The kinetic glomerular filtration rate is not interchangeable with measured creatinine clearance for prediction of piperacillin underexposure in critically ill patients with augmented renal clearance
In the critical care setting, augmented renal clearance (ARC) is increasingly recognized as one of the leading causes of subtherapeutic antibiotic exposure [
1]. However, commonly used formulas for estimating glomerular filtration rate (GFR) are inaccurate in patients with ARC and the 24-h urinary creatinine clearance (Cr
CL) remains the best available approach for optimizing empirical antimicrobial therapy [
2]. On the other hand, no study has evaluated the clinical and prognostic value of the kinetic estimated GFR (KeGFR) in this context. We thus aimed to determine whether KeGFR could be a reliable alternative to measured Cr
CL in critically ill patients needing early initiation of an appropriate piperacillin dosing regimen.
For this purpose, we retrospectively analyzed 60 consecutive patients who underwent 24-h urinary Cr
CL measurements and therapeutic drug monitoring during the first 3 days of antimicrobial therapy of piperacillin administered 16 g/day continuously. The protocol pertaining to this substudy has been published elsewhere [
3]. As previously described, the corresponding KeGFR was calculated as follows:
\( \frac{\mathrm{Baseline}\ \mathrm{sCr}\ \mathrm{x}\ \mathrm{eGFR}}{\mathrm{Mean}\ \mathrm{sCr}}\times \left(1-\frac{24\ \mathrm{x}\ \Delta \mathrm{sCr}}{\Delta \mathrm{t}\ \mathrm{x}\ \mathrm{Max}\Delta \mathrm{sCr}/\mathrm{Day}}\right) \) with eGFR derived from the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation using serum creatinine (sCr) before admission, Δt fixed at 24 h between two sCr measurements, and maximal sCr increase per day approximated to 133 μmol/L [
4]. ARC was defined by a measured Cr
CL ≥ 130 mL/min/1.73 m
2. Piperacillin underdosing was arbitrarily defined by a free drug concentration ≤ 32 μg/ml at steady state.
Anzeige
Among the 180 samples analyzed, the incidence of ARC was 48% (median Cr
CL values = 124 [83–170] ml/min/1.73 m
2) and the incidence of piperacillin underdosing was 51% (median piperacillin concentrations = 32 [22–47] μg/ml). The diagnostic agreement between KeGFR and Cr
CL was only moderate (κ = 0.48 [95% confidence interval 0.4–0.55]) (Fig.
1). Comparison between KeGFR and Cr
CL showed a mean bias of − 8.7 ml/min/1.73 m
2 and limit of agreement from − 99 ml/min/1.73 m
2 to 82 ml/min/1.73 m
2. Finally, the area under the ROC curve generated for KeGFR was significantly lower than the one generated for measured Cr
CL for prediction of piperacillin underdosing (0.76 [0.68–0.83] vs 0.85 [0.79–0.91],
p = 0.03; Fig.
2).
Fig. 1
Correlation between measured Cr
CL and KeGFR (r
2 = 0.54,
p < 0.0001) and repartition of samples with (
white circles) or without (
black circles) piperacillin underdosing, defined by an unbound concentration ≤ 32 μg/ml. ARC was defined by a measured Cr
CL or a KeGFR ≥ 130 ml/min/1.73 m
2. Samples in the
gray shaded area are considered to be well classified
Fig. 2
Receiver operating characteristics (ROC) curves evaluating the ability of KeGFR and measured Cr
CL to predict piperacillin underdosing. Areas under ROC curves between KeGFR and measured Cr
CL were compared using the Handley approach. Piperacillin underdosing was defined by a free drug concentration ≤ 32 μg/ml
×
×
In conclusion, KeGFR is not interchangeable with measured Cr
CL for prediction of piperacillin underexposure in critically ill patients with ARC. Also, scarce data may suggest a better predictive value of Cockcroft-Gault compared to MDRD (Modification of Diet in Renal Disease Study) or CKD-EPI for identifying patients with ARC [
5]; a measured CL
CR should be performed to accurately guide drug dosing. This study emphasizes the need for dosing adjustment and therapeutic drug monitoring in patients with ARC.
Acknowledgements
The authors thank Nicolas d’Houdain for his contribution to sample storage, preparation, and quantification.
Funding
Only departmental funds were used for this study. No external funds were obtained.
Anzeige
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval was obtained from the Institutional Review Board (Comite de Protection des Personnes Sud-Ouest et Outre Mer III, Bordeaux, France; protocol number DC 2016/147), which waived the need for written consent. Patients or next of kin were orally informed of the goal and design of the study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (
http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
The kinetic glomerular filtration rate is not interchangeable with measured creatinine clearance for prediction of piperacillin underexposure in critically ill patients with augmented renal clearance
Autoren:
Cédric Carrié Sébastien Rubin Pierre Sioniac Dominique Breilh Matthieu Biais
