Risk of Developing Acute Kidney Injury with the Combination of

Vancomycin and Piperacillin-tazobactam versus

Piperacillin-tazobactam Alone

Chidiebere Eze, PharmD

PGY-1 Pharmacy Practice Resident
Indiana University Health – Ball Memorial Hospital
Muncie, Indiana

Great Lakes Residency Conference: April 24 - 25, 2018

 Conflict of Interest
2

 The speaker has no actual or potential conflict of

interest in relation to this presentation
 Indiana University Health – Ball Memorial Hospital
3
 Background
4

 Acute kidney injury (AKI) is commonly experienced by hospitalized

patients
 Data from 2011 shows:
 An almost five-fold increase in incidence from 2001
 Mortality rates up to 35-50%
 Risk factors include:
 concomitant nephrotoxic agents
 advanced age
 steady-state vancomycin trough concentration of ≥15 mCg/mL
 total vancomycin dose of ≥4gm/day
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
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
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
 Background
5

 Vancomycin – antimicrobial for gram-positive pathogens

 Current guidelines – more aggressive dosing in methicillin-resistant
Staphylococcus aureus (MRSA) infections
 An anti-pseudomonal beta-lactam agent added empirically
 Incidence of AKI with vancomycin alone ranges from 1 to 42%
 depending on the population studied
 confounding risk factors
 AKI definition
 assessment tool criteria

Hidayat L, Hsu D, Quist R, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infection: efficacy and toxicity. Arch Intern Med 2006; 166:2138-2144.
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.
 Need for study
6

 Percentage use of vancomycin with piperacillin-

tazobactam in our facility
 Increase risk of nephrotoxicity
 Other studies assessed AKI risk in combination with
alternative anti-pseudomonal agents
 ≤1% incidence of nephrotoxicity in patients receiving
piperacillin-tazobactam alone
Pfizer. Zosyn (piperacillin-tazobactam) package insert. Philadelphia, PA: Pfizer; 2012
 Study Objective
7

 To evaluate the difference in the incidence of AKI

between vancomycin plus piperacillin-tazobactam
and piperacillin-tazobactam alone in hospitalized
patients
 Provide appropriate recommendations to healthcare
interdisciplinary team based on patient risk factors and
current medications
 Methods
8

 Retrospective chart review

 Inclusion criteria:
 100 adult patients
 Admitted between July 2017 and September 2017
 Treated for at least 48 hours with either piperacillin-tazobactam or the
combination of vancomycin plus piperacillin-tazobactam
 Baseline serum creatinine drawn within 24 hours of hospitalization
 Exclusion criteria:
 Less than 18 years old, pregnant, or utilized renal replacement therapy
 Expired during admission
 Methods
9

 Received Institutional Review Board (IRB) approval

before beginning study
 Mantel-Haenszel χ2 test
 One-sided α set at 0.05
 Proportional odds model
 Statistical analyses were performed using SAS
software, version 9.4
 Assessment tool
10

 Criteria most commonly

used to define AKI: Serum Glomerular
creatinine Filtration
 Risk, Injury, Failure, Loss of (SCr) Rate (GFR)

Renal Function, End-Stage

Kidney Disease (RIFLE) Urine
output
(UO)
 Acute Kidney Injury Network
(AKIN)

RIFLE criteria
 RIFLE criteria
11

 Stage 0 – defined as no AKI

 SCr increase ≤1.4
 GFR decrease ≤24%
Bellomo R, Ronco C, Mehta R, et al. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute
Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004 Aug. 8(4): R204-212.
 Outcomes
12

 Primary outcome:
 Incidence of AKI, defined as a minimum 1.5-fold increase
from the patient’s baseline serum creatinine
 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
 Data collection
13

Demographics Age, Gender, Ethnicity, Height, Weight, Body mass index (BMI)
Labs Blood urea nitrogen (BUN), Baseline serum creatinine (SCr)
Conditions Evidence of systemic inflammatory response syndrome (SIRS),
Hypotension, Indication of antibiotic
Concurrent Acyclovir
medications Aminoglycosides
Angiotensin converting enzyme inhibitors (ACEi)
Angiotensin receptor blockers (ARBs)
Calcineurin inhibitors
IV contrast
Loop diuretics
Non-steroidal anti-inflammatory drugs (NSAIDs)
Sulfonamides
Tenofovir
 Baseline characteristics
14

Variable (mean) With Vancomycin Without Vancomycin

Age (years) 64 70.2
Gender (n, % female) 24 (48%) 27 (54%)
BMI (kg/m2) 30.3 26.7
BUN (mg/dL) 24 22.5
Baseline GFR (mL/min per 1.73 m2) 78.8 80.6
Baseline SCr (mg/dL) 0.78 0.75
 Baseline characteristics
15

Variable With vancomycin, n (%) Without vancomycin, n (%)

ACEi 16 (32) 14 (28)
ARB 3 (6) 9 (18)
Contrast 25 (50) 38 (76)
Calcineurin inhibitor 0 (0) 1 (2)
Loop diuretics 31 (62) 24 (48)
NSAIDs 31 (62) 32 (64)
Sulfonamides 5 (10) 5 (10)
Tenofovir 2 (4) 0 (0)
Total ≥3 nephrotoxic medications 20 (40) 26 (52)
Vancomycin trough (≥15 mCg/mL) 22 (44) 0 (0)
Vancomycin dose (≥4 gm/day) 5 (10) 0 (0)
 Incidence of AKI
16

50 0.063
45
40
35
Incidence

0.501 0.162
30
25 0.066 With Vancomycin
20
Without Vancomycin
15
10
5 n=14 n=23 n=12 n=15 n=15 n=9 n=9 n=3
0
Stage 0 Stage 1 Stage 2 Stage 3
(No AKI) (Risk) (Injury) (Failure)
 Results
17

Variable With Without P-value

Vancomycin Vancomycin
Baseline GFR (mL/min 78.8 80.6
per 1.73 m2)
Decrease in GFR 26.8 23.6 0.476
Baseline SCr (mg/dL) 0.78 0.75
Increase in SCr 1.86 1.56 0.104
 Results
18

Correction Variable P-value

Stages 0.009

Total ≥3 nephrotoxic medications 0.007

Vancomycin dose (≥4 gm/day) 0.008

Correction Variable Odds Ratio Confidence interval

(Odds Ratio)
With Vancomycin vs. 0.405 0.19 to 0.866
Without Vancomycin
Gender F vs. M 0.608 0.292 to 1.264

BMI 0.971 0.925 to 1.019

Age 0.996 0.974 to 1.019

 Limitations
19

 Retrospective study
 Duration of use for antimicrobials and other
concomitant nephrotoxins was not collected
 Urine output was not consistently documented
 Study was not adequately powered
 Conclusion
20

 Significant increase in incidence of nephrotoxicity in

patients receiving vancomycin plus piperacillin-
tazobactam vs. piperacillin-tazobactam alone
 Re-educate providers on importance of appropriate
therapy
 Confirm results with larger studies
 Self assessment question 1
21

 Which of the following is a risk factor for the

development of acute kidney injury?
a. Combination of vancomycin and scopolamine
b. History of migraine headaches
c. Combination of vancomycin and piperacillin-tazobactam
d. History of creatinine clearance greater than 100 mL/min
 Self assessment question 1
22

 Which of the following is a risk factor for the

development of acute kidney injury?
a. Combination of vancomycin and scopolamine
b. History of migraine headaches
c. Combination of vancomycin and piperacillin-tazobactam
d. History of creatinine clearance greater than 100 mL/min
 Self assessment question 2
23

 Which combination therapy has the highest risk

factor for the development of acute kidney injury?
a. metronidazole + linezolid
b. IV contrast dye + gentamicin
c. clindamycin + piperacillin-tazobctam
d. vancomycin + micafungin
 Self assessment question 2
24

 Which combination therapy has the highest risk

factor for the development of acute kidney injury?
a. metronidazole + linezolid
b. IV contrast dye + gentamicin
c. clindamycin + piperacillin-tazobctam
d. vancomycin + micafungin
 Acknowledgements
25

 Munni Begum, PhD., Professor of Mathematical Sciences,

Department of Mathematical Sciences, Ball State
University, Muncie, IN
 References
26

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.
6. Gomes D, 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: 662–669. doi:10.1002/phar.1428
7. Hammond D, Smith M, Painter J, et al. Comparative Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin-Tazobactam or
Cefepime: A Retrospective Cohort Study. Pharmacotherapy 2016; 36: 463–471. doi:10.1002/phar.1738
8. Navalkele B, Pogue J, Karino S. Risk of Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime.
Clinical Infectious Diseases 2017; 64(2): 116-123
9. Giuliano C, Patel C, Kale-Pradhan P. Is the Combination of Piperacillin-Tazobactam and Vancomycin Associated with Development of Acute Kidney Injury? A Meta-analysis.
Pharmacotherapy 2016; 36: 1217–1228. doi:10.1002/phar.1851
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
11. Hidayat L, Hsu D, Quist R, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infection: efficacy and toxicity. Arch Intern Med 2006; 166:2138-
2144. http://doi.org/10.1001/archinte.166.19.2138
12. Pfizer. Zosyn (piperacillin-tazobactam) package insert. Philadelphia, PA: Pfizer; 2012
13. Pannu N, Nadim M. An overview of drug-induced acute kidney injury. Crit Care Med 2008; 36(Suppl. 4): 216-223
14. Bellomo R, Ronco C, Mehta R, et al. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International
Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004 Aug. 8(4): R204-212.
Risk of Developing Acute Kidney Injury with the Combination of
Vancomycin and Piperacillin-tazobactam versus
Piperacillin-tazobactam Alone

Chidiebere Eze, PharmD

PGY-1 Pharmacy Practice Resident
Indiana University Health – Ball Memorial Hospital
Muncie, Indiana
ceze1@iuhealth.org

Great Lakes Residency Conference: April 24 - 25, 2018