Effect modification of dosing strategy (AUC or trough) on AKI associated with vancomycin in combination with piperacillin/tazobactam or cefepime and meropenem

Antimicrob Agents Chemother. 2024 May 2;68(5):e0108523. doi: 10.1128/aac.01085-23. Epub 2024 Apr 12.


Piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) and vancomycin (VAN) are commonly used in combination for sepsis. Studies have shown an increased risk of acute kidney injury (AKI) with TZP and VAN compared to FEP or MEM. VAN guidelines recommend area under the curve (AUC) monitoring over trough (Tr) to minimize the risk of AKI. We investigated the association of AKI and MAKE-30 with the two VAN monitoring strategies when used in combination with TZP or FEP/MEM. Adult patients between 2015 and 2019 with VAN > 72 hours were included. Patients with AKI prior to or within 48 hours of VAN or baseline CrCl of ≤30 mL/min were excluded. Four cohorts were defined: FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC. A Cox Proportional Hazard Model was used to model AKI as a function of the incidence rate of at-risk days, testing monitoring strategy as a treatment effect modification. Multivariable logistic regression was used to model MAKE-30. Overall incidence of AKI was 18.6%; FEP/MEM/Tr = 115 (14.6%), FEP/MEM/AUC = 52 (14.9%), TZP/Tr = 189 (26%), and TZP/AUC = 96 (17.1%) (P < 0.001). Both drug group [(TZP; P = 0.0085)] and monitoring strategy [(Tr; P = 0.0007)] were highly associated with the development of AKI; however, the effect was not modified with interaction term [(TZP*Tr); 0.085)]. The odds of developing MAKE-30 were not different between any group and FEP/MEM/AUC. The effect of VAN/TZP on the development of AKI was not modified by the VAN monitoring strategy (AUC vs trough). MAKE-30 outcomes were not different among the four cohorts.

Keywords: acute kidney injury, beta lactams; nephrotoxicity; therapeutic drug monitoring; vancomycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury* / chemically induced
  • Aged
  • Anti-Bacterial Agents* / administration & dosage
  • Anti-Bacterial Agents* / adverse effects
  • Area Under Curve
  • Cefepime* / administration & dosage
  • Cefepime* / adverse effects
  • Cefepime* / therapeutic use
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Meropenem* / administration & dosage
  • Meropenem* / adverse effects
  • Meropenem* / therapeutic use
  • Middle Aged
  • Piperacillin, Tazobactam Drug Combination* / administration & dosage
  • Piperacillin, Tazobactam Drug Combination* / adverse effects
  • Piperacillin, Tazobactam Drug Combination* / therapeutic use
  • Retrospective Studies
  • Sepsis / drug therapy
  • Vancomycin* / administration & dosage
  • Vancomycin* / adverse effects
  • Vancomycin* / therapeutic use


  • Vancomycin
  • Meropenem
  • Cefepime
  • Piperacillin, Tazobactam Drug Combination
  • Anti-Bacterial Agents