Therapeutic drug monitoring of beta-lactam antibiotics – Influence of sample stability on the analysis of piperacillin, meropenem, ceftazidime and flucloxacillin by HPLC-UV

Pinder, Nadine; Brenner, Thorsten; Swoboda, Stefanie; Weigand, Markus; Hoppe-Tichy, Torsten

doi:10.1016/j.jpba.2017.05.037

Cited by 68 publications

(84 citation statements)

References 51 publications

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“… 20 Most assays used in TDM programmes and PK studies of critically ill patients measure total β-lactam antibiotic concentrations. 21 , 22 In order to individualize dosing regimens, published plasma protein-binding percentages derived from studies performed in non-critically ill patients are used to calculate unbound concentrations from the measured total concentrations. 20 , 23 Our results show that these assays may not be suitable in clinical practice, where the target is defined as the unbound concentration, i.e.…”

Section: Discussionmentioning

confidence: 99%

Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

Jager

Hest

Xie

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. Objectives To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. Methods First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. Results A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. Conclusions For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.

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Section: Discussionmentioning

confidence: 99%

Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

Jager

Hest

Xie

et al. 2020

Journal of Antimicrobial Chemotherapy

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“…Using scavenged blood from opportunistic sampling requires an understanding of the effect of blood or plasma storage on the degradation of β‐lactam antibiotics over time. For long‐term storage up to 1 year, solutions or plasma containing β‐lactam antibiotics should be stored at −70°C to −80°C to limit degradation and for accurate concentration measurement 8–10 . Recent studies have sought to evaluate β‐lactam antibiotic stability in human whole blood and plasma at various temperatures.…”

mentioning

confidence: 99%

Demonstrating Feasibility of an Opportunistic Sampling Approach for Pharmacokinetic Studies of β‐Lactam Antibiotics in Critically Ill Children

Girdwood

Tang

Murphy

et al. 2020

The Journal of Clinical Pharma

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There has been increasing interest in incorporating β‐lactam precision dosing into routine clinical care, but robust population pharmacokinetic models in critically ill children are needed for these purposes. The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration‐versus‐time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single‐center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or piperacillin/tazobactam and who had residual blood scavenged from samples obtained for routine clinical care were enrolled. A total of 138 samples from 22 pediatric patients were collected in a 2‐week period. For all 3 antibiotics, the samples collected covered the entire dosing intervals and were not clustered around specific times. There was high variability in the free concentrations and in the percentage of drug bound to protein. There was less than 15% degradation for meropenem or piperacillin when stored in whole blood or plasma at 4°C after 6 days. Cefepime degraded by more than 15% after 3 days. The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.

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“…They include mass spectrometry and high-performance liquid chromatography. As can be seen from Table 3, various chromatographic methods allow the determination of the concentration of beta-lactams, however, this requires careful sample preparation, which consists of removing blood cells, followed by precipitation of proteins and a ten-fold dilution of the sample [84]. In this section, we limited ourselves to beta-lactam antibiotics for an overall assessment of the situation, although there is a lot of work in this field.…”

Section: Potential Of Analytical Methods Used To Assess Content Of Anmentioning

confidence: 99%

Monitoring Antibiotics and Inflammatory Markers in Human Blood: Impact in Choice of Antibiotic Therapy and Used Methods

Berlina¹,

Zherdev²,

Dzantiev³

2019

Preprint

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In the modern world, the problem of antibiotic therapy is acute. Despite the diversity of existing antibiotic drugs, their efficacy decreases as new, resistant forms of pathogenic microorganisms emerge. It is extremely difficult to control such processes and even more difficult to treat severe bacterial infections. In such situations, an individual approach to each patient is required and physicians need parameters to estimate the efficacy of antibiotic therapy. This review discusses the significance of monitoring the content of antibiotics in the blood for this purpose, in combination with the content of inflammatory markers, such as C-reactive protein and procalcitonin. The basic principles of antibiotic therapy, and factors in the resistance of microorganisms to antibiotics, are examined. Approaches to assess the efficacy of antibiotic therapy, as well as methods to detect antibiotics and inflammatory markers in the blood of patients, and comparative assessment of their capabilities and limitations, are described.

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Therapeutic drug monitoring of beta-lactam antibiotics – Influence of sample stability on the analysis of piperacillin, meropenem, ceftazidime and flucloxacillin by HPLC-UV

Cited by 68 publications

References 51 publications

Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

Demonstrating Feasibility of an Opportunistic Sampling Approach for Pharmacokinetic Studies of β‐Lactam Antibiotics in Critically Ill Children

Monitoring Antibiotics and Inflammatory Markers in Human Blood: Impact in Choice of Antibiotic Therapy and Used Methods

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