Association of imipenem/cilastatin with development of acute kidney injury in critically ill patients requiring carbapenem treatment

Abstract Cilastatin is an inhibitor of drug metabolism in the kidney which is only available for human use in combination with imipenem, a carbapenem antibiotic, as imipenem/cilastatin (I/C). Animal studies demonstrate cilastatin protects against acute kidney injury (AKI) and clinical studies suggest I/C may reduce the risk of AKI. However, the effective dose of cilastatin in animal studies is higher than that approved with imipenem, and rigorous assessment of the effect of I/C on AKI in patients with high risk of AKI, such as those in the intensive care unit (ICU), is indicated. To address this issue, we conducted a retrospective cohort study using 3 large ICU databases, including Medical Information Mart for Intensive Care III (MIMIC-III), MIMIC-IV, and the Amsterdam University Medical Center database (AUMC). Total 3916 patients were included and patients treated with I/C or non-cilastatin carbapenems (NCC) were compared using propensity score-based overlap weighting analysis. AKI development or progression was less commonly observed in I/C-treated patients than in NCC-treated patients in MIMIC-III (odds ratio [OR] and 95% confidence interval of I/C group: 0.51 [0.30–0.85]) while the outcome was similar between the groups in MIMIC-IV (OR: 1.22 [0.80–1.86]) and in AUMC (OR: 1.07 [0.77–1.48]). The outcome development was also similar between the groups with the overall analysis across all datasets by random effect model meta-analysis (OR: 0.89 [0.54–1.48]). In conclusion, I/C and other carbapenems do not differentially associate with AKI risks in ICU, and its putative effects may depend on patient characteristics and clinical settings.