Combination of vancomycin plus piperacillin and risk of acute kidney injury: a worldwide pharmacovigilance database analysis

Abstract Background Excess of acute kidney injury (AKI) secondary to the association of vancomycin plus piperacillin is debated. Objectives To detect a signal for an increased risk of AKI with the vancomycin and piperacillin combination compared with other vancomycin-based regimens. Methods Using VigiBase, the WHO global database of individual case safety reports (ICSR) from 1997 to 2019, we conducted a disproportionality analysis comparing the reporting of AKI cases between different vancomycin-based regimens (vancomycin plus piperacillin, cefepime or meropenem). To take into account a possible notoriety bias, we secondarily restricted the study period to before 2014, the date of the first publication of AKI in patients receiving vancomycin plus piperacillin. Results are expressed using the reporting OR (ROR) and its 95% CI. Results From 1997 to 2019, 53 701 ICSR concerning vancomycin have been registered in the database, including 6016 reports of AKI (11.2%), among which 925 (15.4%) were reported with vancomycin/piperacillin, 339 (5.6%) with vancomycin/cefepime and 197 (3.7%) with vancomycin/meropenem. ROR (95% CI) for AKI was 2.6 (2.4–2.8) for vancomycin/piperacillin, 2.5 (2.2–2.9) for vancomycin/cefepime and 0.5 (0.4–0.6) for vancomycin/meropenem versus other vancomycin-containing regimens. After restriction of the study period to 1997–2013, the ROR for AKI remains significant only for vancomycin/piperacillin [ROR (95% CI) = 2.1 (1.8–2.4)]. Conclusions We found a disproportionality in reports of AKI in patients receiving vancomycin plus piperacillin compared with vancomycin in other regimens. This suggests a drug–drug interaction between these two antibiotics resulting in an increased risk of AKI.