Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial

Tim M J Ewoldt; Alan Abdulla; Wim J R Rietdijk; Anouk E Muller; Brenda C M de Winter; Nicole G M Hunfeld; Ilse M Purmer; Peter van Vliet; Evert-Jan Wils; Jasper Haringman; Annelies Draisma; Tom A Rijpstra; Attila Karakus; Diederik Gommers; Henrik Endeman; Birgit C P Koch

doi:10.1007/s00134-022-06921-9

Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial

Tim M J Ewoldt^*, Alan Abdulla, Wim J R Rietdijk, Anouk E Muller, Brenda C M de Winter, Nicole G M Hunfeld, Ilse M Purmer, Peter van Vliet, Evert-Jan Wils, Jasper Haringman, Annelies Draisma, Tom A Rijpstra, Attila Karakus, Diederik Gommers, Henrik Endeman, Birgit C P Koch

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

PURPOSE: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.

METHODS: This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.

RESULTS: In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.

CONCLUSIONS: We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

Original language	English
Pages (from-to)	1760-1771
Number of pages	12
Journal	Intensive Care Medicine
Volume	48
Issue number	12
Early online date	9 Nov 2022
DOIs	https://doi.org/10.1007/s00134-022-06921-9
Publication status	E-pub ahead of print - 9 Nov 2022

Bibliographical note

Funding Information:
This project has received funding from the Dutch Organization for Health Research and Development ZonMw (Grant 848017008), Stichting de Merel and Erasmus MC MRace Grant. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Publisher Copyright:
© 2022, The Author(s).

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Ewoldt, T. M. J., Abdulla, A., Rietdijk, W. J. R., Muller, A. E., de Winter, B. C. M., Hunfeld, N. G. M., Purmer, I. M., van Vliet, P., Wils, E-J., Haringman, J., Draisma, A., Rijpstra, T. A., Karakus, A., Gommers, D., Endeman, H., & Koch, B. C. P. (2022). Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial. Intensive Care Medicine, 48(12), 1760-1771. https://doi.org/10.1007/s00134-022-06921-9

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abstract = "PURPOSE: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.METHODS: This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.RESULTS: In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.CONCLUSIONS: We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.",

author = "Ewoldt, {Tim M J} and Alan Abdulla and Rietdijk, {Wim J R} and Muller, {Anouk E} and {de Winter}, {Brenda C M} and Hunfeld, {Nicole G M} and Purmer, {Ilse M} and {van Vliet}, Peter and Evert-Jan Wils and Jasper Haringman and Annelies Draisma and Rijpstra, {Tom A} and Attila Karakus and Diederik Gommers and Henrik Endeman and Koch, {Birgit C P}",

note = "Funding Information: This project has received funding from the Dutch Organization for Health Research and Development ZonMw (Grant 848017008), Stichting de Merel and Erasmus MC MRace Grant. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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Ewoldt, TMJ , Abdulla, A , Rietdijk, WJR , Muller, AE , de Winter, BCM , Hunfeld, NGM, Purmer, IM, van Vliet, P, Wils, E-J, Haringman, J, Draisma, A, Rijpstra, TA, Karakus, A, Gommers, D , Endeman, H & Koch, BCP 2022, 'Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial', Intensive Care Medicine, vol. 48, no. 12, pp. 1760-1771. https://doi.org/10.1007/s00134-022-06921-9

TY - JOUR

T1 - Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients

T2 - a multicentre randomised clinical trial

AU - Ewoldt, Tim M J

AU - Abdulla, Alan

AU - Rietdijk, Wim J R

AU - Muller, Anouk E

AU - de Winter, Brenda C M

AU - Hunfeld, Nicole G M

AU - Purmer, Ilse M

AU - van Vliet, Peter

AU - Wils, Evert-Jan

AU - Haringman, Jasper

AU - Draisma, Annelies

AU - Rijpstra, Tom A

AU - Karakus, Attila

AU - Gommers, Diederik

AU - Endeman, Henrik

AU - Koch, Birgit C P

N1 - Funding Information: This project has received funding from the Dutch Organization for Health Research and Development ZonMw (Grant 848017008), Stichting de Merel and Erasmus MC MRace Grant. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Publisher Copyright: © 2022, The Author(s).

PY - 2022/11/9

Y1 - 2022/11/9

N2 - PURPOSE: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.METHODS: This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.RESULTS: In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.CONCLUSIONS: We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

AB - PURPOSE: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.METHODS: This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.RESULTS: In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.CONCLUSIONS: We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

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U2 - 10.1007/s00134-022-06921-9

DO - 10.1007/s00134-022-06921-9

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VL - 48

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JO - Intensive Care Medicine

JF - Intensive Care Medicine

SN - 0342-4642

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Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial

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