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

Abstract

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.

Fig. 1

Framework for patient inclusion, index date, and follow-up for measures of kidney function. The figure shows follow-up definitions during combined exposure to vancomycin (teal bars) and a beta-lactam (light blue bars, either piperacillin–tazobactam or cefepime). A Two scenarios by which patients could enter the antibiotic cohort. For both scenarios, the index date was defined as the date and time when combined therapy started. B Time frame, with respect to antibiotic exposure, for measurement of kidney function markers at baseline and during follow-up. The period for baseline cystatin C measurement was the 24 h period immediately prior to the index date. The period for follow-up cystatin C measurement was the period from 48 to 72 h after the index date. For direct comparative analyses with cystatin C, change in serum creatinine was measured over the same time frame. Follow-up for KDIGO defined acute kidney injury (AKI) began on the index date and continued until: lapse in concomitant antibiotic exposure > 48 h, hospital discharge, death, or 14 days after the index date. We followed AKI episodes for 7 days after onset to assess severity stage and initiation of renal replacement therapy. Follow-up for mortality began on the index date and continued until death or until 30 days after the index date. C Alignment of antibiotic follow-up with the underlying time-line of the MESSI cohort study. Patients were included in cystatin C analyses if the timing of their blood draws aligned with the allowable time periods for baseline and follow-up cystatin C measurement (hashed gray-white boxes) as defined in B. The vertical solid black line denotes ICU admission (MESSI hour zero) and the gray shaded box is the period around MESSI hour zero during which eligible antibiotic courses had to be initiated (± 48 h). MESSI day zero plasma samples (red X) were obtained from residual citrated plasma collected at emergency department presentation, or for patients transferred from the hospital ward, at the point closest to ICU admission (dashed vertical lines around hour zero). Follow-up residual plasma was obtained approximately 48 h after ICU admission (dashed vertical lines around hour 48)

Fig. 2

Selection of patients from parent sepsis cohort into study-specific analytic cohorts. The study sample was selected from patients enrolled in MESSI from September 2008 to July 2020 (n = 3303). ESRD end stage renal disease, AKI acute kidney injury, HD hemodialysis, VN + PT vancomycin + piperacillin–tazobactam, VN + CP vancomycin + cefepime