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Updated: Jun 16, 2025

Multiplex Therapeutic Drug Monitoring by Isotope-dilution HPLC-MS/MS of Antibiotics in Critical Illnesses
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Multiplex Therapeutic Drug Monitoring by Isotope-dilution HPLC-MS/MS of Antibiotics in Critical Illnesses

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Predictive performance of multi-model approaches for model-informed precision dosing of piperacillin in critically

Lea Marie Schatz1, Sebastian Greppmair1, Alexandra K Kunzelmann1

  • 1Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany.

International Journal of Antimicrobial Agents
|August 15, 2024
PubMed
Abstract

Insights

Model averaging algorithm (MAA) improves model-informed precision dosing (MIPD) for piperacillin/tazobactam, enhancing antibiotic exposure optimization. Integrating a second TDM sample within 24 hours maximizes target attainment, especially for critically ill patients.

Area of Science:

  • Pharmacology
  • Clinical Pharmacy
  • Pharmacometrics

Background:

  • Piperacillin/tazobactam dosing requires optimization to prevent toxicity and resistance.
  • Model-informed precision dosing (MIPD) shows promise in improving antibiotic target attainment.
  • Previous evaluations suggest MIPD can enhance therapeutic outcomes.

Purpose of the Study:

  • To compare the predictive performance of different MIPD approaches: single-model, model selection algorithm (MSA), and model averaging algorithm (MAA).
  • To assess the impact of one (B1) versus two (B2) therapeutic drug monitoring (TDM) samples on MIPD accuracy and precision.
  • To evaluate MIPD strategies for piperacillin (PIP) dosing in a multicenter setting.

Main Methods:

  • A multicenter dataset of 561 patients and 3654 TDM samples was used.
  • Predictive performance was evaluated based on inaccuracy, imprecision, and expected target attainment.
  • Three MIPD approaches (single-model, MSA, MAA) were compared using candidate PIP models.

Main Results:

  • MAA demonstrated superior predictive performance over MSA and single models with one TDM sample (B1).
  • Inaccuracy: MAA (±3%) < single models (±8%) < MSA (<10%). Imprecision: MAA (<25%) < single models (<28%) < MSA (<31%). Target attainment: MAA (>77%) > single models (>73%) > MSA (>71%).
  • A second TDM sample significantly improved precision and target attainment for all approaches, with maximal attainment (>90%) when integrated within 24 hours.

Conclusions:

  • MAA streamlines MIPD by reducing the risk of selecting suboptimal models.
  • MIPD of PIP using MAA optimizes antibiotic exposure in critically ill patients.
  • MAA enhances predictive performance, safety, and usability of MIPD, particularly with a single TDM sample.
Keywords:
Critically illIntensive care unitModel-informed precision dosingPopulation pharmacokineticsSepsisTherapeutic drug monitoring

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