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September 10, 2018

EVALUATING THE RISKS OF AKI

VANCOMYCIN ZOSYN

OBJECTIVES

BACK

GROUND

  • Describe the mechanisms by which vancomycin and piperacillin/tazobactam could cause acute kidney injury.

  • Discuss current evidence regarding AKI in the setting of vancomycin and piperacillin/tazobactam combination therapy.

  • Analyze our own incidences of AKI due to combination Zosyn and vancomycin therapy.

  • Identify strategies to reduce risk of AKI in patients requiring broad spectrum antibiotics.

1

VANCOMYCIN

NEPHROTOXICITY

1

2

MECHANISMS

Although the mechanism underlying renal toxicity from vancomycin is not fully understood,

experimental studies supported proinflammatory oxidation, mitochondrial dysfunction and

cellular apoptosis as the principal modes of injury.

Oxidative phosphorylation by vancomycin induces free oxygen radicals and thereby reduces

the activity of defensive antioxidative enzymes including superoxide dismutase and catalases.

Superoxide production by vancomycin causes depolarization of mitochondrial membrane

potential with a release of cytochrome C, and a subsequent activation of both caspases 9 and 3.

The latter is involved in apoptotic cell death.

3

https://en.wikipedia.org/wiki/Vancomycin

https://www.idstewardship.com/drugs/vancomycin/

1

ZOSYN NEPHROTOXICITY

  • The exact mechanism for Zosyn nephrotoxicity is still uncertain.

  • The prevailing theory from many case studies is that Zosyn may cause acute interstitial nephritis.

  • There is strong evidence that AIN is immunologically mediated. The precise disease mechanism is unclear, but antigen-driven immunopathology is the key mechanism.

  • The presence of helper-inducer and suppressor-cytotoxic T lymphocytes in the inflammatory infiltrate suggests that T-cell mediated hypersensitivity reactions and cytotoxic T-cell injury are involved in pathogenesis of AIN.

  • Associated nephrotoxicity with Zosyn use is less than 1%.

https://theodora.com/drugs/zosyn_zosyn_in_galaxy_containers_wyeth.html

Continued...

  • It is suggested that piperacillin-tazobactam is associated with an increased creatinine due to a reduction in tubular creatinine secretion.

  • In a retrospective analysis by Jensen et. al, the use of piperacillin-tazobactam was identified as a cause of delayed renal recovery in critically ill patients.

  • Interestingly, after the piperacillin/tazobactam was discontinued, the subgroup had more rapid recovery of glomerular filtration rates.

1,2

VANCOMYCIN + ZOSYN

MECHANISM?

  • The exact mechanism behind AKI due to Zosyn and Vancomycin is unknown.

  • The two most common proposed mechanisms for pip-tazo induced AKI include acute interstitial nephritis (AIN) or toxic effects on the renal tubule.

  • It could be an additive effect of AIN and direct cellular necrosis. Some have suggested a decreased clearance of vancomycin by pip-tazo resulting in vancomycin accumulation, however the one prospective study reported no difference in mean vancomycin levels between the two groups.

Current Consensus and Data

1. Navalkele B, et al. - October 2016

"AKI rates were significantly higher in the vanc + pip-tazo than the vanc + cefepime group (81/279 (29%) vs. 31/279 (11%), p<0.0001.) "

2. Lorenz M, et al. - 2016

"Overall, 11.8% (22/186) of patients who received therapy with pip-tazo + vancomycin developed AKI, compared with 1.7% (1/56) who received pip-tazo monotherapy (P < 0.0001)."

3. McQueen KE, et al. - 2016

Nephrotoxicity developed in 3 of 79 patients (3.8%) in the vancomycin group and in 25 of 106 patients (23.6%) on combination therapy (p = 0.0001).

4. Karino S, et al. - 2016

Overall, AKI occurred in 105/320 (33%) of the cohort receiving combination therapy. There were similar rates in those receiving intermittent (53/160 (33.1%)) and extended infusions (52/160 (32.5%)) of pip-tazo.

5. Peyko V, et al. - 2016

The incidence of AKI was significantly higher in the pip-tazo + vancomycin group (37.3%) compared with the cefepime or meropenem + vancomycin group (7.7%; χ2 = 7.80, P = .005).

DRMC

RETROSPECTIVE ANALYSIS

RESULTS

  • Queried medical records from January 2018 to June 2018 for all patients that received Vancomycin + Zosyn. (624 patients).

  • Further separated into patients who received Vanco + Zosyn for 3 days or greater. (n=290)

  • Tracked Serum Creatinine during administration of combination therapy.

https://kmir.com/2018/04/19/desert-regional-medical-center-penalized-for-two-2015-deaths/

DETAILS

3

INCLUSION CRITERIA

  • DEFINITION OF AKI - 100% INCREASE IN SERUM CREATININE

EXCLUSION CRITERIA

PERFORMED BY CHART REVIEW

  • Patients presenting with AKI, and if AKI occurred prior to therapy initiation, within 48 hours of initiation, or more than 7 days after treatment was discontinued.
  • Dialysis
  • CKD

RESULTS

3,4

What does this mean?

  • Data from outside sources commonly cite an AKI rate of 11%-33% from concomitant administration of Zosyn + Vancomycin.
  • DRMC- 11%
  • Comparing monotherapy vs combination therapy.
  • Patients getting combination therapy are sicker and are at greater risk of AKI.

According to the RIFLE (Risk, Injury, Failure, Loss, End Stage Renal Disease) 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%.
  • FAILURE, a rise in creatinine by 3 times baseline or a GFR decrease by 75%.

https://emedicine.medscape.com/article/1925597-overview

4

Why the discrepancy?

0.78 x 1.5 (risk) = 1.17

0.78 x 2 (injury) = 1.56

http://www.enzolifesciences.com/browse/toxicology/assessment-of-kidney-injury---nephrotoxicity/

STRATEGIES

5,6

Risk Factors

2

Risk Reduction Strategies

1. Limit nephrotoxic agents

  • Vasopressors
  • NSAIDS
  • High Dose Diuretics
  • Etc

2. Continually reassess patients

  • Antibiotics indicated?
  • No? DEESCALATE

3. Target lower troughs if possible

  • Minimize doses <4g/day (patient specific)

4. Vanco + Cefepime + Metronidazole (optional)

Conclusion

  • There is evidence of Zosyn and Vancomycin associated AKI.

  • The rates ranges from 11-33% according to multiple studies.

  • Our institution is around 11% based upon our stricter criteria.

  • Providers must take caution in treating patients with combination therapy and take risks to mitigate AKI.

References

1.Bhagyashri Navalkele et al; Risk of Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin–Tazobactam Compared to Those on Vancomycin and Cefepime; Clinical Infectious Diseases; 2016.

2. Olson Logan; Vancomycin and Piperacillin/Tazobactam. Combination Therapy: The Renal Wringer?, Mayo Clinic; 2016

3. Rutter W; Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime; 2017

4. Hayes et al; Piperacillin/Tazobactam and Risk of Acute Kidney Injury with Vancomycin; Academic Life in Emergency Medicine; 2016.

5. Does Piperacillin-Tazobactam Cause Renal Failure?; PulmCC.org; 2018

6. Hammond et al; Systematic Review and Metaanalysis of Acute Kidney Injury Associated With Concomitant Vancomycin and Piperacillin/Tazobactam; Clinical Infectious Disease; 2017.

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