Risk of Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin–Tazobactam Compared to Those on Vancomycin and Cefepime
Risk of Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime
Bhagyashri Navalkele 1 2 3
Jason M. Pogue 1 2 4
Shigehiko Karino 1 2 3
Bakht Nishan 1 2
Madiha Salim 1 2
Shantanu Solanki 1 2
Amina Pervaiz 1 2
Nader Tashtoush 1 2
Hamadullah Shaikh 1 2
Sunitha Koppula 1 2
Jonathan Koons 1 2
Tanveer Hussain 1 2
William Perry 1 2
Richard Evans 0 2
Emily T. Martin 0 2
Ryan P. Mynatt 2 7
Kyle P. Murray 2 6
Michael J. Rybak 1 2 5 7
Keith S. Kaye 1 2 3
0 Department of Epidemiology, University of Michigan School of Public Health , Ann Arbor
1 Wayne State University School of Medicine , Detroit
2 Received 22 June 2016; editorial decision 2 October 2016; accepted 18 October 2016; published online October 20, 2016. Dr., Detroit, MI, 48235
3 Department of Medicine, Detroit Medical Center
4 Department of Pharmacy Services, Sinai-Grace Hospital , Detroit, Michigan
5 Anti-Infective Research Laboratory, Department of Pharmacy Practice, Wayne State University Eugene Applebaum College of Pharmacy and Health Sciences
6 Department of Pharmacy Services, Huron Valley Sinai Hospital
7 Department of Pharmacy Services, Detroit Receiving Hospital
Background. Recent evidence suggests that among patients receiving vancomycin, receipt of concomitant piperacillin-tazobactam increases the risk of nephrotoxicity. Well-controlled, adequately powered studies comparing rates of acute kidney injury (AKI) among patients receiving vancomycin + piperacillin-tazobactam (VPT) compared to similar patients receiving vancomycin + cefepime (VC) are lacking. In this study we compared the incidence of AKI among patients receiving combination therapy with VPT to a matched group receiving VC. Methods. A retrospective, matched, cohort study was performed. Patients were eligible if they received combination therapy for ≥48 hours. Patients were excluded if their baseline serum creatinine was >1.2mg/dL or they were receiving renal replacement therapy. Patients receiving VC were matched to patients receiving VPT based on severity of illness, intensive care unit status, duration of combination therapy, vancomycin dose, and number of concomitant nephrotoxins. The primary outcome was the incidence of AKI. Multivariate modeling was performed using Cox proportional hazards. Results. A total of 558 patients were included. AKI rates were significantly higher in the VPT group than the VC group (81/279 [29%] vs 31/279 [11%]). In multivariate analysis, therapy with VPT was an independent predictor for AKI (hazard ratio = 4.27; 95% confidence interval, 2.73-6.68). Among patients who developed AKI, the median onset was more rapid in the VPT group compared to the VC group (3 vs 5 days P =< .0001). Conclusion. The VPT combination was associated with both an increased AKI risk and a more rapid onset of AKI compared to the VC combination.
Empiric antimicrobial therapy for the treatment of
healthcare-associated infections frequently includes coverage for both
methicillin-resistant Staphylococcus aureus and Pseudomonas
aeruginosa. Common regimens include vancomycin in
combination with an antipseudomonal b-lactam . Piperacillin–
tazobactam and cefepime are among the most common agents
used for empiric antipseudomonal coverage.
A hospital’s selection of piperacillin–tazobactam vs cefepime
as the “workhorse” antipseudomonal antibiotic has traditionally
been based on institutional susceptibility trends, acquisition
costs, and other formulary considerations. Concerns
regarding nephrotoxicity have become increasingly prominent. While
vancomycin has long been associated with acute kidney injury
(AKI), recent evidence suggests that patients receiving
combination therapy with piperacillin–tazobactam have a higher
incidence of AKI compared to patients receiving vancomycin
monotherapy  or those receiving combination therapy with
vancomycin and cefepime (VC) .
However, the finding of increased toxicity in patients
receiving vancomycin and piperacillin–tazobactam (VPT)
combination therapy compared to VC has not been universal. A recent
analysis showed no difference in AKI rates among intensive
care unit (ICU) patients receiving either combination . Prior
studies have been limited by relatively small sample sizes,
notable diversity in the patients receiving the different combination
therapy regimens, and suboptimal study design.
In light of the conflicting results and methodological
limitations of prior studies as well as the importance of clearly
understanding whether or not combination therapy with VPT
is associated with an increased AKI risk, this retrospective,
matched, cohort study was designed to definitively address the
following questions: is combination therapy with VPT
associated with greater AKI risk compared to VC? If so, how much
greater is the risk?
Study Settings and Design
This was a retrospective, matched, cohort study that compared
the incidence of AKI among patients on concomitant VC and
those receiving VPT. The study was conducted at the Detroit
Medical Center (DMC), a tertiary care health system in
metropolitan Detroit, Michigan, comprised of 5 acute care hospitals
with more than 2000 inpatient beds. The institutional review
boards at the DMC and Wayne State University approved the
study prior to initiation.
The study population consisted of patients aged ≥18 years
admitted to the DMC between 1 December 2011 and 31
December 2013. Patients included in the study received
combination therapy with VC or VPT for ≥48 hours and had the 2
antibiotics initiated within 24 hours of one another. For patients
who received combination therapy multiple times during
hospitalization, only the initial regimen was included. Patients were
excluded if the baseline serum creatinine was >1.2 mg/dL or
they required renal replacement therapy at the time of initiation
of combination therapy.
Patients were divided into 2 groups based on the
combination regimen received. The patients in the VC group were
matched to the VPT group on 5 variables associated with the
development of AKI in a 1:1 ratio. The matching was performed
based on severity of sepsis at the time that the combination
antibiotics were started (dichotomized to presence or absence
of severe sepsis/septic shock) , ICU status at onset of
combination therapy, duration of combination therapy (divided
into 3 categories: ≤3 days, 4–7 days, >7 days), the daily dose of
vancomycin received (divided into 3 categories: < 2 grams/day,
2–4 grams/day, and >4 grams/day), and number of concomitant
nephrotoxic agents received while on combination therapy.
Data abstracted from medical records included patient
demographics; comorbidities, including Charlson comorbidity index
; severity of sepsis based on systemic inflammatory response
syndrome criteria ; mechanical ventilation; infectious
diagnosis; and receipt of concomitant nephrotoxins while receiving
combination therapy. Antibiotic therapy variables collected
included dose and duration of therapy. Vancomycin trough
levels were also collected. Vancomycin loading dose was defined
as an initial vancomycin dose that was higher than subsequent
maintenance doses. The variables used for matching were
extracted during the time period between 2 days prior and
2 days after initiation of combination therapy, with the highest
values used for this purpose. Vasopressors, aminoglycosides,
colistin, amphotericin B, angiotensin-converting enzyme
inhibitors, angiotensin II receptor blockers, diuretics, and
intravenous contrast were considered as nephrotoxic agents.
Vancomycin Trough Value Assessment
In order to assess the impact of vancomycin exposures on
development of AKI, the median trough of vancomycin prior
to AKI was calculated. For patients who did not develop AKI,
median vancomycin troughs during the entire duration of
combination therapy were analyzed, whereas among patients who
developed AKI, only trough values obtained before the onset
of AKI were included. Patients in whom trough values were not
obtained during therapy and those who did not have trough
values obtained prior to the development of AKI were excluded
from trough analyses.
Acute Kidney Injury Definitions
Determination of AKI was based on 3 definitions: According to
the RIFLE (Risk, Injury, Failure, Loss, End Stage Renal Disease)
criteria , the Acute Kindey Injury Network (AKIN) criteria
, and vancomycin consensus guideline definition . For
RIFLE criteria, the terms risk, injury, and failure were defined
as follows: risk, a rise in creatinine by 1.5 times baseline or a
decrease in glomerular filtration rate (GFR) by 25%; injury, a
rise in creatinine of 2 times baseline or a decrease in the GFR by
50%; and failure, a rise in creatinine by 3 times baseline or a GFR
decrease by 75%. AKIN criteria were categorized into 3 stages:
a rise in creatinine by 1.5-fold or 0.3 mg/dL was categorized as
stage 1, a 2-fold rise in creatinine was categorized as stage 2, and
a rise in creatinine by 3-fold or ≥ 4 mg/dL or initiation of renal
replacement therapy was categorized as stage 3. For the
vancomycin consensus guidelines, AKI was defined as a rise in
baseline serum creatinine by ≥50% or >0.5 mg/dL sustained over at
least 2 consecutive measurements ranging from the time of
initiation until 72 hours post-completion of vancomycin therapy.
RIFLE-defined AKI was used for all multivariate analyses, where
meeting any stage of the RIFLE criteria was considered AKI.
All statistical analyses were performed using SAS software,
version 9.3 (Cary, North Carolina). Matched bivariate
analyses comparing patients receiving VC to patients receiving VPT
were conducted using conditional logistic regression modeling.
For bivariate unmatched analysis, Fisher exact test and χ2 test
were used to analyze dichotomous variables, and Student t test
and Wilcoxon rank-sum test were used for continuous variables.
To determine the impact of VPT on AKI risk in both bivariate
and multivariate analyses, Cox proportional hazards
methodology was used. In multivariate analysis to control for residual
differences between the VPT and VC groups, all variables with a P
value <.1 in the bivariate matched analysis comparing VPT and
VC groups were included, along with treatment group (VPT vs
VC), in a multivariate model for AKI. In this model the event
of interest was development of RIFLE-defined AKI. All P
values were 2 sided and a P value <.05 was considered statistically
significant. Crude rates of AKI of the 2 study groups were
compared using a Kaplan–Meier curve and the log-rank test.
A total of 320 patients who received VPT and 803 patients
who received VC during the study period were identified. Of
the 320 VPT patients, adequate VC matches were identified
for 279. Thus, 279 VPT–VC pairs were included in the final
study population, for a total of 558 patients. The mean age was
55.9 ± 16.6 years. Patients in both VC and VPT groups had
similar baseline characteristics in terms of age, length of ICU
stay, Charlson comorbidity index score, baseline creatinine, and
use of concomitant nephrotoxins (Table 1). There were more
females in the VC group, and more patients were white in the
VPT group. Patients were more likely to have had connective
tissue disease and hypertension in the VC group compared to
those in the VPT group. Patients in the VPT group had a higher
incidence of septic shock and skin and soft tissue infections.
Combination therapy with both VPT and VC was initiated as
empiric therapy in all patients. There were no differences in the
number of patients receiving vancomycin loading doses, the
median loading or maintenance doses of vancomycin given, or
the median vancomycin trough values between the 2 groups.
Comparative Rates of AKI in VC and VPT Patients
The rate of AKI was higher among patients receiving VPT
compared to those receiving VC combination therapy. Based on
RIFLE criteria, 81 patients in the VPT group developed AKI
compared to 31 patients in the VC group (29.0% vs 11.1%;
hazard ratio [HR] = 4.0; 95% confidence interval [CI], 2.6–6.2;
P < .0001). Rates of AKI were also higher per AKIN criteria
(32% in the VPT vs 14% in the VC group; HR = 3.5; 95% CI,
2.3–5.2; P < .0001) and per vancomycin consensus guidelines
definition (24% in VPT vs 8.2% in VC; HR = 4.4; 95% CI,
2.7–7.3; P < .0001). In multivariate analysis, after controlling
for residual differences between the VPT and VC groups (race,
gender, admission from home, comorbid conditions, presence
of septic shock, baseline serum white blood cell count, and
source of infection), VPT was independently associated with
RIFLE-defined AKI (HR = 4.3; 95% CI, 2.7–6.7; P < .0001).
Characterization of AKI
Of the patients who developed RIFLE-defined AKI (n = 31 in
the VC group and n = 81 in the VPT group), the onset of AKI
was more rapid in patients receiving VPT. The median
duration of combination therapy prior to development of AKI was
5 days (interquartile range [IQR], 3–7 days) in the VC and
3 days (IQR, 2–5 days) in the VPT group; P < .0001. Survival
curves depicting time to AKI in the 2 treatment groups were
constructed (Figures 1 and 2) and demonstrate the increased
incidence and more rapid onset of AKI among patients in the
VPT group compared to those in the VC group (P < .0001).
Importantly, the Kaplan–Meier curves also show that the daily
rate of AKI among at-risk patients remained consistently higher
in the VPT group compared to the VC group throughout the
entire first week of combination therapy.
Other Outcome Variables
The median length of stay after initiation of combination
therapy was longer for VPT patients compared to VC patients
(8 days vs 6 days; P = .01). There was no difference in mortality
between the 2 groups.
Impact of Vancomycin Troughs on AKI
Although there were no differences in median
vancomycin trough values or the number of patients who had troughs
>15 mg/L or >20 mg/L between the VC and VPT groups,
additional analyses were performed to further assess the impact
of vancomycin trough on incidence of AKI (Figures 3a, 3b).
Interestingly, when the trough was dichotomized, there was no
association between vancomycin trough and AKI for patients in
the VPT group (trough <15 mg/L or ≥15 mg/L). Additionally,
there was no association when troughs were categorized into 3
ascending groups: <15, 15–20, or >20 mg/L.
Conversely, a direct relationship was seen between vancomycin
trough and AKI among patients in the VC group. When the
vancomycin troughs were dichotomized, AKI occurred in 1/76 (1%)
patients with median trough values <15 mg/L vs 20/160 (13%)
of patients with values ≥15 mg/L; P = 003. Additionally, when
vancomycin troughs were analyzed in ascending categories, a
significant association was also seen. AKI occurred in 1% of patients
with troughs <15 mg/L, in 5% (4/83) of patients with troughs of
15–20 mg/L, and in 21% (16/77) of patients with median troughs
>20 mg/L. AKI rates among patients in the VC group were
significantly different when patients with troughs of <15 mg/L were
compared to patients with troughs >20 mg/L (P = .0001) and
when patients with vancomycin troughs of 15–20 mg/L were
compared to patients with troughs >20 mg/L (P = .003).
Rates of AKI among patients receiving VPT were approximately
3 times greater than rates in patients receiving VC, regardless of
type of AKI definition used. In multivariate modeling and
controlling for residual differences between these 2 closely matched
groups, receipt of VPT was associated with a greater than 4-fold
increased risk of AKI. These findings are particularly robust
and convincing as, unlike previous analyses comparing toxicity
risk in patients on VPT and VC, this analysis was adequately
powered and groups were matched on 5 widely recognized risk
factors for AKI in patients receiving vancomycin.
n = 279 (%)
n = 279 (%)
Myocardial Infarction Congestive heart failure Peripheral vascular disease Dementia
Mean baseline creatininea
Odds Ratio (95%
Odds Ratio (95%
Table 1. Continued
MT before AKI >20d
These findings are strengthened by 3 additional important
and notable findings. First, among patients who developed
AKI, the onset was more rapid in VPT patients compared to VC
patients (3 days vs 5 days; P < .0001.) Second, the daily rate of
AKI among the at-risk population remained higher throughout
the first week of therapy among VPT patients. This rapid onset
and persistently increased AKI risk are both consistent with
VPT being more toxic than VC.
The third finding supporting an association between VPT
and increased toxicity was both interesting and unexpected.
Data from this study show discordance in the impact of
vancomycin troughs on toxicity in patients receiving VPT
compared to those receiving VC. Among patients receiving VPT,
there was no discernable impact of vancomycin trough on the
incidence of AKI. Conversely, a distinct trough–toxicity
association was noted in patients receiving VC. These discordant
trough associations strengthen the finding that the VPT
combination was a significant driver of AKI. These data suggest
that the concomitant use of VPT had such a nephrotoxic effect
that it muted the impact of vancomycin trough concentrations
on AKI. However, when patients received VC (and the toxic
effect of VPT was not present), the association between
vancomycin troughs and AKI was apparent. These findings could
help to explain the discordant literature with respect to the
impact of vancomycin trough on AKI, as the type of
concomitant antipseudomonal therapy received by patients is rarely
reported, let alone controlled for. Of note, the associations
between vancomycin trough and AKI are particularly robust,
as only trough values obtained before the onset of AKI were
included. Because elevated vancomycin troughs that occurred
as a result of AKI were excluded, the association between
vancomycin trough and AKI was unbiased.
The findings of this study are largely consistent with those
found in other studies that analyzed comparative AKI risks
of VPT and VC. In a smaller analysis, Gomes and colleagues
demonstrated similar findings, with 35% of VPT and 13%
of VC patients developing AKI . In a propensity
scorematched subgroup, VPT was independently associated
with increased AKI risk (OR, 5.67; 95% CI, 1.66–19.33).
Similarly, in an analysis that was conducted to assess the
impact of generic vancomycin product on development of
AKI, Sutton and colleagues reported concomitant VPT to be
the strongest predictor of AKI in the cohort (OR, 3.97; 95%
CI, 1.66–9.50) .
However, the association between VPT and AKI is not
a universal finding. Although Moenster and colleagues
reported that AKI occurred in 29% of patients on VPT
and 13% of patients on VC, this difference failed to reach
statistical significance (OR, 3.45; 95% CI, 0.96–12.4) .
Importantly, the study was underpowered, and numerically
these findings are consistent with those from the
aforementioned studies. Hammond and colleagues also recently
analyzed comparative toxicity rates in an ICU population. In
their analysis AKI was reported in 33% of patients on VPT
and 29% of patients on VC; P = .65 . It warrants
mention that this study was powered to detect a difference in
AKI rates of 36.5% vs 15% in the 2 groups and therefore
was underpowered to identify more subtle differences in
AKI rates, particularly in an ICU population with
competing AKI risks.
n = 279 (%)
n = 279 (%)
Table 2. Outcomes Associated With Receipt of Vancomycin Plus Piperacillin–Tazobactam Combination Therapy Compared to Receipt of Vancomycin
Multivariate Adjusted HR (95% CI)
The data presented here are robust, overcome several
limitations found in the previous literature, and convincingly
demonstrate that, compared to VC, combination therapy
with VPT is associated with a higher overall incidence of
AKI, a more rapid onset of AKI, and a persistently increased
daily AKI risk throughout the first week of therapy. Despite
the robustness of our methodology, there are a few
limitations. This was a single-center, retrospective analysis and is
thus subject to the inherit biases associated with this type of
study design, and the results should be confirmed in other
patient populations. In addition, only approximately 20% of
patients in this study were cared for in the ICU; therefore,
the results might not be generalizable to the ICU patient
harmed by ineffective empiric gram-negative coverage, while
48 hours of one other). However, these relatively minor
population. Furthermore, while the definition of
combinaof combination therapy where each agent was started within
24 hours of the other), definitions used by investigators in
other analyses differ slightly (ranging from a requirement of
without the requirement that the agents were started within
ferences are unlikely to explain differences between the
findings presented here and those in prior publications. Finally,
we chose to exclude patients with baseline renal insufficiency.
Patients with baseline renal insufficiency represent an
important patient population at risk for developing AKI and
warrant evaluation in future studies.
In conclusion, combination therapy with VPT was
independently associated with a 4-fold increased risk of AKI
compared to combination therapy with
VC. Additionally, AKI
with VPT occurred in a more rapid fashion. Despite this rapid
onset of AKI, there are opportunities for providers to limit the
incidence of this adverse event. Data recently published by our
group  demonstrated that the highest daily incidence of
AKI among patients receiving VPT occurred on day 4 and day
5 of therapy. Therefore, timely de-escalation or
discontinuation of 1 or both of the combination agents would likely
mitigate AKI risk. However, given the association between VPT and
increased AKI risk, it is critical that clinicians consider all risks
and benefits of therapy (both efficacy and toxicity) when
selecting empiric combination regimens. Clinicians might choose an
alternative to piperacillin–tazobactam in settings where
vancomycin is coadministered. If antibiogram data demonstrate an
advantage with regard to activity against likely gram-negative
pathogens of empiric piperacillin–tazobactam, clinicians might
with an alternative
grampositive agent. Because overuse of vancomycin alternatives might
be concerning from a stewardship perspective, one approach
might be to limit use of combination therapy with vancomycin
alternatives and piperacillin–tazobactam to patients who are
hemodynamically unstable and thus more likely to be significantly
using vancomycin plus cefepime in more stable patients.
Potential conflicts of interest. Authors certify no potential conflicts
of interest. The authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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