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TITLE
Risk of developing acute kidney injury in hospitalized patients treated with the combination of vancomycin plus
piperacillin-tazobactam versus piperacillin-tazobactam alone

PRINCIPAL INVESTIGATOR
Chidiebere Eze, PharmD.

Introduction
Acute kidney injury (AKI) is commonly experienced by hospitalized patients with data from 2011 showing an
almost five-fold increase in incidence from 2001, and mortality rates up to 35-50%. 1,2,3 Risk factors for the
incidence of AKI include: concomitant nephrotoxic agents, advanced age, steady-state vancomycin trough
concentration of ≥ 15 mCg/mL, total vancomycin dose of ≥ 4gm/day. There are three criteria most commonly used
to define AKI in patients: Risk, Injury, Failure, Loss of Renal Function, End-Stage Kidney Disease (RIFLE); Acute
Kidney Injury Network (AKIN); and Kidney Disease Improving Global Outcomes Group (KDIGO). Each criteria differs
based on the percentage or absolute increase in baseline serum creatinine (SCr), glomerular filtration rate (GFR)
and urine output (UOP).

Recent trials have looked into the combination therapy of vancomycin (VAN) and piperacillin-tazobactam (TZP) and
its effect on renal function. These reports have demonstrated that VAN may lead to an increased incidence of AKI
especially when combined with antipseudomonal beta-lactams (piperacillin – tazobactam or cefepime).4-8 One trial
assessed the incidence of AKI with VAN-TZP vs. VAN-cefepime in adult patients with severe chronic or structural
kidney disease using the RIFLE criteria. The trial results proved with statistical significance that AKI is certainly more
common in patients receiving VAN-TZP than in those receiving VAN-cefepime.5 Another trial with the same goal of
comparing AKI incidence during treatment with VAN-TZP vs. VAN-cefepime studied patients on therapy longer
than 48 hours with no prior history of renal failure. This trial concluded that there might be an association between
the VAN-TZP combination and an increased incidence of AKI.6 There is also a meta-analysis that evaluated 15
observational cohort studies that focused on the development of AKI in VAN-TZP vs. VAN; VAN-TZP vs. VAN+
cefepime.9 It concluded that there is an association with an increased risk of AKI when patients are started in VAN-
TZP compared to VAN combined with other beta-lactams. It also advised practitioners to be vigilant about the
combination of these specific antibiotics or combination with other nephrotoxic agents.

Objective
The primary objective of this study is to evaluate the difference in the incidence of acute kidney injury (AKI)
between vancomycin plus piperacillin-tazobactam and piperacillin-tazobactam alone in hospitalized patients

Rationale
VAN is an antimicrobial commonly used intravenously for the treatment of gram-positive pathogens. Current
guidelines advocate the need for a more aggressive dosing in cases of methicillin-resistant Staphylococcus aureus
(MRSA) infections to combat the risk of treatment failure associated with an increase in MICs.10 To ensure
coverage for moderate to severe infections of unknown etiology or for mixed infections, an antipseudomonal beta-
lactam agent is usually added empirically. Since there are studies to prove the incidence of AKI with VAN therapy
alone, ranging from 1.0 to 42%, depending on the population studied, confounding risk factors, AKI definition, and
assessment tool criteria.11 Some other studies assessed AKI risk in VAN-TZP vs. VAN-cefepime, while the goal of
this trial was to evaluate VAN-TZP vs. TZP alone, as little to no studies have evaluated that. The TZP package insert
does state rare associations with development of AKI. 12

Study Population
The study will include one hundred adult patients 18 years or older who had received at least 48 hours of therapy
with piperacillin-tazobactam alone or vancomycin with concomitant piperacillin-tazobactam, between July 1, 2017
and September 30, 2017 for any indication and had a baseline serum creatinine concentration value within 24
hours of hospital admission. Exclusion criteria include: age less than 18 years, pregnancy, and the use of renal
replacement therapy. Patients will be assessed for an acute kidney injury sustained during hospitalization and the
time to development.
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Subject Recruitment
There will be no advertising for this trial. Patients will be identified utilizing a retrospective chart review based on
inclusion and exclusion and criteria.

Study Design
This study is a single-center, retrospective chart review of the electronic medical record (EMR) at Ball Memorial
Hospital (BMH). The EMR will be used to identify patients who were receiving vancomycin plus piperacillin-
tazobactam versus piperacillin-tazobactam alone. There will be no randomization or placebo involved in this study.

Methods and Procedures

Inclusion criteria: Adult patients who presented to BMH during the months of July 2017, August 2017 and
September 2017, and were treated with either piperacillin-tazobactam alone or the combination of vancomycin
plus piperacillin-tazobactam and had a baseline serum creatinine drawn within 24 hours of hospitalization.

Exclusion criteria: Patients will be excluded from the study if they are less than 18 years, pregnant, or used renal
replacement therapy.

Subjects: This study will include data from 100 adult patients that meet the above inclusion criteria. Each subject
will only be included once. For patients with multiple admissions, only the initial visit will be analyzed.

Data collection: Patient demographics and clinical data will be collected to evaluate the study objectives. Patients
will be assessed for an acute kidney injury sustained during hospitalization and its time to development. The
following data will be collected: age, gender, ethnicity, height, weight, blood urea nitrogen (BUN), baseline serum
creatinine (SCr), hypotension, evidence of a systemic inflammatory response syndrome (SIRS), indication for
antibiotic, and current medications including: angiotensin converting enzyme inhibitors (ACEi), angiotensin
receptor blockers (ARBs), IV contrast exposure, acyclovir, aminoglycosides, calcineurin inhibitors, loop diuretics,
non-steroidal anti-inflammatory drugs (NSAIDs), sulfonamides, and tenofovir. Hypoperfusion is commonly caused
by ACEi and NSAIDs; renal tubular necrosis is commonly associated with aminoglycosides, while inflammatory
damage secondary to hypersensitivity reactions can be attributable to NSAIDs. 13 A vancomycin steady-state serum
trough concentration was defined as the vancomycin concentration measured a maximum of 1 hour prior to
receiving an intravenous vancomycin dose after the third day of consecutively dosing or after the fourth dose (if
patient is on an every 24 hour dose frequency), according to the BMH Pharmacokinetics policy. Changes in renal
function will be evaluated using the RIFLE criteria (Risk, Injury, Failure, Loss of kidney function, and End-stage
kidney disease). The RIFLE criteria will serve as an assessment tool for the development of AKI. (Table 1)

Table 1: 14
Stage Glomerular filtration rate (GFR) criteria Urine Output (UO) criteria
Risk - SCr increase by 1.5-2 times baseline - UO < 0.5 mL/kg/h < 6 h
- GFR decrease by >25%
Injury - SCr increase by 2-3 times baseline - UO < 0.5 mL/kg/h >12 h
- GFR decrease by >50%
Failure - SCr increase by >3 times baseline - UO < 0.3 mL/kg/h 24 h
- GFR decrease by 75% (oliguria)
- SCr ≥4 mg/dL; acute rise ≥0.5 mg/dL - or anuria 12 hr
Loss of function Persistent acute renal failure: complete loss of kidney function >4 wk (requiring dialysis)
End-stage renal disease Complete loss of kidney function >3 mo (requiring dialysis)

Primary outcome: Incidence of AKI, defined as a minimum 1.5-fold increase from the patient’s baseline serum
creatinine concentration (value within 24 hours of hospital admission) for at least 48 hours of therapy.

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Secondary outcome: Percentage of patients who developed AKI and met any of the following criteria: use of
concomitant nephrotoxic agents, advanced age, steady-state vancomycin trough concentration of ≥ 15 mCg/mL,
total vancomycin dose of ≥ 4 gm/day.

Anonymity/Confidentiality of Data
Patient’s charts and medical records will be reviewed retrospectively using the Financial Identification Number
(FIN) specifically for research purposes. Data will be collected, depersonalized and anonymously recorded into a
password-protected Excel document.

Potential Risks
Risks anticipated could be the patient’s personal heath information being compromised while accessing the
electronic medical record (EMR) to retrieve information for the study. To prevent easy identification by name or
date of birth, all patients will be coded and documented according to their FIN into the password-protected Excel
document.

Safety Precautions
Patient data will be collected and monitored in a password protected Excel document to ensure confidentiality.
This retrospective chart review will pose minimal to no risks to the patient’s well being.

Benefits vs. Risks

Potential benefits of the research to society will be to raise the awareness of possible increase in the incidence of
AKI in patients who are on multiple nephrotoxic agents. As soon as culture sensitivities return, therapy should be
narrowed to ensure maximum efficacy while also accounting for patient safety.

Alternatives
Not applicable

Incentives/Inducements to Participate
Not applicable

Other Financial Considerations

Not applicable

Informed Consent
Not applicable

Attachments
Not applicable

References
1. Ali T, Khan I, Simpson E, et al. Incidence and outcomes in acute kidney injury: a comprehensive
population-based study. J Am Soc Nephrol 2007;18(4):1292-1298
2. Bagshaw S, Uchino S, Bellomo R, et al. Septic acute kidney injury in critically ill patients: clinical
characteristics and outcomes. Clin J Am Soc Nephrol 2007; 2(3): 431-439
3. Brown J, Rezaee M, Marshall E, et al. Hospital mortality in the United States following acute kidney injury.
BioMed Research International 2016; Article ID 4278579. https://doi:10.1155/2016/4278579
4. Burgess L, Drew R. Comparison of the Incidence of Vancomycin-Induced Nephrotoxicity in Hospitalized
Patients with and without Concomitant Piperacillin-Tazobactam. Pharmacotherapy 2014; 34: 670–676.
doi:10.1002/phar.1442
5. Rutter W, Cox J, Martin C, et al. Nephrotoxicity during Vancomycin Therapy in Combination with
Piperacillin-Tazobactam or Cefepime. Antimicrobial Agents and Chemotherapy. 2017; 61(2):e02089-16.
doi:10.1128/AAC.02089-16.

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6. Gomes D, Smotherman C, Birch A, et al. Comparison of Acute Kidney Injury During Treatment with
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669. doi:10.1002/phar.1428
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10. Liu C, Bayer A, Cosgrove S, et al. Clinical practice guidelines by the infectious Disease Society of America
for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin
Infect Dis 2011; 52:e18-e55. https://doi.org/10.1093/cid/ciq146
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aureus infection: efficacy and toxicity. Arch Intern Med 2006; 166:2138-2144.
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12. Pfizer. Zosyn (piperacillin-tazobactam) package insert. Philadelphia, PA: Pfizer; 2012
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216-223
14. Bellomo R, Ronco C, Mehta R, et al. Acute renal failure – definition, outcome measures, animal models,
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Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004 Aug. 8(4): R204-212.

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