Research

JAMA Pediatrics | Original Investigation

Association of Acute Kidney Injury With Concomitant

Vancomycin and Piperacillin/Tazobactam Treatment
Among Hospitalized Children
Kevin J. Downes, MD; Carter Cowden, MPH; Benjamin L. Laskin, MD, MS; Yuan-Shung Huang, MS; Wu Gong, MS, MPH; Matthew Bryan, PhD;
Brian T. Fisher, DO, MPH, MSCE; Stuart L. Goldstein, MD; Theoklis E. Zaoutis, MD, MSCE

Supplemental content
IMPORTANCE β-Lactam antibiotics are often coadministered with intravenous (IV)
vancomycin hydrochloride for children with suspected serious infections. For adults, the
combination of IV vancomycin plus piperacillin sodium/tazobactam sodium is associated with
a higher risk of acute kidney injury (AKI) compared with vancomycin plus 1 other β-lactam
antibiotic. However, few studies have evaluated the safety of this combination for children.

OBJECTIVE To assess the risk of AKI in children during concomitant therapy with vancomycin
and 1 antipseudomonal β-lactam antibiotic throughout the first week of hospitalization.

DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study focused on children
hospitalized for 3 or more days who received IV vancomycin plus 1 other antipseudomonal
β-lactam combination therapy at 1 of 6 large children’s hospitals from January 1, 2007,
through December 31, 2012. The study used the Pediatric Health Information System Plus
database, which contains administrative and laboratory data from 6 pediatric hospitals in the
United States. Patients with underlying kidney disease or abnormal serum creatinine levels on
hospital days 0 to 2 were among those excluded. Patients 6 months to 18 years of age who
were admitted through the emergency department of the hospital were included. Data were
collected from July 2015 to March 2016. Data analysis took place from April 2016 through
July 2017. (Exact dates are not available because the data collection and analysis processes
were iterative.)

MAIN OUTCOMES AND MEASURES The primary outcome was AKI on hospital days 3 to 7 and
within 2 days of receiving combination therapy. Acute kidney injury was defined using KDIGO
criteria and was based on changes in serum creatinine level from hospital days 0 to 2 through
hospital days 3 to 7. Multiple logistic regression was performed using a discrete-time failure
model to test the association between AKI and receipt of IV vancomycin plus
piperacillin/tazobactam or vancomycin plus 1 other antipseudomonal β-lactam antibiotic.

RESULTS A total of 1915 hospitalized children who received combination therapy were
identified. Of the 1915 patients, a total of 866 (45.2%) were female and 1049 (54.8%) were
male, 1049 (54.8%) were identified as white in race/ethnicity, and the median (interquartile
range) age was 56 (2.1-12.7) years. Among the cohort who received IV vancomycin plus 1 other
antipseudomonal β-lactam antibiotic, 157 patients (8.2%) had antibiotic-associated AKI. This
number included 117 of 1009 patients (11.7%) who received IV vancomycin plus
piperacillin/tazobactam combination therapy. After adjustment for age, intensive care unit
level of care, receipt of nephrotoxins, and hospital, IV vancomycin plus piperacillin/
tazobactam combination therapy was associated with higher odds of AKI each hospital day
compared with vancomycin plus 1 other antipseudomonal β-lactam antibiotic combination
(adjusted odds ratio, 3.40; 95% CI, 2.26-5.14).
Author Affiliations: Author
affiliations are listed at the end of this
CONCLUSIONS AND RELEVANCE Coadministration of IV vancomycin and piperacillin/ article.
tazobactam may increase the risk of AKI in hospitalized children. Pediatricians must be Corresponding Author: Kevin J.
cognizant of the potential added risk of this combination therapy when making empirical Downes, MD, Division of Infectious
antibiotic choices. Diseases, The Children’s Hospital of
Philadelphia, 2716 South St,
JAMA Pediatr. doi:10.1001/jamapediatrics.2017.3219 Ste 10360, Philadelphia, PA 19146
Published online October 2, 2017. (downeskj@email.chop.edu).

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 Research Original Investigation Acute Kidney Injury and Concomitant Vancomycin and Piperacillin/Tazobactam Treatment
H
ospitalized children commonly receive multiple
antibiotics.1,2 Although they are lifesaving in the set-
ting of severe infection and sepsis, some antibiotics
can result in acute kidney injury (AKI),3,4 which is associated
with an increased risk of chronic kidney disease and death in
children.5-8 Identifying antibiotic combinations with a de-
creased likelihood to cause AKI is important to reduce the nega-
tive sequelae among children treated for suspected serious in-
fection or sepsis.
Vancomycin hydrochloride and a broad-spectrum β-lactam
antibiotic are often administered in combination to empiri-
cally treat children admitted with suspected serious bacterial
infections. Vancomycin is the drug of choice for suspected se-
rious gram-positive infection, and the β-lactam antibiotic pro-
vides the necessary gram-negative coverage. Despite its ef-
fectiveness, vancomycin has been associated with AKI in up
to 22% of children,9-13 a risk that may increase in the setting
of concurrent administration of other nephrotoxic agents.9-13
Several adult studies have suggested that adding pipera-
cillin sodium/tazobactam sodium (TZP) to vancomycin in-
creases the risk of AKI, compared with the use of vancomycin
alone or in combination with certain β-lactam antibiotics.14-20
Limited data exist, however, on whether the combination of
TZP and vancomycin is associated with increased nephrotox-
icity in children.21,22 Using a large administrative data set, we
assessed the risk of AKI in children who concomitantly re-
ceived intravenous (IV) vancomycin plus an antipseudo-
monal β-lactam antibiotic during the first week of hospital-
ization. We hypothesized that the combination of vancomycin
and TZP is associated with an increased risk of AKI in chil-
dren. The results are immediately informative to clinicians ad-
ministering empirical antibiotics to children admitted with sus-
pected severe infection or sepsis.
Methods
Study Design and Data Source
We conducted a retrospective cohort study of hospitalized chil-
dren receiving IV vancomycin plus 1 antipseudomonal β-lactam
antibiotic at 6 large pediatric hospitals between January 1, 2007,
and December 31, 2012. These hospitals contribute adminis-
trative and laboratory data to the Pediatric Health Informa-
tion System Plus (PHIS+) database. The PHIS+ database incor-
porates the clinical and financial data contained in the Pediatric
Health Information System (PHIS),23 augmented with labora-
tory and radiology data of children seen in the ambulatory and
inpatient departments of the 6 hospitals. The Children’s Hos-
pital of Philadelphia Institutional Review Board has judged that
the PHIS+ database contains data that are not readily identi-
fiable, and thus its use exempts our study from the require-
ments for prospective review and approval. According to the
US Department of Health and Human Services Common Rule
45 CFR 46 and the policies of The Children’s Hospital of Phila-
delphia institutional review board, our research did not meet
the definition of human subjects research, and thus no pa-
tient informed consent was obtained. Data were collected from
July 2015 to March 2016. Data analysis took place from April
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Key Points
Question Is the combination of intravenous vancomycin
hydrochloride and piperacillin sodium/tazobactam sodium
associated with the development of acute kidney injury in
children?
Findings In this multicenter cohort study that included 1915
hospitalized children prescribed combination therapy, the
concomitant administration of intravenous vancomycin plus
piperacillin/tazobactam, compared with vancomycin plus other
antipseudomonal β-lactam antibiotics, was significantly associated
with an increased risk of acute kidney injury.
Meaning Pediatricians must be cognizant of the potential added
risk of this combination therapy when making empirical antibiotic
choices.
2016 through July 2017. (Exact dates are not available
because the data collection and analysis processes were
iterative.)
Study Population
We identified children 6 months to 18 years of age who were
admitted through the emergency department and were given
combination therapy, which consisted of IV vancomycin plus
1 antipseudomonal β-lactam agent (ceftazidime sodium,
cefepime hydrochloride, TZP, meropenem, or imipenem/
cilastin sodium), on at least days 1 and 2 of hospitalization; ti-
carcillin disodium/clavulanate potassium was not included be-
cause it was given infrequently (n = 9) and not at each hospital.
Because the first calendar day associated with a hospital ad-
mission is inherently less than 24 hours and antibiotics given
in the emergency department may differ from those admin-
istered when the child becomes an inpatient, the second cal-
endar day of an admission was considered hospital day 1. For
patients admitted more than once during the study period, only
the first admission was included.
We excluded patients who were hospitalized for fewer than
3 days; had an International Classification of Diseases, Ninth
Revision, Clinical Modification (ICD-9-CM) discharge diagno-
sis code of kidney disease other than acute renal failure, in-
cluding chronic kidney disease (580-583, 587, 590-2, 593.1,
593.3-5, 593.7-8; eTable 1 in the Supplement) or an ICD-9-CM
procedure code that may be associated with chronic kidney dis-
ease (39.27, 39.42-3, 39.50, 39.53, 39.93-4, 55.52-4, 55.6; eTable
1 in the Supplement); had an ICD-9-CM procedure code for di-
alysis (39.95 or 54.98) during the first 3 days of hospitaliza-
tion; or had an ICD-9-CM procedure code or charge for extra-
corporeal membrane oxygenation (36.95) during the first 7 days
of hospitalization. To reduce the potential for ascertainment
bias, the level of serum creatinine (SCr) had to be measured
(1) at least once during hospital days 0 to 2, (2) at least once
on hospital days 3 to 7, and (3) no fewer than every 4 days dur-
ing the hospitalization, as validated in the literature.24,25
Exposures
For our primary analysis, we grouped patients on the basis of
the combination therapy they received: vancomycin plus TZP
jamapediatrics.com
 Acute Kidney Injury and Concomitant Vancomycin and Piperacillin/Tazobactam Treatment
or vancomycin plus an antipseudomonal β-lactam antibiotic
(ceftazidime, cefepime, meropenem, or imipenem/cilastin). Pa-
tients who received multiple β-lactam agents plus vancomy-
cin on hospital day 1 or 2 were excluded. Because the choice
of antipseudomonal antibiotics may vary by hospital, the
groups were chosen owing to the similarity in their spectrum
of activity and clinical indications for the drugs they used. In
addition, children receiving non-antipseudomonal, as op-
posed to antipseudomonal, β-lactam agents likely differed at
baseline in several ways, such as severity of illness, number
of previous health care exposures, and underlying condi-
tions. Such differences could introduce bias in the compari-
son of cases of AKI between patients receiving vancomycin plus
TZP and patients receiving vancomycin plus any β-lactam an-
tibiotic.
Outcomes
For each patient, the presence or absence of AKI was deter-
mined each day using SCr data from hospital day 0 through
hospital day 7 (or discharge), whichever was sooner. The KDIGO
(Kidney Disease: Improving Global Outcomes) criteria were
used to define AKI26 as an increase in SCr level by 50% or higher
from baseline or by 0.3 mg/dL or higher (to convert to micro-
moles per liter, multiply by 88.4) within 2 hospital days or
fewer. The SCr level had to be 0.5 mg/dL to qualify as AKI if
the 50% change criterion was met. A SCr-based AKI defini-
tion was used because the PHIS+ database does not include
patient heights to allow for back calculation of the glomeru-
lar filtration rate; urine output was also not captured by the
PHIS+ database. Because laboratory data preceding admis-
sion were unavailable, the baseline SCr level was calculated
using the lowest SCr level on hospital days 0 to 2; the lowest
level was chosen to allow for minor perturbations in the ini-
tial SCr level measurement secondary to dehydration, which
can occur on presentation to care.
The primary outcome was antibiotic-associated AKI (AA-
AKI), defined as AKI occurring on any of hospital days 3 to 7
and within 2 days of the last administration of vancomycin plus
an antipseudomonal β-lactam antibiotic combination therapy.
Given that the primary exposure required combination therapy
on at least hospital days 1 and 2, AKI identified on hospital days
0 to 2 would, by definition, precede the exposure window.
Therefore, patients with AKI on hospital days 0 to 2 or a base-
line SCr level above the upper limit of published normal
values27 for age and sex were excluded.
Covariates
Demographic data, such as age, sex, and race, were collected
from the PHIS+ database. To account for variation in chronic
medical conditions, and identify patients with medical prob-
lems that precede hospitalization, complex chronic condi-
tion codes were derived using ICD-9-CM codes and dichoto-
mized as 0 to 1 or 2 or more. These codes have previously been
used to detect the presence of a chronic condition in a hospi-
talized patient.28
Because patients may present to the hospital with vary-
ing degrees of acuity of illness, data from the PHIS+ database
were leveraged to identify patients requiring intensive care unit
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Original Investigation Research
(ICU) level of care each day based on resource utilization and
any procedure associated with cardiovascular or respiratory
support (vasopressors or mechanical ventilation).29 Physical
admission locations were not used. Patients were catego-
rized based on the ICU level of care received at any time on hos-
pital days 0 to 2 or on any given hospital day.
Receipt of concomitant nephrotoxic medications (eTable
2 in the Supplement) the preceding day was categorized as
fewer than 2 vs 2 or more each day. Because the injurious out-
comes of nephrotoxins may be summative, continuous neph-
rotoxin exposure, defined as receipt of multiple nephrotoxic
medications for more than 2 consecutive days, was also iden-
tified. Intravenous contrast administration on the preceding
day was separately evaluated. Data on the first vancomycin
trough concentration for each patient on hospital day 1 or 2 were
also collected.
Statistical Analysis
Baseline (hospital days 0 to 2) characteristics of patients
with or without subsequent AA-AKI were compared using
the Wilcoxon rank sum test for continuous variables and the
χ2 tests for categorical variables. Baseline characteristics
were also compared across the combination therapy groups.
Temporal trends in AA-AKI incidence were assessed using
negative binomial regression to evaluate AA-AKI by each
year of the study. Median vancomycin trough concentra-
tions were compared for the subset with available data, as
were the proportions of patients in each combination
therapy group with a first vancomycin trough more than 15
μg/mL and more than 20 μg/mL (to convert to micromoles
per liter, multiply by 0.690).
We performed multiple logistic regression using a discrete-
time failure model to test the association between AA-AKI on
any given hospital day and receipt of either vancomycin plus
TZP or vancomycin plus another 1 antipseudomonal β-lactam
antibiotic. Time was modeled using a day indicator. Patients
contributed days to the model until the detection of AA-AKI,
hospital day 7, or 2 days after the end of vancomycin plus an
antipseudomonal β-lactam agent combination therapy, which-
ever occurred first. The association between covariates and AA-
AKI was first evaluated using a model adjusting for the com-
bination therapy group and for hospital day. Then, the final
multivariable model was constructed, including ICU level of
care, exposure to concomitant nephrotoxic medications, and
hospital that admitted the patient a priori, along with other co-
variates if P < .20 or if inclusion resulted in a change in the point
estimate of the combination therapy group by 10% or more.
We did not evaluate vancomycin trough concentrations be-
cause we could not verify through the PHIS+ database the tim-
ing of measurement of the preceding doses. To evaluate the
potential influence of confounding by an unmeasured covar-
iate on the observed measure of association between the com-
bination therapy group and AA-AKI, we conducted a quanti-
tative sensitivity analysis (eAppendix in the Supplement).30,31
In addition, we examined the influence of our definition of
baseline SCr level by repeating the multivariable analysis in a
subset of patients whose SCr level measurements on hospital
days 0 to 2 were less than the median for age and sex.27
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 Research Original Investigation Acute Kidney Injury and Concomitant Vancomycin and Piperacillin/Tazobactam Treatment

Table 1. Baseline (Hospital Days 0 to 2) Characteristics of Patients With or Without AA-AKI Who Received
Vancomycin Hydrochloride Plus 1 Antipseudomonal β-Lactam Agent

Patients, No. (%)a

Without AA-AKI With AA-AKI
Variable (n = 1758) (n = 157) P Value
Sex
Female 792 (91.5) 74 (8.6) .62
Male 966 (92.1) 83 (7.9)
Race
White 960 (91.5) 89 (8.5)
Black 144 (92.3) 12 (7.7) .88
Other, mixed race, or unknown 654 (92.1) 56 (7.9)
Ethnicity
Hispanic or Latino 143 (94.1) 9 (5.9)
.29
Not Hispanic or Latino/unknown 1615 (91.6) 148 (8.4)
Age, median (IQR), y 5.03 12.64 <.001
(1.97-11.81) (7.92-15.82)
Required ICU level of care on hospital days 0-2 497 (88.1) 67 (11.9)
<.001
Required no ICU level of care 1261 (93.3) 90 (6.7)
Had ≥2 complex or chronic conditions 932 (90.8) 95 (9.3)
.07
Had 0-1 complex or chronic conditions 826 (93.0) 62 (7.0)
Received ≥2 concomitant nephrotoxins on hospital days 0-2 319 (88.9) 40 (11.1)
.02
Received 0-1 nephrotoxin on hospital days 0-2 1439 (92.5) 117 (7.5)
Received IV contrast on hospital days 0-2 168 (87.1) 25 (13.0)
.01
Received no IV contrast 1590 (92.3) 132 (7.7)
Year of study
2007 252 (91.6) 23 (8.4)
2008 270 (93.4) 19 (6.6)
2009 267 (91.1) 26 (8.9)
.89
2010 325 (90.8) 33 (9.2)
2011 312 (92.0) 27 (8.0)
2012 332 (92.0) 29 (8.0)
PHIS hospital
1 230 (94.7) 13 (5.4) Abbreviations: AA-AKI,
antibiotic-associated acute kidney
2 541 (90.3) 58 (9.7)
injury; ICU, intensive care unit;
3 412 (90.6) 43 (9.5) IQR, interquartile range; IV,
.04
4 116 (88.6) 15 (11.5) intravenous; PHIS, Pediatric Health
Information System.
5 322 (93.6) 22 (6.4)
a
Percentages are based on the total
6 137 (95.5) 6 (4.2)
for each row.

Hospital outcomes (length of stay and in-hospital mortal-
ity) of patients with or without AA-AKI were compared using
the Wilcoxon rank sum test and the χ2 tests, respectively. Mul-
tiple logistic regression determined the association of AA-AKI
with in-hospital mortality, adjusting for the combination
therapy group and other baseline (hospital days 0-2) covari-
ates if P < .20 or if inclusion resulted in a change in the point
estimate of AA-AKI by 10% or more. P < .05 was considered
significant, and all P values reported were 2-sided. All analy-
ses were performed using Stata, version 13.1 (StataCorp LLC).
Results
We identified 1915 admissions of patients who received the IV
vancomycin plus a β-lactam agent combination therapy on at
least hospital days 1 and 2 during the study period (eFigure in
the Supplement). Of the 1915 patients, a total of 866 (45.2%) were
female and 1049 (54.8%) were male, 1049 (54.8%) were identi-
fied as white in race/ethnicity, and the median age was 5.60 years
(interquartile range [IQR], 2.12-12.65 years). In this combina-
tion therapy cohort, 157 patients (8.2%) developed AA-AKI within
the first hospital week, and 74 (47%) of these patients had
KDIGO26 stage 2 AKI or higher. Table 1 displays the baseline char-
acteristics of patients in the cohort with AA-AKI and patients in
the cohort without AA-AKI. The incidences of AA-AKI were simi-
lar across the years of the study, ranging from 19 (6.6%) in 2008
to 33 (9.2%) in 2010 (P = .89); no trend by study year was ob-
served (negative binomial regression P = .85). Recipients of IV
vancomycin plus a β-lactam agent who sustained AA-AKI, com-
pared with those who did not, were older (median age, 12.64
years [IQR, 7.92-15.82 years] vs 5.03 years [IQR, 1.97-11.81 years];
P < .001), more often required ICU level of care on hospital days
0 to 2 (67/157 [42.7%] vs 497/1758 [28.3%]; P < .001), and were

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 Acute Kidney Injury and Concomitant Vancomycin and Piperacillin/Tazobactam Treatment Original Investigation Research

Table 2. Unadjusted Frequency of AA-AKI Among Patients Who Received Combination Therapy on at Least
Hospital Days 1 and 2

Patients, No. (%)

Courses of Cumulative Incidence
Treatment of AA-AKI % Increase in SCr Level Among
β-Lactam Antibiotic (n = 1915) (n = 157) Those With AA-AKI, Median (IQR)
Piperacillin sodium/tazobactam 1009 117 (11.7) 67 (67-120)
sodium
Ceftazidime sodium 295 17 (5.8) 75 (55-200) Abbreviations: AA-AKI,
Cefepime hydrochloride 422 17 (4.0) 67 (60-120) antibiotic-associated acute kidney
injury; IQR, interquartile range;
Meropenem/imipenem 189 6 (3.2) 69 (43-133)
SCr, serum creatinine.

more often administered 2 or more nephrotoxic medications (40/ Figure. Kaplan-Meier Curves for Antibiotic-Associated Acute Kidney
157 [25.5%] vs 319/1758 [18.1%]; P = .02) or IV contrast on hos- Injury (AA-AKI)–Free Survival in Hospitalized Children
pital days 0 to 2 (25/157 [15.9%] vs 168/1758 [9.6%]; P = .01). The
AA-AKI incidences across the 6 hospitals ranged from 6 pa- 100

tients (4.2%) to 15 patients (11.5%) (P < .001).

Among recipients of any combination therapy on at least

AA-AKI–Free Survival, %
95
hospital days 1 and 2, AA-AKI was detected most often in re-
cipients of vancomycin plus TZP (117 [11.7%]; Table 2). The
90
Figure displays a Kaplan-Meier graph of AA-AKI–free sur-
vival for each combination therapy group. Baseline character- Vancomycin hydrochloride
istics of recipients of combination therapy are shown in Table 3. 85 plus 1 other antipseudomonal
β-lactam agent
The duration of combination therapy and the number of SCr
Vancomycin plus TZP
level measurements were similar among the combination
80
therapy groups. Among the subset of patients with vancomy- 0 1 2 3 4 5 6 7
cin trough concentrations available on day 1 or 2 (1177 [61.5%]), Hospital Day
No. at risk
the median initial troughs were similar between those who re- Other agents 906 906 906 906 825 536 328 219
ceived IV vancomycin plus TZP and those who received van- TZP 1009 1009 1009 1009 883 570 342 226
comycin plus 1 other antipseudomonal β-lactam agent (7.5
Combination therapy was administered to children during the first week of
μg/mL [IQR, 5.0-10.7 μg/mL] vs 7.1 μg/mL [IQR, 5.2-10.2 μg/
hospitalization. TZP indicates piperacillin sodium/tazobactam sodium.
mL]; P = .62; eTable 3 in the Supplement).
On multivariable analysis using a discrete-time failure potential for nephrotoxicity. When serious infections are sus-
model, receipt of IV vancomycin plus TZP combination therapy pected, vancomycin and a β-lactam agent are often coadmin-
was associated with increased odds of AA-AKI each hospital istered to provide appropriate empirical broad-spectrum cov-
day (adjusted odds ratio [aOR], 3.40; 95% CI, 2.26-5.14; erage until a pathogen is identified. Understanding how the
Table 4). These findings were robust for the addition of an un- nephrotoxic potential of vancomycin is altered by the choice
measured confounder to the model across a range of plau- of β-lactam agent can inform empirical antibiotic decisions that
sible clinical scenarios (eTable 4 in the Supplement). In a sen- will reduce the risk for subsequent AKI. This study demon-
sitivity analysis of patients with a baseline SCr level less than strates that AKI in children receiving vancomycin appeared to
the median SCr level for age and sex, a similar association be- be increased by coadministration of TZP compared with simi-
tween IV vancomycin plus TZP combination therapy and lar-spectrum β-lactam antibiotics. Our findings are in keep-
AA-AKI was observed (aOR, 4.14; 95% CI, 2.34-7.33). ing with several recent studies in adults.14-19
Patients who sustained AA-AKI had increased length of stay Limited pediatric data are available, but previous investi-
(median, 13 days [IQR, 6-18 days] vs 10 days [IQR, 9-26 days]; gations have suggested an association between TZP and AKI
P < .001) and increased in-hospital mortality (7 of 157 [4.5%] vs during courses of vancomycin. Knoderer and colleagues32 re-
22 of 1758 [1.3%]; P = .002), compared with patients who did ported that among children administered vancomycin for 8
not sustain AA-AKI. On multiple logistic regression analysis, days or more, a higher percentage of patients experiencing AKI
AA-AKI, ICU level of care on hospital days 0 to 2, and 2 or more received concomitant TZP (62% vs 38%), although this differ-
nephrotoxins on hospital days 0 to 2 were associated with in- ence was not significant on multivariable analyses. McQueen
creased in-hospital mortality, whereas receiving combina- and Clark21 compared the incidence of AKI between children
tion therapy was not (eTable 5 in the Supplement). who received vancomycin alone (3.8%) and children who re-
ceived vancomycin plus TZP (23.6%). This difference was sig-
nificant in bivariate analysis, but a multivariate analysis was
not conducted. To our knowledge, no pediatric studies have
Discussion described an independent association of AKI with concur-
Vancomycin is an important antibiotic for treatment of gram- rent TZP and vancomycin administration. There is a risk of con-
positive infections, but clinicians need to be cognizant of its founding by indication, but sicker patients may have been more

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 Research Original Investigation Acute Kidney Injury and Concomitant Vancomycin and Piperacillin/Tazobactam Treatment

Table 3. Characteristics of Patients Who Received Combination Therapy

Patients, No. (%)a

Vancomycin Hydrochlordie Vancomycin Plus
Plus Piperacillin Sodium/ 1 Antipseudomonal
Tazobactam Sodium β-Lactam Agent
Variable (n = 1009) (n = 906) P Value
Sex
Female 447 (44.3) 419 (46.3)
.39
Male 563 (55.7) 487 (53.8)
Race
White 568 (56.3) 481 (53.1)
Black 81 (8.0) 75 (8.3) .36
Other, mixed race, or unknown 360 (35.7) 350 (38.6)
Hispanic or Latino ethnicity 64 (6.3) 88 (9.7) .006
Age, median (IQR), y 4.42 7.07 <.001
(1.56-11.47) (2.77-13.72)
Required ICU level of care on hospital days 0-2 367 (36.4) 197 (21.7) <.001
Had ≥2 complex or chronic conditions 557 (54.2) 470 (51.9) .15
Received ≥2 concomitant nephrotoxins on hospital 225 (22.3) 134 (14.8) <.001
days 0-2
Received IV contrast on hospital days 0-2 118 (11.7) 75 (8.3) .01
PHIS hospital
1 15 (1.5) 228 (25.2)
2 384 (38.1) 215 (23.7)
3 371 (36.8) 84 (9.3) <.001
4 41 (4.1) 90 (9.9) Abbreviations: AA-AKI,
5 133 (13.2) 211 (23.3) antibiotic-associated acute kidney
injury; ICU, intensive care unit;
6 65 (6.4) 78 (8.6) IQR, interquartile range; IV,
Patients with AA-AKI 117 (11.6) 40 (4.4) <.001 intravenous; PHIS, Pediatric Health
Information System; SCr, serum
AA-AKI onset, median (IQR), d 4 (3-5) 4 (3-6) .25
creatinine.
Duration of combination therapy, median (IQR), d 4 (3-7) 4 (3-7) .69 a
Percentages are based on the total
No. of SCr level measurements on hospital days 3-7, 2 (1-4) 2 (1-3) .66 within each combination
median (IQR) therapy group.

likely to receive vancomycin plus TZP and thus were more likely
to sustain AKI. We attempted to address this by adjusting for
differences in patient characteristics and by comparing pa-
tients receiving similarly broad antibiotic coverage. Our re-
sults were also robust to the potential for unmeasured con-
founding that explains the association between vancomycin
plus TZP combination therapy and AA-AKI.
The negative association of AKI with outcomes of hospi-
talized children receiving vancomycin has been well
documented.11-13 As in our study, AKI has been associated with
increased hospital length of stay and in-hospital mortality.11-13
Few therapeutic approaches exist to mitigate AKI secondary
to nephrotoxic medication exposure, aside from avoidance of
these potentially injurious agents.
With limited alternatives to vancomycin for treatment of
serious gram-positive infections, knowledge that concomi-
tant TZP use carries an added risk of nephrotoxicity for chil-
dren may help guide empirical β-lactam antibiotic selection.
When adequate substitutes to TZP exist, other broad-
spectrum β-lactam antibiotics should be considered. In set-
tings where TZP and vancomycin are both needed, clinicians
should make efforts to limit the duration of combination
therapy. Other β-lactam agents may less often be associated
with AKI, but additional studies should evaluate how these an-
tibiotics are associated with the development of other ad-
verse events, such as Clostridium difficile infection, and anti-
microbial resistance.
The mechanism by which TZP and vancomycin cause
greater nephrotoxicity is unknown. Piperacillin inhibits tubu-
lar secretion and clearance of other drugs, and an interaction
between piperacillin and vancomycin may contribute to toxic
consequences for proximal tubule cells.33,34 Rutter et al18 re-
ported that the incidence of AKI in adults receiving vancomy-
cin plus either TZP or cefepime increased with higher dos-
ages of TZP but not of vancomycin or cefepime. This finding
suggests that TZP plays an important additive or synergistic
role in vancomycin nephrotoxicity. However, because the
PHIS+ data set does not include medication dosing informa-
tion, we could not investigate the association between anti-
biotic dosage and AKI. Future studies need to determine the
association between vancomycin and TZP dosing and subse-
quent AKI in children.
Higher vancomycin trough serum concentrations are as-
sociated with vancomycin nephrotoxicity in children.9,10,13 For
the subset of patients with initial vancomycin trough levels
available in our study, trough concentrations were similar
across the combination therapy groups. However, we did not
incorporate trough concentrations into multivariable analy-

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 Acute Kidney Injury and Concomitant Vancomycin and Piperacillin/Tazobactam Treatment Original Investigation Research

Table 4. Discrete-Time Failure Models of AA-AKI in Patients Who Received IV Vancomycin Hydrochloride Plus 1
Antipseudomonal β-Lactam Antibiotic

Covariate OR (95% CI)a aOR (95% CI)b

Vancomycin plus
1 other antipseudomonal β-lactam agent 1 [Reference] 1 [Reference]
Piperacillin sodium/tazobactam sodium 2.64 (1.83-3.79) 3.40 (2.26-5.14)
Female sex 1.06 (0.77-1.46)
Race
Other, mixed race, or unknown 1 [Reference]
White 1.06 (0.76-1.49)
Black 1.13 (0.60-2.13)
Hispanic or Latino ethnicity 0.77 (0.39-1.53)
Age in years 1.14 (1.12-1.17) 1.15 (1.12-1.18)
Presence of ≥2 complex or chronic conditions 1.16 (0.83-1.60)
Receipt of ≥2 concomitant nephrotoxins on hospital days 0-2 1.17 (0.81-1.70)
Receipt of ≥2 concomitant nephrotoxins on the preceding hospital day 1.12 (0.73-1.73)
Receipt of ≥2 nephrotoxins for >2 consecutive days 1.36 (0.80-2.31) 1.50 (0.87-2.16)
Receipt of IV contrast on hospital days 0-2 1.32 (0.85-2.06)
Receipt of IV contrast on the preceding hospital day 0.49 (0.12-2.00)
Requirement of ICU level of care on hospital days 0-2 1.31 (0.95-1.80)
Requirement of ICU level of care on a given day 1.42 (1.01-2.00) 1.46 (0.99-2.16)
Receipt of mechanical ventilation on a given day 1.22 (0.85-1.76)
Receipt of vasopressors on a given day 1.68 (0.98-2.88)
Year of study
2007 1 [Reference]
2008 0.71 (0.38-1.32)
2009 1.12 (0.63-1.98)
2010 1.15 (0.67-1.99) Abbreviations: AA-AKI,
2011 0.93 (0.52-1.63) antibiotic-associated acute kidney
injury; aOR, adjusted odds ratio; ICU,
2012 1.01 (0.58-1.63) intensive care unit; IV, intravenous;
PHIS hospital OR, odds ratio; PHIS, Pediatric Health
1 1 [Reference] 1 [Reference] Information System.
a
Models adjusted for combination
2 0.76 (0.39-1.45) 0.90 (0.47-1.74)
therapy group and hospital day,
3 0.59 (0.30-1.14) 0.69 (0.34-1.39) along with specific covariate being
4 1.79 (0.83-3.87) 1.88 (0.84-4.21) tested.
b
5 0.66 (0.83-3.88) 0.66 (0.31-1.34) Receipt of nephrotoxins, ICU level of
care, and PHIS hospital included in
6 0.40 (0.15-1.08) 0.40 (0.15-1.10)
the final model a priori, along with
Hospital day covariates with P < .20 or that
3 1 [Reference] 1 [Reference] caused a 10% change in the point
estimate of combination therapy
4 0.61 (0.41-0.93) 0.63 (0.41-0.98)
group. Consecutive days of
5 0.71 (0.44-1.13) 0.70 (0.43-1.14) nephrotoxin receipt were most
6 0.89 (0.53-1.50) 0.89 (0.51-1.56) strongly associated with AA-AKI
among nephrotoxin covariates and
7 0.79 (0.41-1.52) 0.76 (0.38-1.49)
were included in the final model.

ses because of the lack of information about the timing of doses
in the PHIS+ database. We do not suspect that vancomycin
doses or trough goals vary by β-lactam agent coadministra-
tion, given that vancomycin serum trough concentrations have
been similar across combination therapy groups reported in
the adult literature.17,18,21
Limitations
This study has several limitations. To focus on the empirical
antibiotic decisions made on patient presentation, we
restricted our cohort to children admitted through the
emergency department and given combination therapy on
at least hospital days 1 and 2. Our results are not necessarily
generalizable to other clinical scenarios. For instance, the
risk factors for AKI in patients starting antimicrobial therapy
later during hospitalization may be different than in
patients who are treated on admission32; such patients may
be sicker or have more comorbidities. In addition, we lim-
ited our analysis to AKI onset in the first week of hospital-
ization. The factors influencing AKI may differ in children
with prolonged vancomycin administration, as suggested by
Knoderer et al.32

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 Research Original Investigation Acute Kidney Injury and Concomitant Vancomycin and Piperacillin/Tazobactam Treatment

Investigation of AKI using administrative data sets is
challenging. Certain variables, such as vital signs and fluid
status, are not included in the PHIS+ database. Reliance on
billing codes has low sensitivity and underestimates the
incidence of nephrotoxin-associated AKI in children.24,35 To
overcome this potential limitation, we leveraged a large
administrative database supplemented with laboratory data
and applied a systematic approach to defining AKI. This
method resulted in an estimated AKI incidence in our study
that is similar to that previously reported in the pediatric lit-
erature describing vancomycin nephrotoxicity. 10,36 The
method of SCr level measurement likely differs at each of
the 6 hospitals in this study, but the use of an AKI definition
based on percentage change in SCr level allows for more
consistent identification of AKI cases across all hospitals.
Through implementation of rigorous screening criteria, we
believe that we identified a cohort of hospitalized children
with normal baseline kidney function and accurately cap-
tured AA-AKI on days 3 to 7 after admission.
Conclusions
This large, multicenter study using both administrative and labo-
ratory data found that the combination of vancomycin and TZP
was associated with AKI in children during the first week of hos-
pitalization compared with vancomycin combined with 1 other
similar-spectrum β-lactam agent. Because of the deleterious con-
sequences of AKI, including increased length of stay and in-
hospital mortality, clinicians must be cognizant of the potential
added risk of this combination therapy when making empirical
antibiotic choices. Pediatricians must limit the duration of van-
comycin plus TZP combination therapy, as is feasible, and closely
monitor children for whom both of these drugs are necessary.

ARTICLE INFORMATION
Accepted for Publication: July 27, 2017.
Published Online: October 2, 2017.
doi:10.1001/jamapediatrics.2017.3219
Author Affiliations: Division of Infectious Diseases,
The Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania (Downes, Fisher,
Zaoutis); Center for Pediatric Clinical Effectiveness,
The Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania (Downes, Cowden,
Fisher, Zaoutis); The Pediatric Infectious Diseases
Epidemiology and Antimicrobial Stewardship
Research Group, The Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania (Downes,
Cowden, Fisher, Zaoutis); Department of Pediatrics,
Perelman School of Medicine, University of
Pennsylvania, Philadelphia (Downes, Laskin, Fisher,
Zaoutis); Division of Nephrology, The Children’s
Hospital of Philadelphia, Philadelphia, Pennsylvania
(Laskin); Healthcare Analytics Unit, The Children’s
Hospital of Philadelphia, Philadelphia, Pennsylvania
(Huang, Gong); Department of Biostatistics and
Epidemiology, Perelman School of Medicine,
University of Pennsylvania, Philadelphia (Bryan,
Fisher, Zaoutis); Division of Nephrology and
Hypertension, Cincinnati Children’s Hospital
Medical Center, Cincinnati, Ohio (Goldstein);
Department of Pediatrics, University of Cincinnati
College of Medicine, Cincinnati, Ohio (Goldstein).
Author Contributions: Dr Downes 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.
Study concept and design: Downes, Laskin, Fisher,
Goldstein, Zaoutis.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Downes.
Critical revision of the manuscript for important
intellectual content: Downes, Cowden, Gong,
Laskin, Huang, Bryan, Fisher, Goldstein, Zaoutis.
Statistical analysis: Downes, Cowden, Gong, Bryan.
Administrative, technical, or material support:
Downes, Cowden, Laskin, Huang.
Study supervision: Downes, Laskin, Fisher,
Goldstein, Zaoutis.
Conflict of Interest Disclosures: Dr Downes
reported receiving research support (unrelated to
this study) from Merck and Pfizer. Dr Fisher
reported receiving research support (unrelated to
this study) from Pfizer, Merck, Ansun Biopharma,
and T2 Biosystems. Dr Zaoutis reported providing
consultant services to T2 Biosystems and Nabriva
Therapeutics.
Funding/Support: Dr Laskin received support from
the National Institute of Diabetes and Digestive and
Kidney Diseases (grant K23-DK101600).
Role of the Funder/Sponsor: The funder 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.
Additional Contributions: Kelly Getz, PhD, MPH,
Children’s Hospital of Philadelphia, assisted with
bias analysis. Dr Getz received no compensation for
her contribution.
REFERENCES
1. Lasky T, Ernst FR, Greenspan J, Wang S, Gonzalez
L. Estimating pediatric inpatient medication use in
the United States. Pharmacoepidemiol Drug Saf.
2011;20(1):76-82.
2. Feudtner C, Dai D, Faerber J, Metjian TA, Luan X.
Pragmatic estimates of the proportion of pediatric
inpatients exposed to specific medications in the
USA. Pharmacoepidemiol Drug Saf. 2013;22(8):
890-898.
3. Pannu N, Nadim MK. An overview of
drug-induced acute kidney injury. Crit Care Med.
2008;36(4 suppl):S216-S223.
4. Patzer L. Nephrotoxicity as a cause of acute
kidney injury in children. Pediatr Nephrol. 2008;23
(12):2159-2173.
5. Menon S, Kirkendall ES, Nguyen H, Goldstein SL.
Acute kidney injury associated with high
nephrotoxic medication exposure leads to chronic
kidney disease after 6 months. J Pediatr. 2014;
165(3):522-527.
6. Alkandari O, Eddington KA, Hyder A, et al. Acute
kidney injury is an independent risk factor for
pediatric intensive care unit mortality, longer length
of stay and prolonged mechanical ventilation in
critically ill children: a two-center retrospective
cohort study. Crit Care. 2011;15(3):R146.
7. Sutherland SM, Byrnes JJ, Kothari M, et al. AKI in
hospitalized children: comparing the pRIFLE, AKIN,
and KDIGO definitions. Clin J Am Soc Nephrol. 2015;
10(4):554-561.
8. Akcan-Arikan A, Zappitelli M, Loftis LL,
Washburn KK, Jefferson LS, Goldstein SL. Modified
RIFLE criteria in critically ill children with acute
kidney injury. Kidney Int. 2007;71(10):1028-1035.
9. McKamy S, Hernandez E, Jahng M, Moriwaki T,
Deveikis A, Le J. Incidence and risk factors
influencing the development of vancomycin
nephrotoxicity in children. J Pediatr. 2011;158(3):
422-426.
10. Le J, Ny P, Capparelli E, et al. Pharmacodynamic
characteristics of nephrotoxicity associated with
vancomycin use in children. J Pediatric Infect Dis Soc.
2015;4(4):e109-e116.
11. Totapally BR, Machado J, Lee H, Paredes A,
Raszynski A. Acute kidney injury during vancomycin
therapy in critically ill children. Pharmacotherapy.
2013;33(6):598-602.
12. Seixas GT, Araujo OR, Silva DC, Arduini RG,
Petrilli AS. Vancomycin therapeutic targets and
nephrotoxicity in critically ill children with cancer.
J Pediatr Hematol Oncol. 2016;38(2):e56-e62.
13. Knoderer CA, Nichols KR, Lyon KC, Veverka
MM, Wilson AC. Are elevated vancomycin serum
trough concentrations achieved within the first 7
days of therapy associated with acute kidney injury
in children? J Pediatric Infect Dis Soc. 2014;3(2):127-
131.
14. Burgess LD, Drew RH. Comparison of the
incidence of vancomycin-induced nephrotoxicity in
hospitalized patients with and without concomitant
piperacillin-tazobactam. Pharmacotherapy.
2014;34(7):670-676.
15. Kim T, Kandiah S, Patel M, et al. Risk factors for
kidney injury during vancomycin and
piperacillin/tazobactam administration, including
increased odds of injury with combination therapy.
BMC Res Notes. 2015;8:579-589.
16. Fodero KE, Horey AL, Krajewski MP, Ruh CA,
Sellick JA Jr, Mergenhagen KA. Impact of an
antimicrobial stewardship program on patient
safety in veterans prescribed vancomycin. Clin Ther.
2016;38(3):494-502.

E8 JAMA Pediatrics Published online October 2, 2017 (Reprinted) jamapediatrics.com

© 2017 American Medical Association. All rights reserved.

Downloaded From: by a UNIVERSITY OF ADELAIDE LIBRARY User on 10/13/2017

 Acute Kidney Injury and Concomitant Vancomycin and Piperacillin/Tazobactam Treatment
17. Navalkele B, Pogue JM, Karino S, et al. Risk of
acute kidney injury in patients on concomitant
vancomycin and piperacillin-tazobactam compared
to those on vancomycin and cefepime. Clin Infect Dis.
2017;64(2):116-123.
18. Rutter WC, Cox JN, Martin CA, Burgess DR,
Burgess DS. Nephrotoxicity during vancomycin
therapy in combination with piperacillin-
tazobactam or cefepime. Antimicrob Agents
Chemother. 2017;61(2):e02089-16.
19. Gomes DM, Smotherman C, Birch A, et al.
Comparison of acute kidney injury during treatment
with vancomycin in combination with
piperacillin-tazobactam or cefepime.
Pharmacotherapy. 2014;34(7):662-669.
20. Hammond DA, Smith MN, Li C, Hayes SM,
Lusardi K, Bookstaver PB. Systematic review and
meta-analysis of acute kidney injury associated
with concomitant vancomycin and
piperacillin/tazobactam. Clin Infect Dis. 2017;64(5):
666-674.
21. McQueen KE, Clark DW. Does combination
therapy with vancomycin and piperacillin-
tazobactam increase the risk of nephrotoxicity
versus vancomycin alone in pediatric patients?
J Pediatr Pharmacol Ther. 2016;21(4):332-338.
22. LeCleir LK, Pettit RS. Piperacillin-tazobactam
versus cefepime incidence of acute kidney injury in
combination with vancomycin and tobramycin in
pediatric cystic fibrosis patients. Pediatr Pulmonol.
2017;52(8):1000-1005.
23. Cameron DB, Graham DA, Milliren CE, et al.
Quantifying the burden of interhospital cost
jamapediatrics.com
© 2017 American Medical Association. All rights reserved.
Downloaded From: by a UNIVERSITY OF ADELAIDE LIBRARY User on 10/13/2017
variation in pediatric surgery: implications for the
prioritization of comparative effectiveness
research. JAMA Pediatr. 2017;171(2):e163926.
24. Schaffzin JK, Dodd CN, Nguyen H,
Schondelmeyer A, Campanella S, Goldstein SL.
Administrative data misclassifies and fails to
identify nephrotoxin-associated acute kidney injury
in hospitalized children. Hosp Pediatr. 2014;4(3):
159-166.
25. Moffett BS, Goldstein SL. Acute kidney injury
and increasing nephrotoxic-medication exposure in
noncritically-ill children. Clin J Am Soc Nephrol. 2011;
6(4):856-863.
26. Kidney International Supplements. Kidney
Disease: Improving Global Outcomes (KDIGO).
KDIGO clinical practice guideline for acute kidney
injury. http://www.kdigo.org/clinical_practice
_guidelines/pdf/KDIGO%20AKI%20Guideline.pdf.
Published March 2012. Accessed May 11, 2012.
27. Pottel H, Vrydags N, Mahieu B, Vandewynckele
E, Croes K, Martens F. Establishing age/sex related
serum creatinine reference intervals from hospital
laboratory data based on different statistical
methods. Clin Chim Acta. 2008;396(1-2):49-55.
28. Feudtner C, Hays RM, Haynes G, Geyer JR, Neff
JM, Koepsell TD. Deaths attributed to pediatric
complex chronic conditions: national trends and
implications for supportive care services. Pediatrics.
2001;107(6):E99.
29. Maude SL, Fitzgerald JC, Fisher BT, et al.
Outcome of pediatric acute myeloid leukemia
patients receiving intensive care in the United
States. Pediatr Crit Care Med. 2014;15(2):112-120.
(Reprinted) JAMA Pediatrics Published online October 2, 2017
Original Investigation Research
30. Lash TL, Fox MP, Fink AK. Applying
Quantitative Bias Analysis to Epidemiologic Data. New
York, NY: Springer; 2009.
31. Lash TL, Fox MP, MacLehose RF, Maldonado G,
McCandless LC, Greenland S. Good practices for
quantitative bias analysis. Int J Epidemiol. 2014;43
(6):1969-1985.
32. Knoderer CA, Gritzman AL, Nichols KR, Wilson
AC. Late-occurring vancomycin-associated acute
kidney injury in children receiving prolonged
therapy. Ann Pharmacother. 2015;49(10):1113-1119.
33. Najjar TA, Abou-Auda HS, Ghilzai NM. Influence
of piperacillin on the pharmacokinetics of
methotrexate and 7-hydroxymethotrexate. Cancer
Chemother Pharmacol. 1998;42(5):423-428.
34. Landersdorfer CB, Kirkpatrick CM, Kinzig M,
Bulitta JB, Holzgrabe U, Sörgel F. Inhibition of
flucloxacillin tubular renal secretion by piperacillin.
Br J Clin Pharmacol. 2008;66(5):648-659.
35. Grams ME, Waikar SS, MacMahon B, Whelton S,
Ballew SH, Coresh J. Performance and limitations of
administrative data in the identification of AKI. Clin
J Am Soc Nephrol. 2014;9(4):682-689.
36. Cies JJ, Shankar V. Nephrotoxicity in patients
with vancomycin trough concentrations of 15-20
μg/ml in a pediatric intensive care unit.
Pharmacotherapy. 2013;33(4):392-400.
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