Drug Safety

, Volume 42, Issue 10, pp 1149–1155 | Cite as

Evaluating Renal Stress Using Pharmacokinetic Urinary Biomarker Data in Critically Ill Patients Receiving Vancomycin and/or Piperacillin–Tazobactam: A Secondary Analysis of the Multicenter Sapphire Study

  • Sandra L. Kane-GillEmail author
  • Marlies Ostermann
  • Jing Shi
  • Emily L. Joyce
  • John A. Kellum
Short Communication



A drug combination that has gained recent attention for an additive risk of nephrotoxicity is vancomycin plus piperacillin–tazobactam. Clinicians need to better understand whether tubular cell stress occurs with piperacillin–tazobactam administration to establish whether renal injury associated with this combination is a valid clinical concern.


An evaluation of the pharmacokinetics of urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding-protein 7 (IGFBP7) for patients receiving vancomycin alone, piperacillin–tazobactam alone, and vancomycin plus piperacillin–tazobactam in combination was conducted to understand the impact on acute kidney cell stress and compare the rates of dialysis or death at 9 months among these three drug exposure types.


A secondary analysis of the prospective, multicenter Sapphire study ( identifier NCT01209169) including 35 intensive care units (ICUs) in North America and Europe was performed. Critically ill adult patients at risk for acute kidney injury (AKI) were included. Urinary [TIMP-2]∙[IGFBP7] was measured serially. Patients who received vancomycin alone, piperacillin–tazobactam alone, or vancomycin plus piperacillin–tazobactam were grouped according to their maximum AKI stage within 3 days of the first drug dose.


Of 723 critically ill adults admitted to the ICU, 46% received either piperacillin–tazobactam (n = 110), vancomycin (n = 156), or both (n = 67). The urinary [TIMP-2]∙[IGFBP7] was highest on day 1 for the combination group. AKI stage 2/3 occurred more frequently in patients receiving the drug combination than in those receiving piperacillin–tazobactam alone (p = 0.03) but not vancomycin alone (p = 0.29). Risk of death or dialysis at 9 months was greatest for vancomycin plus piperacillin–tazobactam (48%) and similar for patients receiving vancomycin alone (29%) or piperacillin–tazobactam alone (35%) (p = 0.03 for unadjusted and p = 0.048 after adjusting for covariates).


After exposure to piperacillin–tazobactam and vancomycin in combination, there was a greater release of AKI biomarkers in patients who develop AKI than with piperacillin–tazobactam or vancomycin monotherapy and the combination is associated with possible increased long-term adverse outcomes.


Compliance with Ethical Standards


The Sapphire study was funded by Astute Medical, Inc. and they supported this secondary evaluation through resources for statistical analysis.

Conflict of interest

Sandra Kane-Gill, Marlies Ostermann, and Emily Joyce have no conflicts of interest that are directly relevant to the content of this study. Jing Shi has received consulting fees from Astute Medical, Inc. John Kellum has received grant support and consulting fees from Astute Medica, including licensing fees paid to the University of Pittsburgh by Astute Medical for unrelated technology.

Ethical approval

The Sapphire study was approved by the Western Institutional Review Board (Olympia, WA, USA) and individual review boards or ethics committees as required by each study site.

Informed consent

All subjects or authorized representatives provided written informed consent.

Supplementary material

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Supplementary material 1 (DOCX 33 kb)
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Supplementary material 2 (DOCX 25 kb)
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Supplementary material 3 (DOCX 5085 kb)
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Supplementary material 4 (DOCX 27 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.School of PharmacyUniversity of PittsburghPittsburghUSA
  2. 2.Center for Critical Care Nephrology, University of PittsburghPittsburghUSA
  3. 3.Department of Critical Care MedicineUniversity of PittsburghPittsburghUSA
  4. 4.Department of Critical CareKing’s College London, Guy’s and St Thomas’ HospitalLondonUK
  5. 5.Department of BiostatisticsWalker BioscienceCarlsbadUSA
  6. 6.Department of Pediatrics (Nephrology)University of PittsburghPittsburghUSA
  7. 7.UPMC Children’s HospitalPittsburghUSA

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