Pharmacokinetic/pharmacodynamic evaluation of tobramycin dosing in critically ill patients: the Hartford nomogram does not fit

Pharmacokinetic/pharmacodynamic evaluation of tobramycin dosing in critically ill patients: the Hartford nomogram does not fit

Abstract Objectives Extended-interval dosing of tobramycin is widely applied in patients with the Hartford nomogram as a representative, while this dosing approach has not been extensively evaluated in critically ill patients. The goal of this study was to characterize the pharmacokinetics of tobram...

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Veröffentlicht in:Journal of antimicrobial chemotherapy 2021-09, Vol.76 (9), p.2335-2341
Hauptverfasser: Xie, Feifan, Wang, Yan, Peng, Yaru, Cheng, Zeneng, Li, Sanwang
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container_title Journal of antimicrobial chemotherapy
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creator Xie, Feifan
Wang, Yan
Peng, Yaru
Cheng, Zeneng
Li, Sanwang
description Abstract Objectives Extended-interval dosing of tobramycin is widely applied in patients with the Hartford nomogram as a representative, while this dosing approach has not been extensively evaluated in critically ill patients. The goal of this study was to characterize the pharmacokinetics of tobramycin and to evaluate the appropriateness of the Hartford nomogram in critically ill patients. Methods A retrospective analysis was performed based on a medical critical care database. The extracted concentration data of tobramycin were used for the construction of the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Real-world data-based simulations were conducted to evaluate the pharmacodynamic target attainment (Cmax/MIC ≥10) and safety (concentration
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The goal of this study was to characterize the pharmacokinetics of tobramycin and to evaluate the appropriateness of the Hartford nomogram in critically ill patients. Methods A retrospective analysis was performed based on a medical critical care database. The extracted concentration data of tobramycin were used for the construction of the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Real-world data-based simulations were conducted to evaluate the pharmacodynamic target attainment (Cmax/MIC ≥10) and safety (concentration &lt;0.5 mg/L for at least 4 h) of the Hartford nomogram. Results A population pharmacokinetic model was built based on 307 measurements in 140 unique patients and externally validated by an independent study dataset. A two-compartment model was optimal for the structure model and creatinine clearance remained as the only covariate in the final model correlating to the clearance of tobramycin. Simulations indicated that the Hartford nomogram is effective for infections due to pathogens with an MIC of ≤1 mg/L, but not with an MIC of 2 mg/L. The percentage of patients who reached the non-toxicity target was quite low under the Hartford nomogram and a further extension of the dosing interval was necessary to minimize the toxicity. Conclusions The Hartford nomogram was not suitable for critically ill patients with pathogen MICs of 2 mg/L and drug monitoring is required to manage efficacy and toxicity.</description><identifier>ISSN: 0305-7453</identifier><identifier>EISSN: 1460-2091</identifier><identifier>DOI: 10.1093/jac/dkab164</identifier><language>eng</language><publisher>Oxford University Press</publisher><ispartof>Journal of antimicrobial chemotherapy, 2021-09, Vol.76 (9), p.2335-2341</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c334t-3209fdab1f832fbea3ed67170ff02b52a0bebfee12848d7a8ce4241e3e864fb23</citedby><cites>FETCH-LOGICAL-c334t-3209fdab1f832fbea3ed67170ff02b52a0bebfee12848d7a8ce4241e3e864fb23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1578,27901,27902</link.rule.ids></links><search><creatorcontrib>Xie, Feifan</creatorcontrib><creatorcontrib>Wang, Yan</creatorcontrib><creatorcontrib>Peng, Yaru</creatorcontrib><creatorcontrib>Cheng, Zeneng</creatorcontrib><creatorcontrib>Li, Sanwang</creatorcontrib><title>Pharmacokinetic/pharmacodynamic evaluation of tobramycin dosing in critically ill patients: the Hartford nomogram does not fit</title><title>Journal of antimicrobial chemotherapy</title><description>Abstract Objectives Extended-interval dosing of tobramycin is widely applied in patients with the Hartford nomogram as a representative, while this dosing approach has not been extensively evaluated in critically ill patients. The goal of this study was to characterize the pharmacokinetics of tobramycin and to evaluate the appropriateness of the Hartford nomogram in critically ill patients. Methods A retrospective analysis was performed based on a medical critical care database. The extracted concentration data of tobramycin were used for the construction of the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Real-world data-based simulations were conducted to evaluate the pharmacodynamic target attainment (Cmax/MIC ≥10) and safety (concentration &lt;0.5 mg/L for at least 4 h) of the Hartford nomogram. Results A population pharmacokinetic model was built based on 307 measurements in 140 unique patients and externally validated by an independent study dataset. A two-compartment model was optimal for the structure model and creatinine clearance remained as the only covariate in the final model correlating to the clearance of tobramycin. Simulations indicated that the Hartford nomogram is effective for infections due to pathogens with an MIC of ≤1 mg/L, but not with an MIC of 2 mg/L. The percentage of patients who reached the non-toxicity target was quite low under the Hartford nomogram and a further extension of the dosing interval was necessary to minimize the toxicity. 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The goal of this study was to characterize the pharmacokinetics of tobramycin and to evaluate the appropriateness of the Hartford nomogram in critically ill patients. Methods A retrospective analysis was performed based on a medical critical care database. The extracted concentration data of tobramycin were used for the construction of the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Real-world data-based simulations were conducted to evaluate the pharmacodynamic target attainment (Cmax/MIC ≥10) and safety (concentration &lt;0.5 mg/L for at least 4 h) of the Hartford nomogram. Results A population pharmacokinetic model was built based on 307 measurements in 140 unique patients and externally validated by an independent study dataset. A two-compartment model was optimal for the structure model and creatinine clearance remained as the only covariate in the final model correlating to the clearance of tobramycin. Simulations indicated that the Hartford nomogram is effective for infections due to pathogens with an MIC of ≤1 mg/L, but not with an MIC of 2 mg/L. The percentage of patients who reached the non-toxicity target was quite low under the Hartford nomogram and a further extension of the dosing interval was necessary to minimize the toxicity. Conclusions The Hartford nomogram was not suitable for critically ill patients with pathogen MICs of 2 mg/L and drug monitoring is required to manage efficacy and toxicity.</abstract><pub>Oxford University Press</pub><doi>10.1093/jac/dkab164</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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title Pharmacokinetic/pharmacodynamic evaluation of tobramycin dosing in critically ill patients: the Hartford nomogram does not fit
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