4,5
study assesses the predictive performance of Bayesian models for vanco- Jan-Willem Alffenaar, PharmD,
mycin in the critically ill. PhD1,4,5
Sebastiaan Van Hal, MB ChB,
DESIGN: Retrospective cohort study.
FRACP, FRCPA, PhD6
SETTING: Single-center ICU. Asad E. Patanwala, PharmD,
PATIENTS: Data were obtained for all patients in the ICU between 1 MPH, FCCP, FASHP1,7
January, and 31 May 2020, who received IV vancomycin. The predictive
performance of three Bayesian models were evaluated based on their
availability in commercially available software. Predictive performance
was assessed via bias and precision. Bias was measured as the mean
difference between observed and predicted vancomycin concentrations.
Precision was measured as the sd of bias, root mean square error, and
95% limits of agreement based on Bland-Altman plots.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: A total of 466 concentra-
tions from 188 patients were used to evaluate the three models. All models
showed low bias (–1.7 to 1.8 mg/L), which was lower with a posteriori es-
timate (–0.7 to 1.8 mg/L). However, all three models showed low precision
in terms of sd (4.7–8.8 mg/L) and root mean square error (4.8–8.9 mg/L).
The models underpredicted at higher observed vancomycin concentra-
tions (bias 0.7–3.2 mg/L for < 20 mg/L; –5.1 to –2.3 for ≥ 20 mg/L) and
the Bland-Altman plots showed a great deviation between observed and
predicted concentrations.
CONCLUSIONS: Bayesian models of vancomycin show not only low
bias, but also low precision in the critically ill. Thus, Bayesian-guided dos-
ing of vancomycin in this population should be used cautiously.
KEY WORDS: Bayesian forecasting; critically ill; intensive care unit;
pharmacokinetics; therapeutic drug monitoring; vancomycin

S
trategies are needed to improve therapeutic drug monitoring practices of
vancomycin in the critically ill. The pharmacokinetic/pharmacodynamic *See also p. 1845.
target for therapeutic drug monitoring (TDM) that best predicts efficacy Copyright © 2021 by the Society of
and safety of vancomycin is the ratio of the area under the curve during a 24-hour Critical Care Medicine and Wolters
period to minimum inhibitory concentration (AUC24/MIC) (1, 2). Assuming a Kluwer Health, Inc. All Rights
MIC of less than or equal to 1 mg/L, guidelines have suggested a target AUC24 Reserved.
of 400–600 mg × hr/L. For simplicity, steady state trough concentrations (Css) DOI: 10.1097/CCM.0000000000005062

e952     www.ccmjournal.org October 2021 • Volume 49 • Number 10

Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

of 15–20 mg/L have historically been used as a surro-
gate target for AUC24 greater than 400 mg × hr/L in
clinical practice (3). However, this approach has been
challenged recently, on the basis that Css trough con-
centration is poorly predictive of AUC24, with dosing
to achieve nominated trough concentrations associated
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with excessive exposure, and increased risk of nephro-
toxicity without improved efficacy (4–7). Thus, the re-
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cent guidelines for vancomycin TDM recommend that
dosing of this agent should be area under the curve
(AUC) guided (2, 8).
There are a few alternatives to trough-based moni-
toring of vancomycin, all with challenges that limit
their widespread implementation (9). One method
involves measurement of two concentrations dur-
ing a dosage interval, which are obtained during
steady state. AUC24 can then be estimated based on
first-order pharmacokinetic equations. The disadvan-
tage of this approach is the complexity of data inputs
and calculations. It also requires two concentrations
for calculation, which increases blood draws, labo-
ratory utilization, and staff resources. An alternative
approach is Bayesian forecasting, which uses special-
ized software programs which incorporate measured
concentrations with “prior” information derived from
population pharmacokinetic models in order to esti-
mate individual pharmacokinetic parameters and drug
exposure (10). Previous studies have demonstrated
Bayesian forecasting to assist in optimizing AUC24/
MIC while also reducing per patient sampling frequency
(5, 7, 11, 12). However, proprietary software products
providing integrated Bayesian modeling are perceived
as expensive for hospital implementation (10). This has
limited widespread implementation into clinical prac-
tice. There are also limited data regarding the accuracy
of Bayesian models in the critically ill (2).
A few small studies (n = 19–82 patients) have evalu-
ated vancomycin pharmacokinetic models in the crit-
ically ill (13–15). Predictive performance was assessed
using different measures of bias and precision. These
studies have shown low bias, but a variable level of
precision. Thus, additional research is needed before
Bayesian models are routinely incorporated into clin-
ical practice in the critically ill. Studies are also needed
that report predictive performance in readily inter-
pretable measures that help clinicians understand the
utility of Bayesian software guided TDM for vanco-
mycin in this population.
Critical Care Medicine
Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Online Clinical Investigations
Therefore, the objective of this study was to assess
the predictive performance of vancomycin pharma-
cokinetic models that have been incorporated into
commercially available Bayesian dose-optimization
software for use in the critically ill.
METHODS
Study Design and Setting
This was a retrospective cohort study conducted in an
academic hospital in Sydney, NSW, Australia. The hos-
pital has a 54-bed ICU. The selection and dosing of van-
comycin in the ICU is based on clinician preference.
Dose adjustment was primarily based on Css. It is com-
mon in our ICU that several trough concentrations are
taken for the same patient. This may be as often as daily
measures in some cases if renal function is expected to
change. The institution does not use any Bayesian soft-
ware for TDM of vancomycin. The study was approved
by the Human Research Ethics Committee of the Local
Health District (approval number: 2019/ETH12033).
Patient Selection
Data were obtained for all patients in the ICU between
1 January 2019, and 31 May 2020. Patients who received
IV vancomycin delivered via intermittent infusion and
had at least one vancomycin concentration were in-
cluded. Patients were excluded if vancomycin contin-
uous infusions were used as Bayesian models are not
necessary to calculate AUC24 for them. Patients were also
excluded if they received continuous renal replacement
therapy (CRRT) because these patients were not in-
cluded in any of the Bayesian models tested. There were
no patients with intermittent hemodialysis or peritoneal
dialysis in this study. In addition, if the levels were taken
prior to any ICU doses, then the patients were excluded.
This occurs in patients transferred from a ward to ICU,
where initial doses are not given in the ICU.
Data Collection
Data collected included age, sex, weight, height, vanco-
mycin doses, timing of doses, infusion times, vancomycin
concentrations, timing of concentrations, serum cre-
atinine values, and timing of creatinine values. All data
were extracted using automated queries from the elec-
tronic medical record. This minimized the possibility of
any transcription errors. All variables used for estimation
www.ccmjournal.org     e953
 Narayan et al

TABLE 1.
Bayesian Models
Pharmacokinetic
Commercial Variable Estimates
Models Software Compartments From the Final Model Significant Covariates
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Goti et al DoseMeRx Two-compartment Clearance 4.5 L/hr CrCL on clearance

(16) model with zero
Vc 58.4 L Dialysis on clearance
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 10/31/2023

order infusion
Vp 38.4 L Dialysis on Vc
Q 6.5 L/hr
Thomson InsightRx Two-compartment Clearance 2.99 L/hr CrCL on clearance
et al model Vc 0.675 L/kg Total body weight on Vc
(18) (biexponential
elimination) Vp 0.732 L/kg
Q 2.28 L/hr
Colin et al None Two-compartment Clearance 5.31 L/hr/70 kg Serum creatinine on clearance
(19) model Vc 42.9 L/70 kg Postmenstrual age on clearance
Vp 41.7 L/70 kg Weight on Vc
Q 3.22 L/hr/70 kg Weight on Vp
CrCL: = creatinine clearance, Q = intercompartmental clearance, Vc = central volume of distribution, Vp = peripheral volume of
distribution.

(weight, height, vancomycin doses, serum creatinine, age,
and sex) were checked manually in 10% of the sample.
All variables were accurate, with the exception of vanco-
mycin doses, which showed some inconsistencies. Thus,
100% of vancomycin doses were checked manually.
Vancomycin Assay
The analyzer used during this research is the Roche Cobas
8000 c702 (Roche, Basel, Switzerland). The vancomyin
gen.3 (VANC3) vancomycin assay is a homogenous en-
zyme immunoassay technique kinetic interaction of mic-
roparticles in a solution. The VANC3 Vancomycin Assay
and Preciset TDM 1 Calibrators were used as described in
the package insert. All chemicals used were of analytical
grade. The assay was calibrated using six standards (0, 5,
10, 25, 50, 80 mg/L), lower limit of quantification 4.0 mg/L,
and limit of detection 1.5 mg/L. Imprecision was less than
6% across all quality control samples and quality assur-
ance program less than 4%. All routine measurements
were performed as single measurements.
Model Selection
A pragmatic approach was used in selecting vancomycin
models for the study. Commonly used commercially
available Bayesian dose-optimization software were
identified that had incorporated vancomycin models
for use in critically ill adults. The model by Goti et al
(16) has been incorporated by DoseMeRx (Tabula Rasa
HealthCare, Moorestown, NJ) because of its predic-
tive performance based on a comparison of 31 models
(17). The model by Thomson et al (18) was included in
InsightRx (Insight Rx Inc., San Francisco, CA) based
on a study showing this model to be most suitable in
the critically ill (13). In addition, we identified another
model that was not evaluated in these previous investi-
gations because of its subsequent publication. This was a
pooled-population pharmacokinetic model that incor-
porates 14 studies in different populations that could be
suitable to the critically ill (19). Thus, three models were
selected for our analysis: 1) Goti et al (16), 2) Thomson
et al (18), and 3) Colin et al (19). The model specifica-
tions are reported in Table 1.
Predictive Performance
The objective was to determine the predictive perfor-
mance of the three aforementioned models for use of
TDM in clinical practice in the critically ill. This was
evaluated by comparing observed versus predicted

e954     www.ccmjournal.org October 2021 • Volume 49 • Number 10

Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
 Online Clinical Investigations

vancomycin concentrations using the Bayesian mod- precision were calculated for both a priori and a poste-
els. In patients with changing serum creatinine, the riori predictions for all models.
most recent (closest to time of estimation) value was
used for each prediction as would be done in clinical Data Analysis
practice.
Predictive performance was assessed via bias and Models were setup in Tucuxi (22) (revision cd7bd7a8
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precision variables. Bias was measured as the mean dif- joint development by HEIG-VD, Yverdon-les-Bains,
ference between observed and predicted vancomycin Switzerland and CHUV, Lausanne, Switzerland) and
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 10/31/2023

concentrations. Precision was measured as the sd of the
difference, root mean square error (RMSE), and 95%
limits of agreement (LOA) based on Bland-Altman
plots. The Bland-Altman plots serve as a visual depic-
tion of bias and precision (20). From a clinical perspec-
tive, this was most intuitive as it retains the original
scale of the vancomycin concentrations for ease of in-
terpretation. The concordance correlation coefficient
(ρc) was reported as an overall measure of agreement
between observed and predicted values (21). The ρc
combines measures of bias and precision. It determines
how far the predicted values deviate from the line of
perfect agreement (i.e., line of 45 degrees on a square
scatter plot). To allow comparison to previous studies
(13, 14, 17), other variables of bias and precision were
calculated that are reported in the literature. These in-
clude relative bias (rBias) and relative RMSE (rRMSE).
Formulas (17) used for these variable calculations are
in Table A (Supplementary
Appendix, http://links.lww.
com/CCM/G445).
automatically run through the command line interface.
All data analysis and calculation of bias and precision
measures were conducted in STATA 15 (StataCorp,
College Station, TX).
RESULTS
Study Cohort
There were 330 patients given vancomycin doses
with at least one concentration measured during the
study period. Of these, 188 patients were included in
the study. The reasons for exclusion and selection of
the patient cohort are depicted in Figure 1. The mean
(sd) age was 58 (17) years, and 119 (63%) were male.
Patients had a mean serum creatinine of 92.9 ± 66.0
µmol/L. Baseline characteristics patients are in Table 2.
There was a total of 466 concentrations taken in these
patients (mean 17 mg/L, sd 7 mg/L). Of these, 184 were

Stratification
The results were first re-
ported overall for each
model. Furthermore, the
results were also stratified
as a priori or a posteriori
estimates. The first vanco-
mycin level was predicted
using patient covariates
only and was considered to
be an a priori prediction.
Subsequent concentrations
were predicted incorporat-
ing patients’ vancomycin
concentrations and were
considered to be a poste-
riori predictions. Bias and
Figure 1. Flow diagram of patient selection. Patients included in the study.

Critical Care Medicine www.ccmjournal.org     e955

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 Narayan et al
TABLE 2.
Baseline Patient Characteristics
Demographics and Admission Variables Value
Age (yr), mean (sd) 58 (17)
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Sex (male) (%) 119 (63)
Weight (kg), mean (sd) 84 (26)
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Height (cm), mean (sd) 170 (10)
Serum creatinine (µmol/L), mean (sd) 92.9 (66.0)
Acute Physiology and Chronic Health 62 (22)
Evaluation III score, mean (sd)
Mechanical ventilation, n (%) 74 (39)
Vasopressors, n (%) 66 (70)
23 (28)
Planned ICU admission, n (%)
Surgical admission, n (%) 83 (44)
first concentrations and were compared with predicted
level using a priori prediction. The remaining 282 were
taken subsequent to the first level and were compared
with predicted concentrations using a posteriori pre-
diction. Most concentrations were troughs (Figs. D–F,
Supplementary Appendix, http://links.lww.com/CCM/
G445). The median single dose administered was
1,250 mg (interquartile range [IQR], 1,000–1,500 mg)
(weight adjusted 15 mg/kg [IQR, 11–20 mg/kg]).
Predictive Performance
The model by Goti et al (16) had a bias of –1.1 mg/L, sd
of bias 5.8 mg/L, 95% limits of agreement –12.4 to 10.3
mg/L, ρc equals to 0.63 (95% CI, 0.58–0.68) (Fig. 2). The
model by Thomson et al (18) had a bias of –0.5 mg/L, sd
of bias 7.1 mg/L, 95% limits of agreement –14.4 to 13.5
mg/L, ρc equals to 0.45 (95% CI, 0.38–0.52) (Fig. 2). The
model by Colin et al (19) had a bias of 1.3 mg/L, sd of bias
6.6 mg/L, 95% limits of agreement –11.7 to 14.2 mg/L, ρc
equals to 0.56 (95% CI, 0.50–0.62) (Fig. 2). Additional
measures of bias and precision, as well as estimates
stratified by a priori and a posteriori predictions, are in
Table 3. No patients were identified for whom exclu-
sion of data would alter the overall results.
Figures A–C (Supplementary Appendix, http://links.
lww.com/CCM/G445) depict bias (difference between
predicted and observed) versus observed concentra-
tions. All three models underpredict at higher observed
e956     www.ccmjournal.org
Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
vancomycin concentrations. For observed concentra-
tions less than 20 mg/L, bias was 0.7 mg/L for Goti et
al (16), 1.9 mg/L for Thomson et al (18), and 3.2 mg/L
for Colin et al (19). For observed concentrations greater
than or equal to 20 mg/L, bias was –4.4 mg/L for Goti et
al (16), –5.1 mg/L for Thomson et al (18), and 2.3 mg/L
for Colin et al (19). Figures D–F (Supplementary
Appendix, http://links.lww.com/CCM/G445) depict
bias versus time to concentration after a dose (hr),
Figures G–I (Supplementary Appendix, http://links.
lww.com/CCM/G445) depict bias versus dose interval
(i.e., the first dose interval is between the first and second
dose). Figures J–L (Supplementary Appendix, http://
links.lww.com/CCM/G445) depict bias versus creati-
nine clearance calculated using the closest value at time
of estimation. No trends were observed for these vari-
ables with regard to any of the three models.
The potential clinical implications of the discord-
ance between observed and predicted concentrations
are shown in Table B (Supplementary Appendix, http://
links.lww.com/CCM/G445). Dose changes are usually
based on when concentrations are considered thera-
peutic versus nontherapeutic. The analysis shows that a
match between observed and predicted concentrations
for dose range categories was 60.9% for Goti et al (16),
58.6% for Thomson et al (18), and 50.9% for Colin et al
(19). In other words, in approximately half of the cases a
dose change would be made based on predicted values
but not observed values and vice versa.
DISCUSSION
In this study, we evaluated the predictive performance
of Bayesian models for vancomycin in critically ill
patients using an independent real-life cohort of 188
patients. The key finding was that all Bayesian mod-
els showed not only a low level of bias but also a poor
level of precision. In other words, there was great devi-
ation between observed and predicted concentrations.
However, this deviation in predicted values occurred
to a similar extent above and below observed values.
This is clearly depicted in the Bland-Altman plots with
95% LOA. It highlights that Bayesian estimates can be
greatly different from actual values. This has important
implications for the clinical utility of Bayesian mod-
els for vancomycin dose-optimization in critically ill
patients because of this lack of precision.
It is notable that although all models had low preci-
sion, the model by Thomson et al (18) appeared to have
October 2021 • Volume 49 • Number 10

Difference of Predicted and Observed (mg/L)
Bland and Altman Plot (Goti et al.)
−40 −30 −20 −10 0 10 20 30 40
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0 5 10 15 20 25 30
Mean of Predicted and Observed (mg/L)
observed average agreement 95% limits of agreement
Difference of Predicted and Observed (mg/L)
Bland and Altman Plot (Thomson et al.)
−40 −30 −20 −10 0 10 20 30 40
5 10 15 20 25 30
Mean of Predicted and Observed (mg/L)
observed average agreement 95% limits of agreement
Difference of Predicted and Observed (mg/L)
Bland and Altman Plot (Colin et al.)
−40 −30 −20 −10 0 10 20 30 40
5 10 15 20 25 30
Mean of Predicted and Observed (mg/L)
observed average agreement 95% limits of agreement
Figure 2. Bland-Altman plots. Plots for Goti et al (16), Thomson
et al (18), and Colin et al (19).
the lowest precision, especially for a priori estimates. A
priori estimates rely on patient covariates only (as it
is representative of the start of therapy when no con-
centration data are available), whereas a posteriori pre-
diction allows incorporation of patients’ vancomycin
concentrations allowing individualized variable esti-
mates and better predictive performance. The original
model by Thomson et al (18) was based on a smaller
dataset, and it is unclear if the patients included in the
dataset were from the ICU, which could explain greater
imprecision compared with the other models.
Critical Care Medicine
Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Online Clinical Investigations
A recent study by Ter Heine et al (13) retrospec-
tively validated five pharmacokinetic models (n = 30
patients) and prospectively evaluated the model by
Thomson et al (18) (n = 50 patients) to assess its pre-
dictive performance in critically ill patients. The study
by Ter Heine et al (13) showed a mean prediction error
of 8.8% (95% CI, 5.7–11.9%) and rRMSE of 19.8%
(95% CI, 17.5–22.1%) with the model by Thomson et
al (18). The investigators considered this to be suitable
35 40 for model-informed decision-making. Although our
study also found a low level of bias, we had a lower
level of precision using the same model with rRMSE
being 54.6% for a priori and 35.5% for a posteriori es-
timation. Furthermore, we showed underprediction at
higher observed concentrations. This is expected be-
cause very high concentrations are likely to occur in
patients less represented in population pharmacoki-
netic models, such as those with deteriorating renal
clearance that is not reflected in observed serum creat-
inine. The nature of the Bayesian approach is to shrink
35 40
a posteriori predicted concentrations toward the a
priori values, leading to biased predictions in patients
who are not well described by the model.
Another study by Cunio et al (14) evaluated 12
vancomycin models in critically ill patients (n = 82
patients) and identified the Goti et al (16) model to be
most suitable. This model showed a rBias of 3.4% and
rRMSE of 49% for a priori estimates and rBias of 1.5%
and rRMSE of 23.9% for a posteriori estimates. These
findings are similar to our study that also showed a
35 40
low bias and low precision. However, the authors did
not emphasize this low precision, instead considering
this to be suitable for clinical practice. However, based
on the Bland-Altman plots in our study, the precision
appears to be unsatisfactory as this could lead to incor-
rect dosing changes. This low level of precision, and its
interpretation needs more clinical scrutiny. The Bland-
Altman plots with 95% LOA certainly depict that pre-
dicted concentrations using these models could be
considerably different from observed values.
In a small study of 19 critically ill patients, the ac-
curacy and bias of several Bayesian dose-optimizing
software programs was evaluated (15). The reference
AUC (AUCREF) was calculated using the log-linear
trapezoidal rule in this richly sampled dataset, sim-
ilar to our study. Bayesian estimation of AUC was
reported using different subsets of the data. The esti-
mation of AUC, which was based on a single trough
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 Narayan et al

TABLE 3.
Predictive Performance
95% Bland-Altman Concordance Relative
Bias sd Limits of Correlation Relative RMSE RMSE
Models (mg/L) (mg/L) Agreement (mg/L) Coefficient (ρc) Bias (%) (mg/L) (%)
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Goti et al (16)
Overall –1.1 5.8 –12.4 to 10.2 0.63 –4.0 5.9 35.8
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A priori –1.7 7.1 –15.6 to 12.3 0.42 –5.8 7.3 44.1

A posteriori –0.7 4.7 –9.9 to 8.6 0.72 –2.8 4.8 29.1
Thomson et al (18)
Overall –0.5 7.1 –14.4 to 13.3 0.45 –0.5 7.1 42.2
A priori –1.1 8.8 –18.4 to 16.3 0.17 –2.4 8.9 54.6
A posteriori –0.2 5.6 –11.3 to 10.9 0.59 –0.7 5.6 31.6
Colin et al (19)
Overall 1.3 6.6 –11.7 to 14.2 0.56 9.1 6.7 39.7
A priori 0.4 7.4 –14.0 to 14.8 0.45 7.5 7.4 45.2
A posteriori 1.8 6.0 –9.8 to 13.6 0.57 10.2 6.3 35.5
Bias = mean difference between observed and predicted concentrations, RMSE = root mean squared error.

concentration (AUCT), is most comparable with our
study. Bias was reported as a percentage and calculated
as ([AUCT–AUCREF]|/[AUCREF]) × 100. The bias with
DoseMeRx was 21.2% (IQR, 16.3–24.6%), and bias
with InsightRx was 16.4% (IQR, 11.8–22.6%). Thus,
assuming a median AUCREF of approximately 600 mg
× hr/L as reported in their study, we could assume
Bayesian estimates to fluctuate by 100–150 mg × hr/L
around this calculated value.
There are limitations associated with our study. This
was a single-center retrospective cohort study and
should be extrapolated with caution to other centers.
However, due to our large sample size, we expect that
similar findings would be observed at other institu-
tions. Furthermore, this study compared observed
concentrations to predicted concentrations. Although
this is an important step in evaluating the predictive
performance of these models, it provides limited in-
formation regarding how the performance of the
models would affect decision-making or dose changes
that would be considered to be appropriate. This is be-
cause decisions for dose modification would be based
on AUC24. Further studies are needed to prospectively
compare calculated versus Bayesian estimated AUC24
methods and how any imprecision may affect dos-
ing. Patients on CRRT were excluded because they are
not commonly included in Bayesian TDM software.
However, we would likely anticipate even greater im-
precision in these patients. Although we considered
the predictive performance of Bayesian models to be
unsuitable overall, their use may still be superior to
trough-based monitoring. Bayesian programs may
have a graphical user interface that makes it possible
to visualize percentiles around the predicted estimates.
This helps clinicians take into account uncertainty.
Finally, AUC24 can be estimated at steady state using a
single concentration taken during continuous infusion
of vancomycin. This method is straightforward and ac-
curate; however, it requires continual IV access.
CONCLUSIONS
Commonly available Bayesian pharmacokinetic mod-
els lack precision in the critically ill. This can result
in substantial differences between observed and pre-
dicted values. Our findings suggest that Bayesian
model-guided dosing of vancomycin in the critically ill
should be used cautiously when targeting AUC24. The

e958     www.ccmjournal.org October 2021 • Volume 49 • Number 10

Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

performance was even poorer for a priori estimates and
should be avoided for initial vancomycin dosing. Until
this precision is improved, calculated AUC24 using
two concentrations via kinetic equations, or contin-
uous vancomycin infusion with a single concentration
at steady state, may be preferable in this population.
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Prospective trials are needed comparing the effects of
different dosing approaches on patient-centered out-
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 10/31/2023
comes and resource utilization.
1 The University of Sydney, Faculty of Medicine and Health,
School of Pharmacy, Sydney, NSW, Australia.
2 Reconfigurable and Embedded Digital Systems Institute,
School of Business and Engineering Vaud, University of Applied
Sciences Western Switzerland, Yverdon-les-Bains, Switzerland.
3 Oxford University Hospitals NHS Foundation Trust, Oxford,
United Kingdom.
4 Westmead Hospital, Westmead, NSW, Australia.
5 Marie Bashir Institute for Infectious Diseases and Biosecurity,
The University of Sydney, Sydney, NSW, Australia.
6 New South Wales Health Pathology, Department of
Infectious Diseases and Microbiology, Royal Prince Alfred
Hospital, Camperdown, NSW, Australia.
7 Royal Prince Alfred Hospital, Sydney, NSW, Australia.
Supplemental digital content is available for this article. Direct
URL citations appear in the printed text and are provided in the
HTML and PDF versions of this article on the journal’s website
(http://journals.lww.com/ccmjournal).
The authors have disclosed that they do not have any potential
conflicts of interest.
For information regarding this article, E-mail: asad.patanwala@
sydney.edu.au
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