Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study

Intensive Care Med. 2022 Sep;48(9):1144-1155. doi: 10.1007/s00134-022-06811-0. Epub 2022 Jul 14.


Purpose: Although dozens of studies have associated vancomycin + piperacillin-tazobactam with increased acute kidney injury (AKI) risk, it is unclear whether the association represents true injury or a pseudotoxicity characterized by isolated effects on creatinine secretion. We tested this hypothesis by contrasting changes in creatinine concentration after antibiotic initiation with changes in cystatin C concentration, a kidney biomarker unaffected by tubular secretion.

Methods: We included patients enrolled in the Molecular Epidemiology of SepsiS in the ICU (MESSI) prospective cohort who were treated for ≥ 48 h with vancomycin + piperacillin-tazobactam or vancomycin + cefepime. Kidney function biomarkers [creatinine, cystatin C, and blood urea nitrogen (BUN)] were measured before antibiotic treatment and at day two after initiation. Creatinine-defined AKI and dialysis were examined through day-14, and mortality through day-30. Inverse probability of treatment weighting was used to adjust for confounding. Multiple imputation was used to impute missing baseline covariates.

Results: The study included 739 patients (vancomycin + piperacillin-tazobactam n = 297, vancomycin + cefepime n = 442), of whom 192 had cystatin C measurements. Vancomycin + piperacillin-tazobactam was associated with a higher percentage increase of creatinine at day-two 8.04% (95% CI 1.21, 15.34) and higher incidence of creatinine-defined AKI: rate ratio (RR) 1.34 (95% CI 1.01, 1.78). In contrast, vancomycin + piperacillin-tazobactam was not associated with change in alternative biomarkers: cystatin C: - 5.63% (95% CI - 18.19, 8.86); BUN: - 4.51% (95% CI - 12.83, 4.59); or clinical outcomes: dialysis: RR 0.63 (95% CI 0.31, 1.29); mortality: RR 1.05 (95%CI 0.79, 1.41).

Conclusions: Vancomycin + piperacillin-tazobactam was associated with creatinine-defined AKI, but not changes in alternative kidney biomarkers, dialysis, or mortality, supporting the hypothesis that vancomycin + piperacillin-tazobactam effects on creatinine represent pseudotoxicity.

Keywords: Acute kidney injury; Cystatin C; Nephrotoxicity; Sepsis; Vancomycin; piperacillin–tazobactam.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Kidney Injury* / chemically induced
  • Acute Kidney Injury* / epidemiology
  • Adult
  • Anti-Bacterial Agents* / adverse effects
  • Biomarkers
  • Cefepime / adverse effects
  • Creatinine / blood
  • Critical Illness / therapy
  • Cystatin C / blood
  • Drug Therapy, Combination
  • Humans
  • Penicillanic Acid / adverse effects
  • Piperacillin, Tazobactam Drug Combination* / adverse effects
  • Prospective Studies
  • Renal Dialysis
  • Retrospective Studies
  • Vancomycin* / adverse effects


  • Anti-Bacterial Agents
  • Biomarkers
  • Cystatin C
  • Piperacillin, Tazobactam Drug Combination
  • Vancomycin
  • Cefepime
  • Penicillanic Acid
  • Creatinine