Research

JAMA | Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized

With Acute Infection
The ACORN Randomized Clinical Trial
Edward T. Qian, MD, MSc; Jonathan D. Casey, MD, MSc; Adam Wright, PhD; Li Wang, MS; Matthew S. Shotwell, PhD; Justin K. Siemann, PhD;
Mary Lynn Dear, PhD; Joanna L. Stollings, PharmD; Brad D. Lloyd, RRT-ACCS; Tanya K. Marvi, MD; Kevin P. Seitz, MD, MSc; George E. Nelson, MD;
Patty W. Wright, MD; Edward D. Siew, MD, MSc; Bradley M. Dennis, MD; Jesse O. Wrenn, MD, PhD; Jonathan W. Andereck, MD, MBA;
Jin H. Han, MD, MSc; Wesley H. Self, MD, MPH; Matthew W. Semler, MD, MSc; Todd W. Rice, MD, MSc;
for the Vanderbilt Center for Learning Healthcare and the Pragmatic Critical Care Research Group

Visual Abstract
IMPORTANCE Cefepime and piperacillin-tazobactam are commonly administered to Editorial page 1531
hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has
been hypothesized to cause acute kidney injury and cefepime has been hypothesized to Supplemental content

cause neurological dysfunction, their comparative safety has not been evaluated in CME Quiz at
a randomized clinical trial. jamacmelookup.com

OBJECTIVE To determine whether the choice between cefepime and piperacillin-tazobactam

affects the risks of acute kidney injury or neurological dysfunction.

DESIGN, SETTING, AND PARTICIPANTS The Antibiotic Choice on Renal Outcomes (ACORN)
randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom
a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation
to the hospital in the emergency department or medical intensive care unit at an academic
medical center in the US between November 10, 2021, and October 7, 2022. The final date of
follow-up was November 4, 2022.

INTERVENTIONS Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam.

MAIN OUTCOMES AND MEASURES The primary outcome was the highest stage of acute kidney
injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney
injury to death. The 2 secondary outcomes were the incidence of major adverse kidney
events at day 14 and the number of days alive and free of delirium and coma within 14 days.

RESULTS There were 2511 patients included in the primary analysis (median age, 58 years
[IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic;
94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at
enrollment). The highest stage of acute kidney injury or death was not significantly different
between the cefepime group and the piperacillin-tazobactam group; there were 85 patients
(n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who
died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute
kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56).
The incidence of major adverse kidney events at day 14 did not differ between groups
(124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-
tazobactam group; absolute difference, 1.4% [95% CI, −1.0% to 3.8%]). Patients in the Author Affiliations: Author
cefepime group experienced fewer days alive and free of delirium and coma within 14 days affiliations are listed at the end of this
article.
(mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio,
Group Information: The members of
0.79 [95% CI, 0.65 to 0.95]).
the Vanderbilt Center for Learning
Healthcare and the Pragmatic Critical
CONCLUSIONS AND RELEVANCE Among hospitalized adults in this randomized clinical trial,
Care Research Group appear in
treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury Supplement 3.
or death. Treatment with cefepime resulted in more neurological dysfunction. Corresponding Author: Edward T.
Qian, MD, MSc, Vanderbilt University
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05094154
Medical Center, 1161 21st Ave S,
Nashville, TN 37232 (edward.t.qian@
vumc.org).
Section Editor: Christopher
Seymour, MD, Associate Editor, JAMA
JAMA. 2023;330(16):1557-1567. doi:10.1001/jama.2023.20583 (christopher.seymour@jamanetwork.
Published online October 14, 2023. org).

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 Research Original Investigation
A
cutely ill adults presenting to a hospital with sus-
pected infection frequently receive empirical antibi-
otics. For patients at risk for infection with resistant
gram-negative bacteria, guidelines recommend the adminis-
tration of antipseudomonal antibiotics such as cefepime or
piperacillin-tazobactam.1
Because cefepime and piperacillin-tazobactam have simi-
lar activity against many gram-negative bacteria (efficacy), se-
lection between the 2 is likely to depend on differences within
their adverse effect profiles (safety). Some observational stud-
ies have reported an association between cefepime and
neurotoxicity,2-4 ranging from agitation to coma.5 Some ob-
servational studies have reported an association between
piperacillin-tazobactam and acute kidney injury (AKI), par-
ticularly with concurrent receipt of vancomycin.6-8 A random-
ized clinical trial comparing treatments for methicillin-
resistant Staphylococcus aureus found that the addition of
an antistaphylococcal β-lactam antibiotic to vancomycin
increased the risk of AKI.9 To our knowledge, no random-
ized clinical trial has compared cefepime vs piperacillin-
tazobactam; therefore, it is unknown whether the risks of AKI
or neurological dysfunction differ between the 2 drugs.
To compare the safety of cefepime vs piperacillin-
tazobactam in adults presenting to the hospital with sus-
pected infection, we conducted the Antibiotic Choice on Renal
Outcomes (ACORN) randomized clinical trial.
Methods
Trial Design and Oversight
Between November 10, 2021, and October 7, 2022, we con-
ducted a pragmatic, open-label, parallel-group, random-
ized comparative safety trial of cefepime vs piperacillin-
tazobactam in adult patients with suspected infection in the
emergency department (ED) or medical intensive care unit
(ICU) at Vanderbilt University Medical Center. The trial was ini-
tiated by the investigators, approved by the institutional re-
view board with a waiver of informed consent, registered be-
fore enrollment commenced, and overseen by an independent
data and safety monitoring board. The trial protocol and sta-
tistical analysis plan were published before enrollment
concluded10 and appear in Supplement 1.
Patient Population
Adults (≥18 years of age) in the ED or medical ICU for whom a
clinician initiated an order for cefepime or piperacillin-
tazobactam within 12 hours of presentation to the hospital were
eligible. Patients were excluded if they had an allergy to cepha-
losporins or penicillins, had received more than 1 dose of an
antipseudomonal cephalosporin or penicillin within the pre-
vious 7 days (patients who had received other antipseudo-
monal antibiotics were eligible), were incarcerated, or if the
treating clinician determined that 1 of the 2 drugs repre-
sented a better treatment option for that patient. An elec-
tronic health record tool screened all patients for eligibility and
an automated alert within the electronic order entry system
confirmed patient eligibility with clinicians.
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Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection
Key Points
Question Does the choice between cefepime and
piperacillin-tazobactam affect the risks of acute kidney injury or
neurological dysfunction in adults hospitalized with acute
infection?
Findings Among 2511 adults hospitalized with acute infection,
the highest stage of acute kidney injury or death was not
significantly different between patients randomized to cefepime
and those randomized to piperacillin-tazobactam. Patients
randomized to cefepime experienced more neurological
dysfunction, a secondary outcome.
Meaning Among hospitalized adults, the risk of acute kidney injury
did not differ between cefepime and piperacillin-tazobactam, but
neurological dysfunction was more common with cefepime.
Randomization
Using software within the electronic health record, pa-
tients were assigned via simple randomization without strati-
fication in a 1:1 to ratio to receive cefepime or piperacillin-
tazobactam (Figure 1). Trial group assignment was concealed
until enrollment.
Treatments
A clinical decision support tool in the electronic health record
facilitated placement of an order for the assigned antibiotic
and recommended a dose and frequency based on the
patient’s estimated glomerular filtration rate. Per institu-
tional protocols, the standard administration of cefepime
was a 2-g intravenous push over 5 minutes every 8 hours and
piperacillin-tazobactam was administered as a 3.375-g bolus
over 30 minutes for the initial administration followed by an
extended infusion of 3.375 g every 8 hours infused over 4
hours for subsequent doses (additional information appears
in the eMethods in Supplement 2). Cefepime was the only
antipseudomonal cephalosporin and piperacillin-tazobactam
was the only antipseudomonal penicillin available in the
trial settings.
Treating clinicians determined the duration of antipseu-
domonal antibiotic therapy and whether to administer addi-
tional antibiotics, such as vancomycin or metronidazole. For
the 7 days after enrollment, if treating clinicians discontin-
ued the assigned antibiotic or ordered the unassigned antibi-
otic, an automated alert reminded them of the trial and re-
corded the reason for the change. The study ED and ICU were
each staffed by a dedicated clinical pharmacist; non-ICU in-
patient units were not. Clinical pharmacists remotely moni-
tored drug levels for intravenous vancomycin but not for the
β-lactam antibiotics.
Data Collection
Data were collected in routine care and electronically ex-
tracted from the electronic health record of the study institu-
tion. Data included information on demographics; diagnoses;
preenrollment kidney function; medication administration; vi-
tal signs; laboratory values; microbiological cultures; organ sup-
port therapies; Sequential Organ Failure Assessment score11;
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 Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection
Figure 1. Flow of Participants Through the ACORN Trial
3806 Adults hospitalized with acute
infection assessed for eligibilitya
1172 Excluded
2634 Randomized
1277 Randomized to receive cefepime 1357 Randomized to receive piperacillin-tazobactam
1214 Received an antipseudomonal
cephalosporin or penicillin
60 Did not receive an antipseudomonal
cephalosporin or penicillin
3 Withdrawn from analysis after
randomization (incarcerated)
1214 Included in primary analysis
Confusion Assessment Method for the ICU (CAM-ICU) score12;
Richmond Agitation-Sedation Scale (RASS) score13; Glasgow
Coma Scale score14; dates of admission, transfer, and dis-
charge; and vital status at hospital discharge (eMethods in
Supplement 2).
Race and ethnicity were self-reported by patients or re-
ported by their surrogates as part of clinical care. Race and eth-
nicity were automatically extracted from the electronic health
record using fixed categories to facilitate assessment of the rep-
resentativeness of the trial population and the generalizabil-
ity of the trial results. The frequency of assessments and labo-
ratory measurements were determined by treating clinicians
and preexisting clinical protocols. At the study institution, the
RASS and Glasgow Coma Scale scores were recorded every 12
hours for all patients and the CAM-ICU score was recorded
every 12 hours for patients admitted to the ICU.
Trial personnel adjudicated whether sepsis was present at
enrollment using Sepsis-3 criteria,15 the presumed source of
infection using previously published categories,16 whether kid-
ney replacement therapy (KRT) had been received, and the in-
dication for KRT.
Outcomes
The primary outcome was the highest stage of AKI or death aris-
ing between randomization and day 14, measured on a 5-level
ordinal scale. The stages of AKI were defined using the Kidney
Disease: Improving Global Outcomes criteria for creatinine
level.17 Surviving patients who did not experience new or wors-
ening AKI were assigned a value of 0, those who experienced
stage 1 AKI (creatinine level that was 1.5-1.9 times the baseline
level or increased by ≥0.3 mg/dL [≥26.5 μmol/L]) were as-
signed a value of 1, those who experienced stage 2 AKI (creati-
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Original Investigation Research
542 Required treatment with piperacillin-tazobactam
358 Required treatment with cefepime
132 Received antipseudomonal cephalosporin
or penicillin within prior 7 d
22 Incarcerated
18 Did not meet screening criteria
5 Aged <18 y
5 Allergic to penicillin or cephalosporin but
allergy not noted in electronic health record
3 Reason for exclusion missing
87 Other reasonsb
ACORN indicates Antibiotic Choice on
Renal Outcomes.
a
A tool in the electronic health record
screened all patients presenting to
the study hospital for the presence
of inclusion criteria (ⱖ18 years of
1297 Received an antipseudomonal age; being treated in participating
cephalosporin or penicillin emergency department or intensive
59 Did not receive an antipseudomonal care unit; <12 hours since
cephalosporin or penicillin presentation to the hospital; and
1 Withdrawn from analysis after
order initiated for antipseudomonal
randomization (incarcerated)
cephalosporin or penicillin).
b
Included clinician preference,
1297 Included in primary analysis
metronidazole shortage, and no
reason recorded.
nine level that was 2.0-2.9 times the baseline level) were as-
signed a value of 2, and those who experienced stage 3 AKI
(creatinine level that was ≥3.0 times the baseline level, AKI with
a creatinine level ≥4.0 mg/dL [≥353.7 μmol/L], or receipt of new
KRT) were assigned a value of 3. To account for the competing
risk of death, patients who died were assigned a value of 4.
The value for baseline creatinine level was determined
using a previously described hierarchical approach in which
creatinine values obtained during the year before hospitaliza-
tion were given priority over in-hospital measurements
obtained before enrollment and an estimated value was used
when no preenrollment measurements were available.18,19
For patients with AKI at enrollment, new AKI was defined as
a creatinine level that was at least 0.3-mg/dL greater than the
lowest prior creatinine level since enrollment. Patients
who had received KRT before enrollment could not experi-
ence AKI and received a value of 0 if they survived and 4 if
they died. All data were censored at hospital discharge. The
primary outcome was selected to assess for an effect of
piperacillin-tazobactam on the development of AKI using an
international consensus definition over the same period used
in prior observational studies.17,20
Two secondary outcomes were prespecified. The first was
the proportion of patients who experienced a major adverse
kidney event at day 14, which was the composite of death, re-
ceipt of new KRT, or persistent kidney dysfunction (final in-
patient creatinine level that was ≥2 times the baseline level),
and censored at hospital discharge or 14 days after enroll-
ment, whichever occurred first. This outcome was recom-
mended by the National Institute of Diabetes and Digestive and
Kidney Diseases work group on clinical trials in AKI as a patient-
centered outcome for phase 3 trials, and it is considered more
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 Research Original Investigation
clinically meaningful than outcomes based purely on labora-
tory values.18,21 The other secondary outcome was the num-
ber of days alive and free of delirium and coma within 14 days,
which was defined as the number of calendar days on which
the patient was alive and without a positive assessment on the
CAM-ICU12 or a RASS13 score of −4 or −5, and censored at hos-
pital discharge. This outcome was selected to assess the ef-
fect of cefepime on the development of neurological dysfunc-
tion using a common measure of neurological function among
acutely ill adults22-24 (eMethods in Supplement 2).
Statistical Analysis
Details regarding the sample size estimation and reestima-
tion have been reported previously.10 The trial was initially
designed to enroll 2050 patients to provide 80% statistical
power to detect an odds ratio (OR) of 0.65 in the primary
analysis (eMethods in Supplement 2). Because the associa-
tion between piperacillin-tazobactam and AKI has been
hypothesized to be conditioned on concurrent receipt of
vancomycin6-8 and the timing of the trial’s interim analysis,
75% of patients in the trial population were receiving vanco-
mycin at enrollment; therefore, the data and safety monitor-
ing board recommended increasing the sample size from
2050 to 2500 patients. Assuming a 2-sided α of .05 and a dis-
tribution of the primary outcome with approximately 70% of
patients experiencing no AKI, 10% experiencing stage 1 AKI,
7% experiencing stage 2 AKI, 7% experiencing stage 3 AKI,
and 6% experiencing death, we calculated that enrollment of
2500 patients would provide 92% statistical power to detect
an OR of 0.75 in the primary analysis. An OR of 0.75 would
equate to an absolute between-group difference of 5% in
patients who experienced AKI of any stage or death.
The primary analysis population included all random-
ized patients who received at least 1 dose of either cefepime
or piperacillin-tazobactam, analyzed in the group to which they
were assigned. The primary analysis compared trial groups
using an unadjusted proportional odds regression model with
between-group differences expressed using an unadjusted OR
and 95% CI, for which values less than 1.0 indicate a lower odds
of AKI or death with cefepime compared with piperacillin-
tazobactam. Major adverse kidney events were compared
between groups using an unadjusted logistic regression model.
Days alive and free of delirium and coma were compared be-
tween groups using an unadjusted proportional odds regres-
sion model.
As a secondary analysis, an adjusted analysis of the pri-
mary outcome was performed using a multivariable propor-
tional odds regression model with prespecified baseline co-
variates including age, sex, baseline creatinine level, prior
receipt of KRT, receipt of vasopressors, receipt of mechanical
ventilation, Sequential Organ Failure Assessment score, pre-
sumed source of infection, and location at enrollment. Simi-
lar variables were used for the adjusted analyses of the sec-
ondary outcomes.
Prespecified sensitivity analyses included (1) an analysis
of all enrolled patients, including those who never received
cefepime or piperacillin-tazobactam; (2) an analysis re-
stricted to patients who received treatment with cefepime or
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Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection
piperacillin-tazobactam for more than 48 hours (greater ex-
posure to the antibiotics under study); (3) an analysis remov-
ing race as a variable in the equation to calculate creatinine for
those without measurement of creatinine level prior to the cur-
rent illness; (4) an analysis restricted to patients with a mea-
sured creatinine level prior to the current hospitalization; and
(5) an analysis using only the preillness creatinine level as the
baseline creatinine level.
In accordance with published guidelines,25 we examined
whether the prespecified baseline variables modified the
effect of trial group assignment on the primary and second-
ary outcomes using models with independent variables for
each trial group, the proposed effect modifier, and the inter-
action between the 2 (eMethods in Supplement 2). The base-
line variables prespecified as potential effect modifiers
included presence of sepsis, source of infection, receipt of
vancomycin on the day of enrollment, chronic kidney dis-
ease, presence and stage of AKI at enrollment, and admitting
service (medical or surgical).
When data were missing for the secondary or exploratory
outcomes, a complete case analysis was performed, exclud-
ing cases in which data were missing for the analyzed out-
come. Missing data were not imputed for these outcomes
(eMethods in Supplement 2).
The data and safety monitoring board reviewed a single
planned interim analysis after enrollment of the first 1025 pa-
tients, with a stopping boundary of P ≤ .001 for the between-
group difference in the primary outcome. For the final analy-
sis of the primary outcome, a 2-sided P value of less than .05
was considered to indicate statistical significance.26 Between-
group differences in the secondary and exploratory out-
comes are reported as point estimates and 95% CIs. The widths
of the 95% CIs for the secondary analyses were not adjusted
for multiplicity and should not be used to infer definitive
between-group differences in the treatment effects. All analy-
ses were performed with R version 4.2.2 (R Foundation for
Statistical Computing).
Results
Trial Population
Among 3806 patients who met inclusion criteria, 1172
(30.8%) were excluded. Of the 2634 patients (69.2%)
enrolled, 4 (0.2%) were incarcerated and excluded from sub-
sequent data collection and analysis and 119 (4.5%) did not
receive a dose of cefepime or piperacillin-tazobactam during
the 7 days after enrollment and were not included in the pri-
mary analysis. A total of 2511 patients (95.3%) were included
in the primary analysis (Figure 1). The median age was 58
years (IQR, 43-69 years), 2378 patients (94.7%) were enrolled
in the ED, and the median time between presentation to the
hospital and enrollment was 1.2 hours (IQR, 0.4-3.5 hours).
At the time of enrollment, 1362 patients (54.2%) had sepsis
and the most common suspected sources of infection were
intra-abdominal and pulmonary. A total of 1214 patients
(48.3%) in the cefepime group and 1297 patients (51.7%)
in the piperacillin-tazobactam group were included in the
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 Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection
primary analysis (Table 1 and eTables 1-6 in Supplement 2).
The final date of follow-up was November 4, 2022.
Antibiotic Therapy
In the 14 days after enrollment, 1154 of 1214 patients (95.1%) in
the cefepime group received at least 1 dose of cefepime and 1276
of 1297 patients (98.4%) in the piperacillin-tazobactam group
received at least 1 dose of piperacillin-tazobactam. Patients re-
ceived the assigned antibiotic for a median of 3 days (IQR, 1-4
days) in each group (Figure 2 and eFigures 1-2 and eTables 7-8
in Supplement 2). In the 14 days after enrollment, 228 of 1214
patients (18.8%) in the cefepime group received at least 1 dose
of piperacillin-tazobactam and 223 of 1297 patients (17.2%) in
the piperacillin-tazobactam group received at least 1 dose of
cefepime. A total of 85 patients (7.0%) in the cefepime group
and 92 patients (7.1%) in the piperacillin-tazobactam group re-
ceived other extended-spectrum gram-negative antibiotics,
most commonly an aminoglycoside or carbapenem.
A total of 942 patients (77.6%) in the cefepime group and
997 patients (76.9%) in the piperacillin-tazobactam group
were receiving intravenous vancomycin at the time of enroll-
ment. In the first 14 days, at least 1 dose of vancomycin was
received by 1004 patients (82.7%) in the cefepime group and
1049 patients (80.9%) in the piperacillin-tazobactam group.
Patients received vancomycin for a median duration of 2 days
(IQR, 1-4 days).
Primary Outcome
The highest stage of AKI or death by day 14 did not signifi-
cantly differ between the cefepime group and the piperacillin-
tazobactam group (OR, 0.95 [95% CI, 0.80 to 1.13], P = .56;
Table 2 and eTable 9 and eFigures 3-6 in Supplement 2). Of the
2511 patients included in the primary outcome analysis, 75.0%
in the cefepime group (910 of 1214) vs 73.4% in the piperacillin-
tazobactam group (952 of 1297) did not die or experience AKI
of any stage by day 14; 7.1% (n = 86) vs 7.7% (n = 100), respec-
tively, experienced stage 1 AKI; 3.4% (n = 41) vs 5.4% (n = 70)
experienced stage 2 AKI; 7.0% (n = 85) vs 7.5% (n = 97) expe-
rienced stage 3 AKI; and 7.6% (n = 92) vs 6.0% (n = 78) died.
The results were similar in the adjusted analyses and in all
the prespecified sensitivity analyses, including among the
intention-to-treat population of all enrolled patients and
the analysis limited to the 1798 patients who received at least
48 hours of antipseudomonal antibiotic therapy (eTables 10-11
in Supplement 2). The results were also similar in all the post
hoc analyses, including an analysis limited to patients who re-
ceived at least 72 hours of antipseudomonal antibiotic therapy,
an analysis limited to patients who received at least 96 hours
of antipseudomonal antibiotic therapy, and an analysis ex-
cluding patients who were receiving KRT or who had AKI at
enrollment (eTables 11-13 in Supplement 2). The results of the
prespecified subgroup analyses appear in Figure 3 and eTable 14
in Supplement 2.
Secondary Outcomes
A total of 124 patients (10.2%) in the cefepime group and 114
patients (8.8%) in the piperacillin-tazobactam group experi-
enced a major adverse kidney event at day 14 (absolute differ-
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Original Investigation Research
ence, 1.4% [95% CI, −1.0% to 3.8%]; eTable 15 in Supple-
ment 2). Patients in the cefepime group experienced fewer days
alive and free of delirium and coma within 14 days compared
with patients in the piperacillin-tazobactam group (mean, 11.9
[SD, 4.6] days vs 12.2 [SD, 4.3] days, respectively; OR, 0.79 [95%
CI, 0.65 to 0.95]), consistent with a greater burden of de-
lirium, coma, or death in the cefepime group compared with
the piperacillin-tazobactam group.
A total of 252 patients (20.8%) in the cefepime group ex-
perienced coma or delirium between enrollment and day 14
compared with 225 patients (17.3%) in the piperacillin-
tazobactam group (absolute difference, 3.4% [95% CI, 0.3%-
6.6%]). The results were similar in the post hoc analyses of days
alive and free of delirium and coma within 14 days, adjusting
for receipt of sedation at enrollment (OR, 0.78 [95% CI, 0.62-
0.99]), baseline delirium and coma (OR, 0.80 [95% CI, 0.63-
1.01]), and using alternative definitions of delirium and coma
(eTables 16-20 in Supplement 2). The subgroup analyses of the
secondary outcomes appear in Figure 3 and eTables 21-22 in
Supplement 2.
Exploratory Outcomes
The trial groups did not differ with regard to the highest stage
of AKI or death at 7 days (OR, 0.99 [95% CI, 0.82 to 1.19]) or
major adverse kidney events at 7 days (absolute difference,
1.8% [95% CI, −0.4% to 3.9%]). Death by day 28 occurred in
104 patients (8.6%) in the cefepime group and 106 patients
(8.2%) in the piperacillin-tazobactam group (absolute differ-
ence, 0.4% [95% CI, −1.9% to 2.6%]). Kidney replacement
therapy was initiated by day 28 in 44 patients (3.9%) in the
cefepime group and 28 patients (2.3%) in the piperacillin-
tazobactam group (absolute difference, 1.6% [95% CI, 0.1% to
3.1%]). Indications for KRT were similar between groups
(eTable 23 in Supplement 2). Additional exploratory out-
comes, allergic drug reactions, and adverse events appear in
Table 2 and eTables 24-28 in Supplement 2.
Discussion
Among adults presenting to the hospital with suspected in-
fection in this pragmatic trial, the highest stage of AKI or death
did not differ between patients randomized to cefepime or
piperacillin-tazobactam. Patients randomized to cefepime ex-
perienced more neurological dysfunction, as measured by the
number of days alive and free of delirium and coma.
Prior preclinical and observational studies of the relation-
ship between piperacillin-tazobactam and AKI have yielded
conflicting results. Preclinical studies found piperacillin-
tazobactam decreased the secretion of creatinine into the urine
and increased creatinine levels in the blood by inhibiting or-
ganic anion transporters 1 and 3 on kidney tubular cells with-
out affecting glomerular filtration rate as measured by cysta-
tin C.27,28 Piperacillin-tazobactam was protective against
vancomycin-induced AKI in animal models.29,30
In contrast, some observational studies reported an
association between piperacillin-tazobactam and AKI in
hospitalized adults, particularly with concurrent receipt
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 Research Original Investigation Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection

Table 1. Patient Characteristics at Baseline

Cefepime Piperacillin-tazobactam
Patient characteristicsa (n = 1214) (n = 1297)
Age, median (IQR), y 57 (42 to 68) 59 (44 to 69) [n = 1296]
Sex, No. (%)
Female 523 (43.1) 548/1296 (42.3)
Male 691 (56.9) 748/1296 (57.7)
Race and ethnicity, No./total (%)
Hispanic 59/1186 (5.0) 73/1264 (5.8)
Non-Hispanic Black 190/1186 (16.0) 209/1264 (16.5)
Non-Hispanic White 913/1186 (77.0) 950/1264 (75.2)
Other raceb 24/1186 (2.0) 32/1264 (2.5)
Hours from hospital presentation to enrollment, median (IQR) 1.3 (0.5 to 3.7) 1.1 (0.4 to 3.2)
Location at enrollment, No. (%)
Emergency department 1135 (93.5) 1243 (95.8)
Intensive care unit 79 (6.5) 54 (4.2)
Sepsis, No. (%)c 658 (54.2) 704 (54.3)
Suspected source of infection at enrollment, No. (%)d
Intra-abdominal 319 (26.3) 293 (22.6)
Lung 257 (21.2) 300 (23.1)
Skin and soft tissue 201 (16.6) 245 (18.9)
Genitourinary 100 (8.2) 144 (11.1)
Other 104 (8.6) 97 (7.5)
Unknown 233 (19.2) 218 (16.8)
Sequential Organ Failure Assessment score, median (IQR)e 2 (0 to 5) 2 (0 to 4)
Type of treatment, No. (%)
Mechanical ventilation 110 (9.1) 95 (7.3)
Vancomycin on day of enrollment 942 (77.6) 997 (76.9)
Charlson Comorbidity Index, median (IQR)f 4 (2 to 7) [n = 1191] 4 (2 to 6) [n = 1276]
Chronic kidney disease, No./total (%)g 243/1191 (20.4) 259/1276 (20.3)
Assessment at enrollment, No. (%)h
No acute kidney injury 623 (51.3) 652 (50.3)
Stage 1 acute kidney injury 231 (19.0) 311 (24.0)
Stage 2 acute kidney injury 134 (11.0) 123 (9.5)
Stage 3 acute kidney injury 148 (12.2) 144 (11.1)
Prior receipt of kidney replacement therapy 78 (6.4) 67 (5.2)
(ineligible for acute kidney injury)
Creatinine level, median (IQR), mg/dLi
Lowest in prior 12 mo (between 365 d and 12 h before enrollment) 0.7 (0.6 to 0.8) [n = 1136] 0.8 (0.6 to 0.9) [n = 1229]
At enrollment 1.0 (0.8 to 1.6) [n = 1136] 1.0 (0.8 to 1.5) [n = 1229]
Richmond Agitation-Sedation Scale score, median (IQR)j 0 (−1 to 0) [n = 1158] 0 [n = 1211]
Coma, No. (%)j 84 (6.9) 77 (5.9)
Delirium, No. (%)k 62 (5.1) 51 (3.9)
SI conversion factor: To convert creatinine to μmol/L, multiply by 88.4. (from 1-6) based on the adjusted risk of mortality or resource use. The sum of
a
Additional baseline characteristics appear in eTable 1 in Supplement 2. all the weights results in a single comorbidity score that ranges from 0
b
(no comorbidities) to 37 (higher probability of death).
American Indian, Asian, Multiple, and Pacific Islander.
g
c Defined as the presence of 1 or more of the ICD-10 diagnoses codes associated
Defined according to the Sepsis-3 criteria.15
with chronic kidney disease.
d
Collected for 21 categories and condensed into these 6. “Other” includes bone h
Acute kidney injury stages are defined according to the Kidney Disease:
and joint, central nervous system, intravascular catheter, primary
Improving Global Outcomes criteria17 for creatinine level.
bloodstream, or other. “Unknown” was used when clinicians were uncertain
i
about the suspected source of infection at enrollment. Patients had not received kidney replacement therapy prior to enrollment.
j
e
Composed of scores from 6 organ systems and graded from 0 to 4 according to Scale assesses the level of alertness and agitated behavior; range, –5
the degree of organ dysfunction or failure. Scores range from 0 (no evidence of (unarousable) to 0 (alert and calm) to 4 (combative). Coma defined as −4 or
organ dysfunction or failure) to 24 (evidence of severe organ dysfunction or −5 on the Richmond Scale in the 12 hours before or 6 hours after enrollment.
k
failure) and were calculated using the data collected during the 6 hours prior to Defined as “positive” in the 12 hours before or 6 hours after enrollment.
enrollment or 12 hours after enrollment. Among patients not experiencing coma, a value of “negative” suggests
f
Based on the International Classification of Diseases, 10th Revision (ICD-10) delirium is not present.
diagnosis codes. Each comorbidity category has an associated weight

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 Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection
Figure 2. Receipt of Antibiotics by Group
A Randomized to cefepime
100
80
Patients, %
60
40
20
0 0
0 1 2 3 4 5 6 7
Study day
No. of patients alive and hospitalized
1214 1152 1052 908 743 617 512 439
Patients may have received both cefepime and piperacillin-tazobactam on a study day when switching from one antibiotic to the other; 32 patients (1.3%) received
both antibiotics on more than 1 consecutive study day.
of vancomycin, prompting the US Food and Drug Admin-
istration to add the following statement to the package
insert for piperacillin-tazobactam: “co-administration of
[piperacillin-tazobactam] with vancomycin may increase
the incidence of acute kidney injury.”31 The potential for
indication bias and unmeasured confounding in prior obser-
vational studies was addressed by the randomized clinical
trial design of the current study.
Piperacillin-tazobactam did not appear to affect the risk
of AKI at any of the measured time points, overall, or among
the 1939 patients receiving vancomycin at enrollment. We in-
cluded patients with preexisting AKI at enrollment because
these patients are at high risk of worsening kidney injury and
death, outcomes that could be affected by the choice of anti-
biotics. The results were similar, however, in the analyses in
which these patients were excluded.
Cefepime crosses the blood-brain barrier, 32 exhibits
concentration-dependent inhibition of γ-amino butyric acid
receptors,33 and has been reported in case series and cohort stud-
ies to be associated with neurotoxicity, including coma, de-
lirium, encephalopathy, and seizures.34 Neurotoxicity with
cefepime has been reported to occur more commonly among
patients with impaired kidney function and conditions that dis-
rupt the blood-brain barrier, such as sepsis.34-36 In the current
trial, patients in the cefepime group experienced fewer days alive
and free of delirium and coma than patients in the piperacillin-
tazobactam group. Available data from preclinical studies,
observational studies, and the current randomized clinical trial
suggest that cefepime may modestly increase the risk of neu-
rological dysfunction in hospitalized adults.
This trial has several strengths. A large randomized clini-
cal trial embedded within real-world clinical care through the
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Original Investigation Research
Received cefepime
Received both cefepime and piperacillin-tazobactam
Received piperacillin-tazobactam
B Randomized to piperacillin-tazobactam
100
80
Patients, %
60
40
20
0 1 2 3 4 5 6 7
Study day
No. of patients alive and hospitalized
1297 1251 1147 970 823 679 563 460
electronic health record represents a rigorous approach to com-
paring the safety of 2 commonly used, effective treatment
options.37 The trial design included randomization to bal-
ance baseline characteristics, concealment of group assign-
ment until enrollment to prevent selection bias, and enroll-
ment occurring at a median of 1 hour after hospital presentation
to minimize exposure to antibiotics prior to enrollment. The
sample size permitted precise estimates of treatment effect,
overall, and among the 1939 patients receiving concurrent van-
comycin at enrollment.
Limitations
This trial has several limitations. First, conducting a trial at a
single academic center may limit generalizability. Second, pa-
tients and clinicians were not blinded to group assignment,
which could have affected clinical assessments like RASS and
CAM-ICU or the frequency of laboratory measurements like cre-
atinine, although the number of clinical and laboratory as-
sessments appeared to be similar between groups.
Third, almost 1 in 5 patients in each group received a least
1 dose of the unassigned antibiotic within the first 14 days,
which decreases the separation between groups and in-
creases the risk of failing to detect a true between-group dif-
ference in the outcomes (type II error). Fourth, a preillness cre-
atinine measure was not available for all patients, although
creatinine level was available prior to or at enrollment for 99%
of patients and the results were similar in the analyses re-
stricted to patients with available measurements.
Fifth, outcome assessment was censored at hospital dis-
charge. Sixth, patients in the trial received a median of only 3
days of treatment with cefepime or piperacillin-tazobactam;
however, the outcomes were similar among the 1798 patients
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 Research Original Investigation Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection

Table 2. Primary, Secondary, and Exploratory Outcomes

Between-group difference
Cefepime Piperacillin-tazobactam expressed as RD or OR
(n = 1214) (n = 1297) (95% CI)a
Primary outcome
Acute kidney injury or death by day 14, No. (%) OR, 0.95 (0.80 to 1.13)
No stage (survived) 910 (75.0) 952 (73.4)
Stage 1 (survived) 86 (7.1) 100 (7.7)
Stage 2 (survived) 41 (3.4) 70 (5.4)
Stage 3 (survived) 85 (7.0) 97 (7.5)
Stage 4 (died) 92 (7.6) 78 (6.0)
Secondary outcomes
Major adverse kidney events at day 14, No. (%)b 124 (10.2) 114 (8.8) RD, 1.4 (−1.0 to 3.8)
Death, No. (%) 92 (7.6) 78 (6.0) RD, 1.6 (−0.5 to 3.6)
New kidney replacement therapy, No./total (%) 37/1136 (3.3) 28/1230 (2.3) RD, 1.0 (−0.4 to 2.4)
Final creatinine level ≥2 times the baseline level, 15/1136 (1.3) 29/1230 (2.4) RD, −1.0 (−2.2 to 0.1)
No./total (%)
Delirium- and coma-free days within 14 dc
Median (IQR) 14 (14 to 14) 14 (14 to 14)
OR, 0.79 (0.65 to 0.95)
Mean (SD) 11.9 (4.6) 12.2 (4.3)
d
Delirium, No. (%) 200 (16.5) 181 (14.0) RD, 2.5 (−0.4 to 5.4)
Coma, No. (%)d 164 (13.5) 162 (12.5) RD, 1.0 (−1.7 to 3.7)
Delirium or coma, No. (%)d 252 (20.8) 225 (17.3) RD, 3.4 (0.3 to 6.6)
Exploratory outcomes
Major adverse kidney events at day 28, No. (%)b 135 (11.1) 132 (10.2) RD, 0.9 (−1.6 to 3.4)
Death, No. (%) 104 (8.6) 106 (8.2) RD, 0.4 (−1.9 to 2.6)
New kidney replacement therapy, No./total (%) 44/1136 (3.9) 28/1230 (2.3) RD, 1.6 (0.1 to 3.1)
Final creatinine level ≥2 times the baseline level, 14/1136 (1.2) 26/1230 (2.1) RD, −0.9 (−2.0 to 0.2)
No./total (%)
Delirium- and coma-free days within 28 dc
Median (IQR) 28 (28 to 28) 28 (28 to 28)
OR, 0.80 (0.66 to 0.97)
Mean (SD) 24.4 (8.6) 24.8 (8.2)
Kidney replacement therapy–free days within 28 dc
Median (IQR) 28 (28 to 28) 28 (28 to 28)
OR, 0.78 (0.62 to 0.98)
Mean (SD) 24.4 (9.1) 25.0 (8.5)
Vasopressor-free days within 28 dc
Median (IQR) 28 (28 to 28) 28 (28 to 28)
OR, 0.96 (0.80 to 1.16)
Mean (SD) 24.8 (8.3) 25.1 (7.9)
Ventilator-free days within 28 dc
Median (IQR) 28 (28 to 28) 28 (28 to 28)
OR, 0.84 (0.68 to 1.03)
Mean (SD) 24.8 (8.4) 25.0 (8.2)
Intensive care unit–free days within 28 dc
Median (IQR) 28 (25 to 28) 28 (26 to 28)
OR, 0.92 (0.77 to 1.09)
Mean (SD) 23.9 (8.6) 24.2 (8.4)
Hospital-free days within 28 dc
Median (IQR) 22 (15 to 24) 22 (15 to 24)
OR, 0.99 (0.86 to 1.13)
Mean (SD) 18.1 (8.6) 18.3 (8.5)
Allergic reaction to study antibiotic, No. (%)e 16 (1.3) 15 (1.2) RD, 0.2 (−0.8 to 1.1)
a c
The absolute risk difference (RD) or odds ratio (OR). The ORs were generated An OR greater than 1.0 indicates a better outcome (eg, more days alive and
by a proportional odds model. free from mechanical ventilation) with cefepime compared with
b
Defined as a composite of death, receipt of new kidney replacement therapy, piperacillin-tazobactam.
d
or final creatinine level that was at least 2 times the baseline level, with all Post hoc outcome that was included to characterize components of the
events censored at hospital discharge or at the study day of assessment, prespecified secondary outcome of delirium- and coma-free days.
whichever occurred first. The effect of study group on major adverse kidney e
Reported by the clinician via the trial’s electronic health record alert.
events was the conditional effect. Data on the receipt of new kidney
replacement therapy and final creatinine level that was at least 2 times the
baseline level are provided for the 2366 patients not known to have received
kidney replacement therapy before enrollment.

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 Figure 3. Effect Modification of the Primary and Secondary Outcomes

jama.com
Acute kidney
injury ordinal scale, Major adverse kidney events at Delirium- and coma-free
median (IQR)a Favors 14 d, No./total (%)b Favors days, median (IQR)c Favors
No. of Piperacillin- Favors piperacillin- Piperacillin- Favors piperacillin- Piperacillin- Favors piperacillin-
Subgroup patients Cefepime tazobactam cefepime tazobactam Cefepime tazobactam cefepime tazobactam Cefepime tazobactam cefepime tazobactam
Sepsis
Yes 1362 0 (0-2) 0 (0-2) 115/658 (17.5) 101/704 (14.3) 14 (8-14) 14 (11-14)
No 1149 0 0 9/556 (1.6) 13/593 (2.2) 14 (14-14) 14 (14-14)
Source of infection
Intra-abdominal 612 0 0 23/319 (7.2) 22/293 (7.5) 14 (14-14) 14 (14-14)
Lung 557 0 (0-2) 0 (0-1) 44/257 (17.1) 38/300 (12.7) 14 (8-14) 14 (11-14)
Skin and soft tissue 446 0 0 7/201 (3.5) 4/245 (1.6) 14 (14-14) 14 (14-14)
Urinary 244 0 (0-1) 0 (0-1) 5/100 (5) 9/144 (6.2) 14 (14-14) 14 (14-14)
Other 201 0 0 5/104 (4.8) 5/97 (5.2) 14 (14-14) 14 (14-14)
Unknownd 451 0 (0-1) 0 (0-2) 40/233 (17.2) 36/218 (16.5) 14 (9-14) 14 (10-14)
Vancomycin
Yes 1939 0 (0-1) 0 (0-1) 111/942 (11.8) 107/997 (10.7) 14 (12-14) 14 (14-14)
No 572 0 0 13/272 (4.8) 7/300 (2.3) 14 (14-14) 14 (14-14)
Chronic kidney disease
Yes 502 0 (0-1) 0 (0-2) 28/243 (11.5) 22/259 (8.5) 14 (14-14) 14 (14-14)
No 1965 0 0 95/948 (10) 92/1017 (9) 14 (14-14) 14 (14-14)
Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection

Acute kidney injurye

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No 1275 0 0 25/623 (4) 26/652 (4) 14 (14-14) 14 (14-14)
Stage 1 542 0 (0-1) 0 (0-1) 19/231 (8.2) 21/311 (6.8) 14 (14-14) 14 (14-14)
Stage 2 257 0 (0-3) 0 (0-2) 19/134 (14.2) 18/123 (14.6) 14 (9-14) 14 (10-14)
Stage 3 292 3 (0-3) 3 (0-3) 55/148 (37.2) 44/144 (30.6) 12 (0-14) 14 (2-14)
Prior kidney 145 0 0 6/78 (7.7) 5/67 (7.5) 14 (10-14) 14 (14-14)
replacement therapy
Admission type
Medical 1966 0 (0-1) 0 (0-1) 111/948 (11.7) 109/1018 (10.7) 14 (13-14) 14 (14-14)
Surgical 496 0 0 11/240 (4.6) 5/256 (2) 14 (14-14) 14 (14-14)
Post hoc subgroup

© 2023 American Medical Association. All rights reserved.

Coma
Yes 161 3 (0-4) 2 (0-4) 42/84 (50) 34/77 (44.2) 0 (0-8) 2 (0-10)
No 2350 0 0 82/1130 (7.3) 80/1220 (6.6) 14 (14-14) 14 (14-14)
Overall 2511 0 (0-1) 0 (0-1) 124/1214 (10.2) 114/1297 (8.8) 14 (14-14) 14 (14-14)

0.2 1 4 0.2 1 8 4 2 1 0.5 0.3

OR (95% CI) OR (95% CI) OR (95% CI)

c
The results of tests for interaction appear in eTables 14, 21, and 22 in Supplement 2. The number of days from randomization to day 14. An OR >1.0 indicates a better outcome with cefepime.
a d
The primary outcome was the highest stage or death by day 14 (score range, 0 [alive without acute kidney Clinician uncertain about the suspected source of infection at enrollment.
injury] to 4 [dead]). An odds ratio (OR) <1.0 indicates a better outcome with cefepime. e
Presence or absence at enrollment.
b
Defined as a composite of death, receipt of new kidney replacement therapy, or final creatinine level that was at
least 2 times the baseline level. An OR <1.0 indicates a better outcome with cefepime.

(Reprinted) JAMA October 24/31, 2023 Volume 330, Number 16

Original Investigation Research

1565
 Research Original Investigation Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection

who received longer courses of therapy. Seventh, the current
trial collected data on delirium and coma, but not other types
of neurological dysfunction that might be attributed to
cefepime, such as agitation, myoclonus, and seizures.
Eighth, unlike trials evaluating the effect of 1 treatment on
a single efficacy outcome, the current trial compared 2 treatments
with regard to 2 safety outcomes (kidney injury and neurologi-
cal dysfunction), which may increase the risk of type I error but
for which guidance on addressing multiplicity is lacking.38 Ninth,
in the setting of this trial, piperacillin-tazobactam was admin-
istered as an extended infusion. These results may be less infor-
mative in settings that use a different approach.
Conclusion
Among hospitalized adults in this randomized clinical trial,
treatment with piperacillin-tazobactam did not increase the
incidence of AKI or death. Treatment with cefepime resulted
in more neurological dysfunction.

ARTICLE INFORMATION
Accepted for Publication: September 21, 2023.
Published Online: October 14, 2023.
doi:10.1001/jama.2023.20583
Author Affiliations: Division of Allergy, Pulmonary,
and Critical Care Medicine, Vanderbilt University
Medical Center, Nashville, Tennessee (Qian, Casey,
Seitz, Semler, Rice); Department of Bioinformatics,
Vanderbilt University Medical Center, Nashville,
Tennessee (A. Wright); Division of General Internal
Medicine, Vanderbilt University Medical Center,
Nashville, Tennessee (A. Wright, Marvi);
Department of Biostatistics, School of Medicine,
Vanderbilt University, Nashville, Tennessee (Wang,
Shotwell); Vanderbilt Institute for Clinical and
Translational Research, Vanderbilt University
Medical Center, Nashville, Tennessee (Siemann,
Dear, Self, Semler, Rice); Department of
Pharmaceutical Services, Vanderbilt University
Medical Center, Nashville, Tennessee (Stollings);
Department of Emergency Medicine, Vanderbilt
University Medical Center, Nashville, Tennessee
(Lloyd, Wrenn, Andereck, Han, Self); Division of
Infectious Diseases, Vanderbilt University Medical
Center, Nashville, Tennessee (Nelson, P. W. Wright);
Division of Nephrology and Hypertension,
Vanderbilt University Medical Center, Nashville,
Tennessee (Siew); Division of Acute Care Surgery,
Vanderbilt University Medical Center, Nashville,
Tennessee (Dennis); Geriatric Research, Education,
and Clinical Center, Tennessee Valley Healthcare
System, Nashville (Han).
Author Contributions: Dr Qian had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis. Drs Semler and Rice contributed
equally.
Concept and design: Qian, Casey, A. Wright, Wang,
Stollings, Nelson, P. Wright, Siew, Wrenn, Andereck,
Han, Self, Semler, Rice.
Acquisition, analysis, or interpretation of data: Qian,
Casey, A. Wright, Wang, Shotwell, Siemann, Dear,
Stollings, Lloyd, Marvi, Seitz, Nelson, Siew, Dennis,
Wrenn, Andereck, Han, Self, Semler, Rice.
Drafting of the manuscript: Qian, Casey, Nelson,
Semler.
Critical review of the manuscript for important
intellectual content: All authors.
Statistical analysis: Casey, Wang, Shotwell, Seitz,
Nelson, Semler.
Obtained funding: Qian, Semler.
Administrative, technical, or material support:
Casey, A. Wright, Siemann, Dear, Stollings, Marvi,
Seitz, Wrenn, Andereck, Self, Semler, Rice.
Supervision: Casey, A. Wright, Nelson, P. Wright,
Dennis, Han, Self, Semler, Rice.
Conflict of Interest Disclosures: Dr Casey reported
receiving a travel grant from Fisher & Paykel
Healthcare to speak at conference. Dr P. Wright
reported receiving travel support from the
Infectious Diseases Society of America for travel to
the national meeting and for being a committee
member. Dr Siew reported receiving personal fees
from the American Society of Nephrology for
serving on its editorial board and from Novartis for
serving on a data and safety monitoring board and
receiving royalties from UptoDate. Dr Dennis
reported receiving travel support as the chair of the
Eastern Association for Surgery of Trauma annual
scientific assembly committee. Dr Wrenn reported
receiving unrelated research support from Bristol
Myers Squibb. Dr Semler reported serving as an
advisory board member for Baxter International.
Dr Rice reported receiving honoraria from the
American College of Chest Physicians and the
American Society of Parenteral and Enteral
Nutrition and personal fees from Cumberland
Pharmaceuticals, Cytovale, and Sanofi. No other
disclosures were reported.
Funding/Support: Drs Qian and Seitz were
supported by grant T32HL087738-17 from the
National Heart, Lung, and Blood Institute. Dr Casey
was supported in part by grant K23HL153584 from
the National Heart, Lung, and Blood Institute and
grants from the National Institutes of Health and
the US Department of Defense. The project was
supported by the Vanderbilt Institute for Clinical
and Translational Research and the Vanderbilt
Center for Learning Healthcare under Vanderbilt
Clinical and Translational Science awards 5UL1
TR002243-07 and 1U24TR004437 from the
National Center for Advancing Translational
Sciences (supported the work of Ms Wang and
Drs Siemann, Dear, Self, Semler, and Rice).
Dr Shotwell was supported by grants
R18HS025910, R01HL164909, R01HL161635,
R35GM145375, R18HS026158, R18HS026616,
R33HL155810, VUMC91864/OT2HL156812, and
U01HL168478 from the National Institutes of
Health. Dr Siew was supported by grant
P30-DK114809 from the Vanderbilt O’Brien Kidney
Center. Dr Semler was supported by grant
K23HL143053 from the National Heart, Lung, and
Blood Institute. Dr Rice was supported by grants
UL1 RR 024975 and U24 TR 001608 from the
National Center for Advancing Translational
Science.
Role of the Funder/Sponsor: The funders/
sponsors had no role in the design and conduct of
the study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Group Information: The members of the
Vanderbilt Center for Learning Healthcare and the
Pragmatic Critical Care Research Group appear in
Supplement 3.
Disclaimer: The views expressed in this article are
those of the authors and do not necessarily reflect
the official views of the National Center for
Advancing Translational Sciences or the National
Institutes of Health.
Meeting Presentation: Presented in part at
IDWeek 2023, a joint annual meeting of the
Infectious Diseases Society of America, the Society
for Healthcare Epidemiology of America, the HIV
Medicine Association, the Pediatric Infectious
Diseases Society, and the Society of Infectious
Diseases Pharmacists; October 14, 2023; Boston,
Massachusetts.
Data Sharing Statement: See Supplement 4.
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