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β-lactam precision dosing in critically ill children: Current state and knowledge gaps.

ABSTRACT: There has been emerging interest in implementing therapeutic drug monitoring and model-informed precision dosing of β-lactam antibiotics in critically ill patients, including children. Despite a position paper endorsed by multiple international societies that support these efforts in critically ill adults, implementation of β-lactam precision dosing has not been widely adopted. In this review, we highlight what is known about β-lactam antibiotic pharmacokinetics and pharmacodynamics in critically ill children. We also define the knowledge gaps that present barriers to acceptance and implementation of precision dosing of β-lactam antibiotics in critically ill children: a lack of consensus on which subpopulations would benefit most from precision dosing and the uncertainty of how precision dosing changes outcomes. We conclude with opportunities for further research to close these knowledge gaps.

SUBMITTER: Tang Girdwood S

PROVIDER: S-EPMC9752101 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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β-lactam precision dosing in critically ill children: Current state and knowledge gaps.

Tang Girdwood Sonya S Pavia Kathryn K Paice Kelli K Hambrick H Rhodes HR Kaplan Jennifer J Vinks Alexander A AA

Frontiers in pharmacology 20221201

There has been emerging interest in implementing therapeutic drug monitoring and model-informed precision dosing of β-lactam antibiotics in critically ill patients, including children. Despite a position paper endorsed by multiple international societies that support these efforts in critically ill adults, implementation of β-lactam precision dosing has not been widely adopted. In this review, we highlight what is known about β-lactam antibiotic pharmacokinetics and pharmacodynamics in criticall ...[more]

PMID: 36532752

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Project description:Dose optimization of novel β-lactam antibiotics (NBLA) has become necessary given the increased prevalence of multidrug-resistant infections in intensive care units coupled with the limited number of available treatment options. Unfortunately, recommended dose regimens of NBLA based on PK/PD indices are not well-defined for critically ill patients presenting with special situations (i.e., obesity, extracorporeal membrane oxygenation (ECMO), augmented renal clearance (ARC), and renal replacement therapies (RRT)). This review aimed to discuss and summarize the available literature on the PK/PD attained indices of NBLA among critically ill patients with special circumstances. PubMed, MEDLINE, Scopus, Google Scholar, and Embase databases were searched for studies published between January 2011 and May 2022. Articles relevant to NBLA (i.e., ceftolozane/tazobactam, ceftazidime/avibactam, cefiderocol, ceftobiprole, imipenem/relebactam, and meropenem/vaborbactam) were selected. The MeSH terms of "obesity", "augmented renal clearance", "renal replacement therapy", "extracorporeal membrane oxygenation", "pharmacokinetic", "pharmacodynamic" "critically ill", and "intensive care" were used for identification of articles. The search was limited to adult humans' studies that were published in English. A narrative synthesis of included studies was then conducted accordingly. Available evidence surrounding the use of NBLA among critically ill patients presenting with special situations was limited by the small sample size of the included studies coupled with high heterogeneity. The PK/PD target attainments of NBLA were reported to be minimally affected by obesity and/or ECMO, whereas the effect of renal functionality (in the form of either ARC or RRT) was more substantial. Critically ill patients presenting with special circumstances might be at risk of altered NBLA pharmacokinetics, particularly in the settings of ARC and RRT. More robust, well-designed trials are still required to define effective dose regimens able to attain therapeutic PK/PD indices of NBLA when utilized in those special scenarios, and thus aid in improving the patients' outcomes.

Project description:Fluconazole is frequently used for the treatment of invasive Candida infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target fAUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.).

Dataset Information

β-lactam precision dosing in critically ill children: Current state and knowledge gaps.

Publications

β-lactam precision dosing in critically ill children: Current state and knowledge gaps.

Similar Datasets

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