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

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)239-243
Number of pages5
JournalInternational Journal of Antimicrobial Agents
Volume51
Issue number2
DOIs
StatePublished - Feb 2018

Fingerprint

Vancomycin
Acute Kidney Injury
Kidney
Wounds and Injuries
Poisons
PubMed
MEDLINE
Biomarkers
Sensitivity and Specificity
Therapeutics
Pharmaceutical Preparations

Keywords

  • Biological markers
  • Nephrotoxicity
  • Pharmacokinetics
  • Pharmacology
  • Vancomycin

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

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

In: International Journal of Antimicrobial Agents, Vol. 51, No. 2, 02.2018, p. 239-243.

Research output: Contribution to journalArticle

O'Donnell, JN, Rhodes, NJ, Miglis, CM, Catovic, L, Liu, J, Cluff, C, Pais, G, Avedissian, S, Joshi, MD, Griffin, B, Prozialeck, W, Gulati, A, Lodise, TP & Scheetz, MH 2018, 'Dose, duration, and animal sex predict vancomycin-associated acute kidney injury in preclinical studies', International Journal of Antimicrobial Agents, vol. 51, no. 2, pp. 239-243. https://doi.org/10.1016/j.ijantimicag.2017.08.012
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. / Dose, duration, and animal sex predict vancomycin-associated acute kidney injury in preclinical studies. In: International Journal of Antimicrobial Agents. 2018 ; Vol. 51, No. 2. pp. 239-243.
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abstract = "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.",
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T1 - Dose, duration, and animal sex predict vancomycin-associated acute kidney injury in preclinical studies

AU - O'Donnell, J. Nicholas

AU - Rhodes, Nathaniel J.

AU - Miglis, Cristina M.

AU - Catovic, Lejla

AU - Liu, Jiajun

AU - Cluff, Cameron

AU - Pais, Gwendolyn

AU - Avedissian, Sean

AU - Joshi, Medha D.

AU - Griffin, Brooke

AU - Prozialeck, Walter

AU - Gulati, Anil

AU - Lodise, Thomas P.

AU - Scheetz, Marc H.

PY - 2018/2

Y1 - 2018/2

N2 - 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.

AB - 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.

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