Dose, duration, and animal sex predict vancomycin-associated acute kidney injury in preclinical studies

作者：O'Donnell J Nicholas; Rhodes Nathaniel J; Miglis Cristina M; Catovic Lejla; Liu Jiajun; Cluff Cameron; Pais Gwendolyn; Avedissian Sean; Joshi Medha D; Griffin Brooke; Prozialeck Walter; Gulati Anil; Lodise Thomas P; Scheetz Marc H^*

来源：International Journal of Antimicrobial Agents, 2018, 51(2): 239-243.

DOI：10.1016/j.ijantimicag.2017.08.012

• Vancomycin
• Biological markers
• Nephrotoxicity
• Pharmacokinetics
• Pharmacology

Background: Although the exposure-dependent efficacy thresholds of vancomycin have been probed, less is known about acute kidney injury (AKI) thresholds for this drug. Sensitive urinary biomarkers, such as kidney injury molecule 1 (KIM-1), have shown high sensitivity and specificity for vancomycin-associated AKI. The aims of the study were to determine if there were dose-response curves with urinary KIM-1, and to evaluate the impact of therapy duration and sex on observed relationships.
Methods: A systematic review was conducted via PubMed/MEDLINE. Data were compiled from preclinical studies that reported individual subject data for urinary KIM-1 concentrations, vancomycin dose (mg/kg), duration of treatment, and sex. Sigmoidal Hill-type models were fit to the individual dose-response data.
Results: A total of 15 studies were identified, 6 of which reported vancomycin dose and KIM-1 data. Of these, three included individual animal-level data suitable for analysis. For all pooled rats, increasing total daily vancomycin doses displayed a dose-response curve with urinary KIM-1 concentrations (50% maximal toxic response=130.4 mg/kg/day). Dose-response curves were shifted left for females vs. males (P=0.05) and for long (i.e. >= 7 days) vs. short (i.e. <4 days) duration of vancomycin therapy (P=0.02).
Conclusions: The collective findings demonstrate a clear dose-response relationship between vancomycin dose and AKI. As these analyses focused exclusively on dose-response relationships, additional preclinical data are needed to more clearly define vancomycin exposures that predict the onset of AKI.

• 出版日期2018-2