Pharmacology | Full-Length Text

Effect modification of dosing strategy (AUC or trough) on AKI

associated with vancomycin in combination with piperacillin/
tazobactam or cefepime and meropenem
Breanne Mefford,1,2 Katie L. Wallace,1,2 J. Chris Donaldson,1,2 Brittany D. Bissell Turpin,1,2 Parijat Sen,3 Aric D. Schadler,2,4 Lucas J. Liu,5
Melissa L. Thompson Bastin1,2

AUTHOR AFFILIATIONS See affiliation list on p. 11.

ABSTRACT Piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) and

vancomycin (VAN) are commonly used in combination for sepsis. Studies have shown
an increased risk of acute kidney injury (AKI) with TZP and VAN compared to FEP or
MEM. VAN guidelines recommend area under the curve (AUC) monitoring over trough
(Tr) to minimize the risk of AKI. We investigated the association of AKI and MAKE-30 with
the two VAN monitoring strategies when used in combination with TZP or FEP/MEM.
Adult patients between 2015 and 2019 with VAN > 72 hours were included. Patients
with AKI prior to or within 48 hours of VAN or baseline CrCl of ≤30 mL/min were
excluded. Four cohorts were defined: FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC.
A Cox Proportional Hazard Model was used to model AKI as a function of the incidence
rate of at-risk days, testing monitoring strategy as a treatment effect modification.
Multivariable logistic regression was used to model MAKE-30. Overall incidence of AKI
was 18.6%; FEP/MEM/Tr = 115 (14.6%), FEP/MEM/AUC = 52 (14.9%), TZP/Tr = 189 (26%),
and TZP/AUC = 96 (17.1%) (P < 0.001). Both drug group [(TZP; P = 0.0085)] and moni­
toring strategy [(Tr; P = 0.0007)] were highly associated with the development of AKI;
however, the effect was not modified with interaction term [(TZP*Tr); 0.085)]. The odds
of developing MAKE-30 were not different between any group and FEP/MEM/AUC. The
effect of VAN/TZP on the development of AKI was not modified by the VAN monitoring

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strategy (AUC vs trough). MAKE-30 outcomes were not different among the four cohorts.

KEYWORDS vancomycin, therapeutic drug monitoring, nephrotoxicity, acute kidney

injury, beta lactams

E arly administration of appropriate antimicrobials is essential in reducing sepsis-rela­

ted mortality (1). For patients with sepsis or septic shock at high risk of methicillin-
resistant Staphylococcus aureus (MRSA) and other multidrug-resistant organisms (MDR),
a combination of piperacillin-tazobactam (TZP) or cefepime (FEP) or meropenem (MEM)
and vancomycin (VAN) are frequently utilized. Recent evidence suggests that patients
receiving a combination therapy of TZP and VAN have an increased risk of acute kidney Editor Ryan K. Shields, University of Pittsburgh,
injury (AKI) as compared to FEP or MEM and VAN (2, 3). However, the risk of AKI among Pittsburgh, Pennsylvania, USA
intensive care unit (ICU) patients with TZP and VAN compared to FEP and VAN remains Address correspondence to Breanne Mefford,
controversial (4, 5). Additionally, there are little data regarding the long-term clinical Breanne.mefford@uky.edu.
impact of AKI associated with TZP and VAN as most studies have focused on the
The authors declare no conflict of interest.
incidence of serum creatinine defined-AKI rather than the meaningful outcomes of AKI.
Nephrotoxicity associated with VAN is typically seen 4.3 days after the initiation of Received 21 September 2023
Accepted 6 February 2024
vancomycin therapy; high troughs (≥15 mg/L) are associated with increased nephrotox­ Published 12 April 2024
icity compared to low troughs (<15 mg/L) (6). Historically, vancomycin troughs were
Copyright © 2024 American Society for
utilized as a surrogate marker for the pharmacodynamic parameter of area under the
Microbiology. All Rights Reserved.

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curve/ minimal inhibitory concentration (AUC/MIC) given the difficulty in estimating

AUC in clinical practice. However, recent guidelines from the American Society of
Health-System Pharmacists (ASHP), in conjunction with the Infectious Diseases Society
of America (IDSA), and Society of Infectious Diseases Pharmacists (SIDP) have changed
their recommendations to AUC-based monitoring of vancomycin, which has shown to
decrease the risk of AKI over trough monitoring (7). A meta-analysis of eight observatio­
nal studies found that the incidence of AKI associated with AUC-based monitoring was
significantly lower than trough-based monitoring (OR 0.68, 95% CI, 0.46–0.99) (8).
There is an abundance of observational data suggesting a higher association of AKI
with TZP/VAN over FEP/MEM/VAN, including a large recent database study; however,
the impact of AUC monitoring has not been robustly evaluated (6, 9–16). While a
recent retrospective analysis evaluated the incidence of AKI with TZP/VAN compared
to FEP/MEM/VAN with AUC based monitoring, a direct comparison of TZP/VAN and
FEP/MEM/VAN with both trough and AUC monitoring has not been evaluated (17). VAN
AUC monitoring has been associated with reduced nephrotoxicity presumably due to
reduced VAN exposure; thus, we hypothesize that the association between TZP/VAN
and AKI will be impacted by VAN therapeutic drug monitoring (TDM) strategy (18). In
addition, the clinically significant variables of death, dialysis, and persistent kidney injury
have been inconsistently evaluated, and no study to date has evaluated these antibiotic
combinations on MAKE-30 outcomes, nor in an ICU population (19). Therefore, we also
sought to understand the impact of these antibiotic combinations and VAN monitor­
ing strategy on clinical outcomes beyond a serum creatinine elevation, specifically the
incidence of MAKE-30.

MATERIALS AND METHODS

Design and setting
This was a retrospective, single-center cohort study at the University of Kentucky
HealthCare, a large tertiary 1,000 bed academic medical center. The study was approved
by the University of Kentucky Institutional Review Board with a waiver of informed
consent due to the observational nature of the data. The Strengthening the Reporting of
Observational Studies in Epidemiology checklist for observational studies was followed.

Study population

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The electronic health record was queried, and data were extracted from the University
of Kentucky Center for Clinical and Translational Science Enterprise Data Trust. Adults
admitted to the hospital from 1 August 2015 to 30 September 2019, who received
VAN for at least 72 hours with VAN level(s) drawn within 96 hours of initiation with
concomitant beta-lactams (for ≥1 day) during the time frame of VAN exposure were
included. Vancomycin AUC24 monitoring was implemented in September 2017. The
trough-based cohort was defined as having a trough level drawn within 2 hours prior
to administration of VAN dose during the period of August 2015 to July 2017. The
AUC-based cohort was required to have a trough level and random level drawn within
2 to 5 hours after the administration of VAN between October 2017 and September
2019. AUC24 monitoring was performed using 2-level pharmacokinetics by the team of
pharmacists per institutional protocols. The detailed process of AUC24 monitoring in this
institution has previously been defined (20).
Patients were excluded if they had a diagnosis of cystic fibrosis, chronic kidney
disease (CKD) stages 3–5, history of kidney transplant, or were pregnant while receiving
VAN. Those with creatinine clearance (CrCl) ≤30 mL/min using the corrected Cockcroft-
Gault equation at the time of VAN initiation were excluded. Patients were also excluded if
they experienced AKI during their hospitalization prior to the initiation of VAN, within 48
hours of VAN, or seven or more days after VAN was discontinued as AKI in these patients
is unlikely to be attributed to VAN (20–22). Those receiving both TZP and MEM, TZP and

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FEP, no concomitant beta lactams, or throughout study period received TZP, FEP, and
MEM were excluded (Fig. 1).

Independent variable
The primary independent variable in this study is the two antibiotic combination groups:
stratified by Tr or AUC monitoring. The exposure period of AUC monitoring occurred
following an institution-wide change, with a 3-month washout time period chosen to
minimize treatment overlap. Vancomycin AUC24 monitoring was implemented house-
wide within this facility in September 2017. The pre-implementation (trough monitoring)
time frame was from August 2015 to July 2017, and the post-implementation time frame
(AUC monitoring) was from October 2017 to September 2019. Within these two time
frames, four cohorts were defined: patients receiving FEP or MEM with trough-based VAN
(FEP/MEM/Tr), FEP or MEM with AUC-based VAN (FEP/MEM/AUC), TZP with trough-based
VAN (TZP/Tr), and TZP with AUC-based VAN (TZP/AUC).

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FIG 1 Flow chart for patient inclusion.

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Study outcomes
The primary study outcome was the incidence of AKI as defined by the Kidney Dis­
ease Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines Definition.
Secondary outcomes include the incidence of MAKE-30, which is a composite dichot­
omous outcome [in-hospital mortality, new dialysis as defined within 48 hours to
hospital discharge, and renal dysfunction at discharge (defined as a discharge serum
creatinine >200% times baseline)], the individual components of MAKE-30, hospital
length of stay, intensive care unit (ICU) length of stay, and the trajectory of serum
creatinine concentrations over time (23). For the MAKE-30 calculation, the change in
serum creatinine from baseline was calculated using the following formula:

Change from baseline (x) = discharge serum creatinine / admission serum creatinine

AKI was observed within the outcome window, which was defined from 48 hours after
VAN initiation to 7 days after VAN was discontinued. If no serum creatinine value was
available prior to initiation of VAN, the first available serum creatinine value was used
after vancomycin therapy commenced. We defined the highest serum creatinine as the
maximum serum creatinine within the outcome window.

Subgroup analyses
Several a priori sub-group analyses were identified. We evaluated the incidence of AKI
in the TZP cohort, comparing TZP/Tr to TZP/AUC. We also evaluated the cohort of
AUC-only monitoring, comparing the incidence of AKI between FEP/MEM/AUC and TZP/
AUC. Finally, we evaluated the incidence of AKI among all cohorts in those who were
admitted to the ICU.

Time to event curves

Kaplan-Meier time to event curves were generated to describe the incidence rate of AKI
over time across the four treatment groups (Fig. 2).

Serum creatinine trajectory over time according to group

Spline graphs were developed using piece-wise polynomial regression with polynomial

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degrees of 3 (Fig. 3). The fitted line in Panel A represents individual patients' daily median
serum creatinine values per group. The fitted line in Panel B represents the groups’ daily
median serum creatinine values. The shaded area on either side of the line denotes the
95% CI.

Statistical analysis
Categorical variables were analyzed using the Pearson’s χ2 or Fisher’s exact test, as
appropriate. A Kruskal–Wallis test for non-parametric continuous variables was used,
while analysis of variance (ANOVA) for parametric continuous variables was used. The
outcome of AKI was modeled as a function of the incidence rate of at-risk days, to
account for the differing times at risk among the groups, using a Cox Proportional
Hazard Model. A multivariable logistic regression model was built for MAKE-30. Variables
were included in the analysis according to clinical rationale. Backward elimination at the
0.05 level was used to build the models and was not adjusted for multiple analyses.
The final models were adjusted for additional concomitant nephrotoxins, vancomycin
duration of therapy, ICU admission, moderate to severe chronic kidney disease, and
trough >20 μg/mL. We log transformed the highly skewed variables for the models,
including vancomycin duration of therapy and concomitant beta-lactam days. One
hundred ninety observations were omitted due to the missing values for response or
explanatory variable and missing data were not imputed.

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FIG 2 Kaplan-Meier curve of development of AKI over the exposure time at risk.

RESULTS
Clinical characteristics
Overall, 2,425 patients met eligibility criteria and were included in the study cohort
(Fig. 1). Baseline characteristics were similar between groups with the exception of
myocardial infarction (MI), congestive heart failure (CHF), chronic obstructive pulmonary
disease (COPD), cancer, and moderate to severe chronic kidney disease (Table 1). Baseline
serum creatinine was not different between cohorts: median serum creatinine of 0.79 in
FEP/MEM/Tr (interquartile range IQR, 0.62–0.99); 0.79 in FEP/MEM/AUC (IQR 0.66–0.96);
0.81 in TZP/Tr (IQR 0.65–1.04); and 0.82 (IQR 0.65–0.99) in TZP/AUC (P = 0.107). The
Charlson Comorbidity Index (CCI) score differed: 3 [(IQR), 1–6] in FEP/MEM/Tr; 3 (IQR,
1–5) in FEP/MEM/AUC; 3 (IQR, 1–6) in TZP/Tr; and 3 (IQR, 1–5) in TZP/AUC (P = 0.008).
Incidence of serum creatinine-defined AKI by stage is presented in Table 2. Treatment
characteristics, including beta-lactam days, additional nephrotoxins, vancomycin dosing,
AUC measurements, and trough concentrations are presented in Tables 3 and 4.

Study outcomes

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Unadjusted study outcomes are found in Table 5. Serum creatinine-defined AKI was
statistically different among the four cohorts: overall incidence of 18.6%; FEP/MEM/Tr =
115 (14.6%); FEP/MEM/AUC = 52 (14.9%); TZP/Tr = 189 (26%); and TZP/AUC = 96 (17.1%),
ANOVA (P < 0.001) (Table 2). Additionally, the incidence of developing MAKE-30 differed
(overall 26.5%): FEP/MEM/Tr = 231 (29.4%); FEP/MEM/AUC = 97 (27.8%); TZP/Tr = 190
(26.1%); and TZP/AUC = 125 (22.3%) (P = 0.003). Hospital length of stay differed between
groups with a median length of stay of 11 days (IQR, 6–21) in FEP/MEM/Tr, 12 days (IQR,
7–21) in FEP/MEM/AUC, 9 days (IQR, 5–17) in TZP/Tr, and 9 days (5-17) in TZP/AUC (P
< 0.001). Overall, mortality was seen in 76 (9.7%) in FEP/MEM/Tr, 27 (7.7%) in FEP/MEM/
AUC, 45 (6.2%) in TZP/Tr, and 19 (3.4%) in TZP/AUC (P < 0.001) (Table 2).
The results of the Cox Proportional Hazard analysis are found in Table 6. Both drug
group [(TZP; P = 0.0085)] and method [(Tr; P = 0.0007)] were highly associated with the
development of AKI; however the effect was not modified with interaction term [(TZP*Tr;
0.085)]. Additionally, the odds of developing MAKE-30 were not different between any
group and FEP/MEM/AUC (referent category) (Table 7).

Sub-group analysis
Within the TZP groups, we compared the incidence of AKI in TZP/Tr to TZP/AUC.
Controlling for nephrotoxins, days of beta-lactam therapy, total daily dose of vancomy­
cin, admission to ICU, and CKD, those who received AUC monitoring with TZP were

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FIG 3 Serum creatinine trajectory over time according to group.

44% less likely to develop serum creatinine-defined AKI as compared to those who
received trough monitoring with TZP (OR 0.559, 95% CI 0.412–0.760). Within the cohort
of AUC-only monitoring, we compared the incidence of AKI between FEP/MEM/AUC
and TZP/AUC. Controlling for nephrotoxins, days of beta-lactam therapy, admission to
the ICU, CKD, and vancomycin trough >20, TZP/AUC were 2.12× more likely to develop
serum creatinine-defined AKI as compared to FEP/MEM/AUC (OR 2.12, 95% CI 1.35–
3.32). When evaluating ICU only patients, we modeled the incidence of AKI among all
four cohorts, with FEP/MEM/AUC as the referent group. Controlling for nephrotoxins,
vancomycin days, CKD, and vancomycin trough >20, TZP/Tr was 3.32× more likely to
develop AKI as compared to FEP/MEM/AUC (OR 3.32, 95% CI 1.78–6.17). There was no
difference between FEP/MEM/Tr and FEP/MEM/AUC, nor was there a difference between
TZP/AUC and FEP/MEM/AUC for ICU patients.

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Time to event curves
As depicted in Fig. 2, the incidence rate of AKI trajectory is plotted for all four treatment
groups. There is a separation of the lines prior to day 10 and shows a higher rate in the
TZP/Tr group.

Serum creatinine trajectory over time according to group

As depicted in Fig. 3, the trajectories of all four groups are plotted over the first 7 days
of vancomycin therapy. Fig. 3A displays the median of all creatinine values and shows
an increase of TZP/Tr over the other groups. Fig. 3B represents the daily median of the
medians of each group, for which groups TZP/Tr and TZP/AUC show a greater increase in
values over the same time frame.

DISCUSSION
This study addresses three key questions that remain unanswered in the current
literature. First, what is the impact of AUC-based monitoring on AKI with beta-lactam
combinations. Second, what impact do these antibiotic combinations have on clinical
renal outcomes (MAKE-30). And, third, what is this association in an ICU cohort. This was
the largest study thus far to evaluate the incidence of AKI among AUC and trough-gui­
ded VAN with concomitant TZP and FEP/MEM, and it is the only study to date to evaluate
the overall impact on clinical renal outcomes (MAKE-30).

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TABLE 1 Baseline characteristics

Characteristic FEP/MEM/Tr FEP/MEM/AUC TZP/Tr TZP/AUC Total P-value

N = 787 N = 349 N = 728 N = 561 N = 2,425
Agea,d 50 (16.52) 52 (14.92) 51 (16.09) 50 (15.59) 51 (15.96) 0.419
Gender (male)b,f 447 (56.8) 203 (58.2) 450 (61.8) 328 (58.5) 1,428 (58.9) 0.250
Race (white)b,f 735 (93.4) 329 (94.3) 682 (93.7) 527 (93.9) 2,273 (93.7) 0.946
Weight (kg)c,e 80 (65.9–98.67 82 (68.37–100) 80 (65.5–97.4 79.6 (65.9–97.5) 80 (66-98) 0.560
Height (m)c,e 1.72 (1.64–1.80) 1.72 (1.65–1.80) 1.72 (1.65–1.80) 1.72 (1.65–1.80) 1.73 (1.65–1.80) 0.462
BMI (kg/m2)c,e 27.1 (23.0–32.4) 27.24 (23.23–32.61) 26.6 (22.45–32.39 27.19 (22.57–32.13) 27.04 0.765
(22.82–32.4)
Charlson Indexc,e 3 (1-6) 3 (1-5) 3 (1-6) 3 (1-5) 3 (1-5) 0.008
MIb,f 104 (13.2) 31 (9.2) 83 (11.4) 48 (8.6) 266 (11) 0.039
CHFb,f 142 (18) 42 (12.4) 102 (14) 66 (11.9) 352 (14.6) 0.006
COPDb,f 291 (37) 97 (28.7) 222 (30.5) 176 (31.7) 786 (32.6) 0.012
Mild liver diseaseb,f 118 (15) 64 (18.9) 108 (14.8) 77 (13.8) 367 (15.2) 0.209
Moderate to severe 54 (6.9) 17 (5) 33 (4.5) 13 (2.3) 117 (4.9) 0.002
chronic kidney
diseaseb,f
Cancerb,f 141 (17.9) 58 (17.2) 86 (11.8) 43 (7.7) 328 (13.6) <0.001
HIV/AIDSb,f 8 (1) 9 (2.7) 10 (1.4) 5 (0.9) 32 (1.3) 0.113
Diabetesb,f 254 (32.3) 113 (33.4) 217 (29.8) 168 (30.2) 752 (31.2) 0.549
Baseline serum 0.79 (0.62–0.99) 0.79 (0.66–0.96) 0.81 (0.65–1.04) 0.82 (0.65–0.99) 0.83 (0.67–1.03) 0.107
creatinine (prior to
first vancomycin
dose)c,e
Baseline creatinine 106 (79–137) 103 (81–132) 103 (76–133) 101.31 (80.45–134) 103 (79–135) 0.320
clearancec,e
a
Mean (standard deviation).
b
Number of patients (%).
c
Median (interquartile range [IQR]).
d
ANOVA.
e
Independent-samples Kruskal-Wallis test.
f
Pearson χ2.

The risk of vancomycin-associated nephrotoxicity is estimated to be 5% to 43% and is

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associated with a 6.5-fold increase in the odds of death, a 3.5-day increase in length
of stay (LOS), and nearly $7,500 in excess hospital costs (6, 24). Thus, when treat­
ing hospitalized patients, minimizing the development of AKI while achieving clinical
efficacy is of utmost importance. Over the past decade, there has been a growing body
of evidence linking the concomitant usage of VAN and TZP with increased association
of AKI. Many of these studies are retrospective in nature, and are limited to evaluation
of serum creatinine defined AKI, and do not take into consideration the impact of AUC
based dosing (6, 9–15).
The statistically significant finding of increased association of AKI in the TZP/Tr-dosing
group within our study is consistent with much of the existing literature evaluating
trough data (25). Thus, it was not unexpected to find that patients receiving TZP/Tr

TABLE 2 Incidence of serum creatinine-defined acute kidney injury by group

Characteristic FEP/MEM/Tr FEP/MEM/AUC TPZ/Tr TZP/AUC Total P-value

N = 787 N = 349 N = 728 N = 561 N = 2,425
No AKIa,b 672 (85.4) 297 (85.1) 539 (74) 465 (82.9) 1,973 (81.4) <0.001
KDIGO stage 1a,b 63 (8) 29 (8.3) 100 (13.7) 53 (9.4) 245 (10.1)
KDIGO stage 2a,b 23 (2.9) 14 (4) 46 (6.3) 19 (3.4) 102 (4.2)
KDIGO stage 3a,b 29 (3.7) 9 (2.6) 43 (5.9) 24 (4.3) 105 (4.3)
a
Number of patients (%).
b
Pearson χ2.

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TABLE 3 Treatment characteristics according to group

Characteristic FEP/MEM/Tr FEP/MEM/AUC TPZ/Tr TZP/AUC Total P-value

N = 787 N = 349 N = 728 N = 561 N = 2,425
Beta-lactam, daysb,c 5 (4-8) 6 (4-9) 5 (4-7) 5 (4-7) 5 (4-7) <0.001
Piperacillin, daysb,c - - 4 (3-6) 5 (3-7) 5 (3-7) n/a
Cefepime, daysb,c 5 (3-7) 5 (4-8) - - 5 (3-7) n/a
Meropenem, daysb,c 4 (3-7) 5 (3-7) - - 4 (3-7) n/a
Vancomycin, daysb,c 6 (4-9) 7 (5-12) 5 (4-8) 6 (4-8) 6 (4-9) <0.001
Additional concomitant nephrotoxinsb,c 1 (0–2) 1 (1-2) 1 (0–2) 1 (0–1) 1 (0–2) <0.001
Concomitant nephrotoxins, daysb,c 2 (0–6) 5 (1-10) 2 (0–5) 2 (0–5) 3 (0–6) <0.001
ICU admissiona,d 284 (36.1) 116 (33.2) 241 (33.1) 171 (30.5) 812 (33.5) 0.193
a
Number of patients (%).
b
Median (interquartile range [IQR]).
c
Independent-samples Kruskal-Wallis test.
d
Pearson χ2.

combination therapy had the highest association with serum creatinine-defined AKI.
When controlling for known confounders in the Cox Proportional Hazard model analyses,
both drug exposure (TZP) and method (Tr) were associated with an increased risk of
developing AKI. This was not modified when testing the interaction of the two terms,
meaning the method of TDM (Tr vs AUC) did not significantly modify the effect of AKI
seen in the TZP/VAN group. In the ICU cohort, TZP/Tr was the only group associated with
increased odds of AKI. Interestingly, patients receiving FEP/MEM/Tr had the highest ICU
length of stay, and overall unadjusted mortality relative to the other groups. This could
be explained by several unmeasured confounding variables in our retrospective analysis
including patients who decompensated necessitating the need for MEM, patients with
multidrug-resistant organisms, or patients who were deemed more acutely ill at baseline
and initiated on MEM therapy empirically. In our study, the higher incidence of AKI in
TZP/Tr relative to TZP/AUC is likely explained by the limitations of trough-based VAN
monitoring as aforementioned.
The mechanism of potential nephrotoxicity of the VAN/TZP combination at a
physiologic level is largely unknown. Hypothetical mechanisms for potential synergy
in nephrotoxicity include the pseudotoxicity hypothesis, which is caused by a drug
interaction through VAN-induced externalization of OAT1-OAT3 and piperacillin as

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a substrate, limiting creatine passage to the tubular cell, and causing an apparent
elevation in serum creatinine, which is unrelated to tubular injury and should be
transient. The second hypothesis is the VAN exposure hypothesis: acute interstitial
nephritis potential of TZP combined with VAN-induced acute tubular necrosis, induction
of reactive oxygen species, and oxidative stress (25). However, such hypotheses remain

TABLE 4 Vancomycin dosing and pharmacokinetics according to group

Characteristic FEP/MEM/Tr FEP/MEM/AUC TPZ/Tr TZP/AUC Total P-value

N = 787 N = 349 N = 728 N = 561 N = 2,435
Loading dose (initial dose ≥20 mg/kg)a,d 251 (31.9) 169 (48.4) 238 (32.7) 278 (49.6) 936 (38.6) <0.001
AUC >600a,d - 95 (27.2) - 141 (25.1) 236 (25.9) 0.485
Trough >20 mcg/mLa,d 74 (9.4) 31 (8.9) 48 (6.6) 37 (6.6) 190 (7.8) 0.114
Vancomycin trough, mcg/mLb,c 12 (8.4–16.6) 12.2 (9.5–16.6) 11.7 (8.7–16) 11.1 (7.65–15.2) 11.7 (8.3–16) <0.001
Area under the curve (AUC24)b,c - 507 (412–613) - 483 (391–601) 493 (398–604) 0.040
Volume of distributionb,c - 53.82 (41.54–68.08) - 52.3 (40–65.2) 52.75 (40.49–66.73) 0.196
Clearanceb,c - 4.65 (3.47–6.08) - 4.85 (3.54–6.11) 4.76 (3.5–6.0) 0.191
Elimination rate constant (Ke)c - 0.092 (0.062–0.12) - 0.095 (0.07–0.12) 0.09 (0.07–0.12) 0.103
Maximum serum concentration, mcg/mLb,c - 33.19 (28-40) - 32.7 (27.4–39.1) 33.07 (27.81–39.38) 0.170
a
Number of patients (%).
b
Median (interquartile range [IQR]).
c
Independent-samples Kruskal-Wallis test.
d
Pearson χ2.

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TABLE 5 Unadjusted study outcomes according to treatment group

Outcomes FEP/MEM/Tr FEP/MEM/AUC TZP/Tr TZP/AUC Total P-value

N = 787 N = 349 N = 728 N = 561 N = 2,425
Any stage AKIa,d 115 (14.6) 52 (14.9) 189 (26) 96 (17.1) 452 (18.6) <0.001
Make-30a,d 231 (29.4) 97 (27.8) 190 (26.1) 125 (22.3) 643 (26.5) 0.033
ICU LOS stay, daysb,c 8 (4–12.75) 7 (3-13) 7 (3-11) 5 (2-10) 7 (3-12) 0.012
LOS, daysb,c 11 (6–21) 12 (7–21) 9 (5-17) 9 (5-17) 10 (6–19) <0.001
Dialysis at dischargea,e 14 (1.8) 8 (2.3) 10 (1.4) 4 (0.7) 36 (1.5) 0.202
In hospital mortalitya,d 76 (9.7) 27 (7.7) 45 (6.2) 19 (3.4) 167 (6.9) <0.001
Serum creatinine at dischargeb,c 0.69 (0.56–0.88) 0.73 (0.58–0.88) 0.83 (0.66–1.06) 0.81 (0.65–0.97) 0.77 (0.61–0.95) <0.001
Renal dysfunction at 155 (19.7) 67 (20) 143 (19.7) 110 (20.1) 475 (19.8) 0.998
dischargea,d
a
Number of patients (%).
b
Median (interquartile range [IQR]).
c
Independent-samples Kruskal-Wallis test.
d
Pearson χ2.
e
Fishers exact test.

unproven. A study refuting the second hypothesis was conducted in mice, where AKI was
seen only with VAN but not with combination therapy (26). When kidney histopathology
was examined as well as kidney epithelial cells, VAN was associated with biologically
proven acute kidney damage; whereas, interestingly, the combination was not. This
finding aligns with the previously established mechanism of VAN-associated AKI through
VAN-mediated oxidative stress and uromodulin interaction/cast formation. In a separate
murine study looking at tubular cast formation, VAN was associated with nephrotoxicity
while the combination with TZP was not (27). Based on currently available evidence,
it is likely that the predominate mechanism of tubular damage with this combination
is not synergistic, but instead comes from the VAN therapy alone. Taken together, the
utilization of AUC monitoring should presumably decrease the total daily dose of VAN
needed to attain a therapeutic goal. Thus, AUC monitoring may lead to decreased rates
of AKI in TZP/AUC given the translation from murine models into humans.
A recent prospective study evaluated the hypothesis of pseudotoxicity via OAT1-
OAT3 inhibition in adult critically ill patients. Authors found an increased risk of serum
creatinine defined AKI with VAN/TZP but no changes in Cystatin C or clinical outcomes
including dialysis or mortality (19). The discordance between serum creatinine and

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Cystatin C-defined AKI aligns with the animal-derived hypothesis of interference in
glomerular secretion of creatinine, termed a pseudotoxicity. Miano et al. paper was
the first to evaluate the alternative criteria for AKI diagnosis and the need for dialysis,
and 30-day mortality. The VAN/TZP-associated AKI did not translate to higher rates
of dialysis or mortality, further suggesting that the association of AKI represents a
pseudotoxicity. In order to confirm these findings, we opted to assess MAKE-30 between
FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC. As MAKE-30 outcomes did not differ
among our groups, the rise of serum creatinine seen in our study in those receiving
VAN/TZP may be attributed to a transient pseudotoxicity, rather than a true injury. These
findings enhance the hypothesis that true synergistic TZP/VAN tubular toxicity does not
exist. Another recent publication of the Cefepime vs Piperacillin-Tazobactam in Adults
Hospitalized with Acute Infection (ACORN) randomized clinical trial corroborates our

TABLE 6 Time to AKI

Time to event analysis (AKI)a,b P-value

Drug (TZP) 0.0085
Method (Tr) 0.0007
TZP/Tr 0.085
a
Model constructed using a Cox Proportional Hazard Model.
b
Model adjusted for CKD, vancomycin trough >20, concomitant days of (beta lactam and VAN) exposure, and
Charlson Comorbidity Index.

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TABLE 7 Adjusted study outcomes of incidence of MAKE-30

MAKE-30a,b OR 95% CI
c
FEP/MEM/Tr 1.120 0.84–1.49
TZP/Trc 0.977 0.72–1.31
TZP/AUCc 0.795 0.57–1.09
a
Model adjusted for additional nephrotoxins, CHF, total daily dose.
b
Models constructed using logistic regression.
c
Referent category FEP/MEM/AUC.

findings (28). ACORN investigators randomized sepsis patients to either cefepime or

piperacillin through the emergency department. Overall, there were no differences in
the primary composite outcome of the highest stage AKI or death. There were also no
differences in MAKE-14 outcomes between groups. While vancomycin exposure was not
controlled, a post-hoc analysis of patients who received concomitant therapy revealed
no differences in AKI (on an ordinal scale) (28).
This study has several limitations. First, the retrospective study design may have
inherently introduced bias as a significant number of patients were excluded as a
result of missing trough and/or peak levels within 96 hours of VAN initiation. Second,
our primary outcome, the incidence of AKI was based on KDIGO criteria which utilizes
changes in serum creatinine. We did not include any data with Cystatin C, biomarkers,
or kidney histopathology, all of which may be more accurate in identifying true kidney
injury. Third, the inclusion of patients who received concomitant beta-lactams for ≥1 day.
This was done as previous studies have identified the VAN/combination toxicity at 48
hours (19). Furthermore, the indiscriminate use of FEP over TZP due to concerns for
nephrotoxicity may have introduced a treatment selection bias which is not easily
overcome in a retrospective evaluation. Patients who are initially started on TZP and
deemed at risk for AKI are often subsequently transitioned to FEP. Additionally, the use
of MAKE-30 criteria as a marker for renal clinical outcomes is limited by patients who
may have been discharged before 30 days, as patients could have had resolved renal
dysfunction after hospital discharge. MAKE-30 outcome utilizes mortality as a composite
outcome as previously defined. In our study, while unadjusted mortality was higher in
FEP/MEM groups, the adjusted odds of developing MAKE-30 were not different between
any group and FEP/MEM/AUC (referent category), following multivariable adjustment.
Moreover, it’s worth noting that renal dysfunction at discharge and dialysis at discharge
were not statistically significant in the unadjusted outcomes. We chose to exclude

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patients who had AKI 7 days after VAN was discontinued as AKI is likely not due to
VAN after this timepoint. However, this may limit the study population towards those
with AKI during VAN and introduce selection bias.
Study strengths include a large cohort of patients receiving AUC monitoring and who
were admitted to the ICU. We evaluated MAKE-30 as a clinically meaningful outcome for
AKI patients. Additional strengths exist in our patient selection requiring VAN patients
to have pharmacokinetic data available. Additionally, utilizing pharmacokinetic data,
we were able to control for the known confounding of supratherapeutic vancomycin
concentrations. We restricted this analysis to patients without AKI at VAN initiation,
and truncated data at 7 days post-VAN completion, which allowed us to identify any
associations between any AKI event and the VAN exposure. However, we recognize the
time to onset of AKI development for VAN/TZP has yet to be fully elucidated (23).

Conclusions
The effect of VAN/TZP therapy on the development of AKI was not modified by VAN AUC
monitoring. No difference was found between groups for overall incidence of MAKE-30.
Future research is needed to confirm these findings with alternatives to serum creatinine
for evaluating kidney function and the long-term clinical impact of AKI.

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ACKNOWLEDGMENTS

We wish to thank the University of Kentucky Infectious Disease group for the use of the
database and feedback on this work.
We wish to thank Nannan Li in her support through her Data Manager role in the
Department of Statistics at the University of Kentucky.
The project described was supported by the NIH National Center for Advancing
Translational Sciences through grant number UL1TR001998. The content is solely the
responsibility of the authors and does not necessarily represent the official views of the
NIH.
B.M. formulated the study question. B.M. and M.L.T.B. conceptualized the study
design. B.M., M.L.T.B., B.D.B.T., J.C.D., and P.S. approved the study design. K.L.W. was
responsible for data curation. B.M., M.L.T.B., and K.L.W. cleaned and investigated the
data. A.D.S. conducted the statistical analysis. L.J.L. generated graph visualizations.
B.M., M.L.T.B., B.D.B.T., and J.C.D. wrote the original draft, and all authors reviewed and
approved the final manuscript.

AUTHOR AFFILIATIONS
1
Department of Pharmacy Services, University of Kentucky HealthCare, Lexington,
Kentucky, USA
2
Department of Pharmacy Practice and Science, University of Kentucky College of
Pharmacy, Lexington, Kentucky, USA
3
Division of Pulmonary, Critical Care and Sleep Medicine, University of Kentucky,
Lexington, Kentucky, USA
4
University of Kentucky Children’s Hospital, Lexington, Kentucky, USA
5
Department of Computer Science, University of Kentucky, Lexington, Kentucky, USA

AUTHOR ORCIDs

Breanne Mefford http://orcid.org/0000-0003-2144-2724

Katie L. Wallace http://orcid.org/0000-0002-9718-8067
Melissa L. Thompson Bastin http://orcid.org/0000-0001-8047-5978

AUTHOR CONTRIBUTIONS

Breanne Mefford, Conceptualization, Data curation, Formal analysis, Investigation,

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Methodology, Project administration, Resources, Supervision, Validation, Visualization,
Writing – original draft, Writing – review and editing | Katie L. Wallace, Data curation,
Formal analysis, Investigation, Methodology, Resources, Validation, Writing – original
draft, Writing – review and editing | J. Chris Donaldson, Investigation, Methodology,
Resources, Validation, Visualization, Writing – original draft, Writing – review and editing
| Brittany D. Bissell Turpin, Methodology, Resources, Validation, Visualization, Writing –
original draft, Writing – review and editing | Parijat Sen, Investigation, Methodology,
Visualization, Writing – original draft, Writing – review and editing | Aric D. Schadler,
Formal analysis, Investigation, Software, Visualization, Writing – original draft, Writing
– review and editing | Lucas J. Liu, Formal analysis, Methodology, Software, Visualiza­
tion, Writing – original draft, Writing – review and editing | Melissa L. Thompson
Bastin, Conceptualization, Data curation, Formal analysis, Investigation, Methodology,
Validation, Visualization, Writing – original draft, Writing – review and editing

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