Personalised antimicrobial dosing: standing on the shoulders of giants

Wallenburg, Eveline; Heine, Rob ter; Schouten, Jeroen; Brüggemann, Roger J. M.

doi:10.1016/j.ijantimicag.2020.106062

Cited by 6 publications

(3 citation statements)

References 53 publications

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“…Additionally, routine TDM strategies could be applied in clinical practice to ensure therapeutic and non-toxic drug exposure after the starting dose has been given. Given the large inter-individual variability in critically ill children, the relatively well-known PK targets associated with efficacy and/or safety, and the inability to judge therapeutic effect by other parameters, routine TDM for antibiotics could be beneficial in this patient population (Wallenburg et al, 2020). Ultimately, model-informed precision dosing applications that are currently under development can translate these robust PK data into tailored dosing regimens for an individual patient, using TDM samples and Bayesian feedback to further improve and individualize dosing of antibiotics in special populations (Darwich et al, 2017;Keizer et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept

et al. 2020

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Background: Modeling and simulation is increasingly used to study pediatric pharmacokinetics, but clinical implementation of age-appropriate doses lags behind. Therefore, we aimed to develop model-informed doses using published pharmacokinetic data and a decision framework to adjust dosing guidelines based on these doses, using piperacillin and amikacin in critically ill children as proof of concept.Methods: Piperacillin and amikacin pharmacokinetic models in critically ill children were extracted from literature. Concentration-time profiles were simulated for various dosing regimens for a virtual PICU patient dataset, including the current DPF dose and doses proposed in the studied publications. Probability of target attainment (PTA) was compared between the different dosing regimens. Next, updated dosing recommendations for the DPF were proposed, and evaluated using a new framework based on PK study quality and benefit-risk analysis of clinical implementation.Results: Three studies for piperacillin (critically ill children) and one for amikacin (critically ill pediatric burn patients) were included. Simulated concentration-time profiles were performed for a virtual dataset of 307 critically ill pediatric patients, age range 0.1–17.9 y. PTA for unbound piperacillin trough concentrations >16 mg/L was >90% only for continuous infusion regimens of 400 mg/kg/day vs. 9.7% for the current DPF dose (80 mg/kg/6 h, 30 min infusion). Amikacin PTA was >90% with 20 mg/kg/d, higher than the PTA of the DPF dose of 15 mg/kg/d (63.5%). Using our new decision framework, altered DPF doses were proposed for piperacillin (better PTA with loading dose plus continuous infusion), but not for amikacin (studied and target population were not comparable and risk for toxicity with higher dose).Conclusions: We show the feasibility to develop model-informed dosing guidelines for clinical implementation using existing pharmacokinetic data. This approach could complement literature and consensus-based dosing guidelines for off-label drugs in the absence of stronger evidence to support pediatricians in daily practice.

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Section: Discussionmentioning

confidence: 99%

A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept

et al. 2020

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“…Several factors might lead to this treatment failure, including inadequate penetration of the antimicrobial to the target site [7][8][9], since site drug levels may substantially vary from the corresponding plasma drug concentrations [15]. Suboptimal antibiotic doses in the site of infection may also result in adverse reactions, toxicity, resistance, and higher costs [10].…”

Section: Introductionmentioning

confidence: 99%

“…Various strategies have been proposed to improve antibiotic use, such as antibiotic stewardship [12,13], therapeutic drug monitoring (TDM), and precision dosing [14][15][16]. Dose adjustments have recently shown promising evidence for improved outcomes and reduction of antimicrobial resistance [17].…”

Section: Introductionmentioning

confidence: 99%

Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review

Codina

Jorda

2022

Clin Pharmacokinet

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The pathophysiology of sepsis alters drug pharmacokinetics, resulting in inadequate drug exposure and target-site concentration. Suboptimal exposure leads to treatment failure and the development of antimicrobial resistance. Therefore, we seek to optimize antimicrobial therapy in sepsis by selecting the right drug and the correct dosage. A prerequisite for achieving this goal is characterization and understanding of the mechanisms of pharmacokinetic alterations. However, most infections take place not in blood but in different body compartments. Since tissue pharmacokinetic assessment is not feasible in daily practice, we need to tailor antibiotic treatment according to the specific patient's pathophysiological processes. The complex pathophysiology of sepsis and the ineffectiveness of current targeted therapies suggest that treatments guided by biomarkers predicting target-site concentration could provide a new therapeutic strategy. Inflammation, endothelial and coagulation activation markers, and blood flow parameters might be indicators of impaired tissue distribution. Moreover, hepatic and renal dysfunction biomarkers can predict not only drug metabolism and clearance but also drug distribution. Identification of the right biomarkers can direct drug dosing and provide timely feedback on its effectiveness. Therefore, this might decrease antibiotic resistance and the mortality of critically ill patients. This article fills the literature gap by characterizing patient biomarkers that might be used to predict unbound plasma-to-tissue drug distribution in critically ill patients. Although all biomarkers must be clinically evaluated with the ultimate goal of combining them in a clinically feasible scoring system, we support the concept that the appropriate biomarkers could be used to direct targeted antibiotic dosing.

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Advances in clinical antibiotic testing

Rentsch

2022

Advances in Clinical Chemistry

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Personalised antimicrobial dosing: standing on the shoulders of giants

Cited by 6 publications

References 53 publications

A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept

A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept

Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review

Advances in clinical antibiotic testing

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