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

Drug Saf. 2019 Oct;42(10):1149-1155. doi: 10.1007/s40264-019-00846-x.


Introduction: 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.

Objective: 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.

Methods: A secondary analysis of the prospective, multicenter Sapphire study (ClinicalTrials.gov 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.

Results: 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).

Conclusion: 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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / adverse effects*
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / urine
  • Biomarkers / urine
  • Critical Illness
  • Drug Therapy, Combination
  • Humans
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / urine
  • Piperacillin, Tazobactam Drug Combination / adverse effects*
  • Piperacillin, Tazobactam Drug Combination / pharmacokinetics
  • Piperacillin, Tazobactam Drug Combination / urine
  • Vancomycin / adverse effects*
  • Vancomycin / pharmacokinetics
  • Vancomycin / urine


  • Anti-Bacterial Agents
  • Biomarkers
  • Piperacillin, Tazobactam Drug Combination
  • Vancomycin

Associated data

  • ClinicalTrials.gov/NCT01209169