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An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria

BACKGROUND: Evidence supports therapeutic drug monitoring of polymyxin B, but clinical data for establishing an area under the concentration–time curve across 24 h at steady state (AUC(ss,24 h)) threshold are still limited. This study aimed to examine exposure–response/toxicity relationship for poly...

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Autores principales: Yang, Jing, Liu, Shaohua, Lu, Jingli, Sun, Tongwen, Wang, Peile, Zhang, Xiaojian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578216/
https://www.ncbi.nlm.nih.gov/pubmed/36258197
http://dx.doi.org/10.1186/s13054-022-04195-7
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author Yang, Jing
Liu, Shaohua
Lu, Jingli
Sun, Tongwen
Wang, Peile
Zhang, Xiaojian
author_facet Yang, Jing
Liu, Shaohua
Lu, Jingli
Sun, Tongwen
Wang, Peile
Zhang, Xiaojian
author_sort Yang, Jing
collection PubMed
description BACKGROUND: Evidence supports therapeutic drug monitoring of polymyxin B, but clinical data for establishing an area under the concentration–time curve across 24 h at steady state (AUC(ss,24 h)) threshold are still limited. This study aimed to examine exposure–response/toxicity relationship for polymyxin B to establish an AUC(ss,24 h) threshold in a real-world cohort of patients. METHODS: Using a validated Bayesian approach to estimate AUC(ss,24 h) from two samples, AUC(ss,24 h) threshold that impacted the risk of polymyxin B-related nephrotoxicity and clinical response were derived by classification and regression tree (CART) analysis and validated by Cox regression analysis and logical regression analysis. RESULTS: A total of 393 patients were included; acute kidney injury (AKI) was 29.0%, clinical response was 63.4%, and 30-day all-cause mortality was 35.4%. AUC(ss,24 h) thresholds for AKI of > 99.4 mg h/L and clinical response of > 45.7 mg h/L were derived by CART analysis. Cox and logical regression analyses showed that AUC(ss,24 h) of > 100 mg h/L was a significant predictor of AKI (HR 16.29, 95% CI 8.16–30.25, P < 0.001) and AUC(ss,24 h) of ≥ 50 mg h/L (OR 4.39, 95% CI 2.56–7.47, P < 0.001) was independently associated with clinical response. However, these exposures were not associated with mortality. In addition, the correlation between trough concentration (1.2–2.8 mg/L) with outcomes was similar to AUC(ss,24 h). CONCLUSIONS: For critically ill patients, AUC(ss,24 h) threshold of 50–100 mg h/L was associated with decreased nephrotoxicity while assuring clinical efficacy. Therapeutic drug monitoring is recommended for individualizing polymyxin B dosing. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13054-022-04195-7.
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spelling pubmed-95782162022-10-19 An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria Yang, Jing Liu, Shaohua Lu, Jingli Sun, Tongwen Wang, Peile Zhang, Xiaojian Crit Care Research BACKGROUND: Evidence supports therapeutic drug monitoring of polymyxin B, but clinical data for establishing an area under the concentration–time curve across 24 h at steady state (AUC(ss,24 h)) threshold are still limited. This study aimed to examine exposure–response/toxicity relationship for polymyxin B to establish an AUC(ss,24 h) threshold in a real-world cohort of patients. METHODS: Using a validated Bayesian approach to estimate AUC(ss,24 h) from two samples, AUC(ss,24 h) threshold that impacted the risk of polymyxin B-related nephrotoxicity and clinical response were derived by classification and regression tree (CART) analysis and validated by Cox regression analysis and logical regression analysis. RESULTS: A total of 393 patients were included; acute kidney injury (AKI) was 29.0%, clinical response was 63.4%, and 30-day all-cause mortality was 35.4%. AUC(ss,24 h) thresholds for AKI of > 99.4 mg h/L and clinical response of > 45.7 mg h/L were derived by CART analysis. Cox and logical regression analyses showed that AUC(ss,24 h) of > 100 mg h/L was a significant predictor of AKI (HR 16.29, 95% CI 8.16–30.25, P < 0.001) and AUC(ss,24 h) of ≥ 50 mg h/L (OR 4.39, 95% CI 2.56–7.47, P < 0.001) was independently associated with clinical response. However, these exposures were not associated with mortality. In addition, the correlation between trough concentration (1.2–2.8 mg/L) with outcomes was similar to AUC(ss,24 h). CONCLUSIONS: For critically ill patients, AUC(ss,24 h) threshold of 50–100 mg h/L was associated with decreased nephrotoxicity while assuring clinical efficacy. Therapeutic drug monitoring is recommended for individualizing polymyxin B dosing. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13054-022-04195-7. BioMed Central 2022-10-18 /pmc/articles/PMC9578216/ /pubmed/36258197 http://dx.doi.org/10.1186/s13054-022-04195-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Yang, Jing
Liu, Shaohua
Lu, Jingli
Sun, Tongwen
Wang, Peile
Zhang, Xiaojian
An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria
title An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria
title_full An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria
title_fullStr An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria
title_full_unstemmed An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria
title_short An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria
title_sort area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin b dosing in patients with carbapenem-resistant gram-negative bacteria
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578216/
https://www.ncbi.nlm.nih.gov/pubmed/36258197
http://dx.doi.org/10.1186/s13054-022-04195-7
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