Intensive
Care Medicine (2022) Published: 14
July 2022
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.
