UPLC–MS/MS method for therapeutic drug monitoring of 10 antibiotics used in intensive care units

El‐Najjar, Nahed; Hösl, Julian; Holzmann, Thomas; Jantsch, Jonathan; Gessner, André

doi:10.1002/dta.2253

Cited by 28 publications

(28 citation statements)

References 38 publications

(70 reference statements)

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“…The data was linear for the range of 0.2–100 μg/mL (R 2 = 0.98) with a LOD of 0.07 μg/mL and a LLOQ of 0.25 μg/mL. The range of this calibration curve is consistent with other methods in the literature for monitoring ampicillin plasma concentrations for TDM . The average AUC for the 1 μg/mL ampicillin plasma calibrant increased from 500 to 21,000 with the optimized conditions compared with the original method.…”

Section: Resultssupporting

confidence: 80%

“…The range of this calibration curve is consistent with other methods in the literature for monitoring ampicillin plasma concentrations for TDM. 28 The average AUC for the 1 μg/mL ampicillin plasma calibrant increased from 500 to 21,000 with the optimized conditions compared with the original method. Likewise, the S/B ratio at the 1 μg/mL level increased from 2 to 58.…”

Section: Analysis Of Dried Plasma Samplesmentioning

confidence: 94%

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A statistical approach to optimizing paper spray mass spectrometry parameters

Skaggs

Kirkpatrick

Wichert

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale Paper spray mass spectrometry (PS‐MS) was used to analyze and quantify ampicillin, a hydrophilic compound and frequently utilized antibiotic. Hydrophilic molecules are difficult to analyze via PS‐MS due to their strong binding affinity to paper substrates and low ionization efficiency, among other reasons. Methods Solvent and paper parameters were optimized to increase the extraction of ampicillin from the paper substrate. After optimizing these key parameters, a Resolution IV 1/16 fractional factorial design with two center points was employed to screen eight different design parameters simultaneously. Results Pore size, sample volume, and solvent volume were the most significant factors affecting average peak area under the curve (AUC) and the signal‐to‐blank (S/B) ratio for the 1 μg/mL ampicillin calibrant. After optimizing the key parameters, a linear calibration curve with a range of 0.2 μg/mL to 100 μg/mL was generated (R2 = 0.98) and the limit of detection (LOD) and lower limit of quantification (LLOQ) were calculated to be 0.07 μg/mL and 0.25 μg/mL, respectively. Conclusions The statistical optimization procedure undertaken here increased the mass spectral signal intensity by more than a factor of 40. This statistical method of screening followed by optimization experiments proved faster and more efficient, and produced more drastic improvements than typical one‐factor‐at‐a‐time experiments.

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Section: Resultssupporting

confidence: 80%

Section: Analysis Of Dried Plasma Samplesmentioning

confidence: 94%

A statistical approach to optimizing paper spray mass spectrometry parameters

Skaggs

Kirkpatrick

Wichert

et al. 2020

Rapid Comm Mass Spectrometry

View full text Add to dashboard Cite

show abstract

“…Therefore, to reduce adverse events caused by an overexposure of linezolid, a lower drug dose or longer intervals should be clinically considered. Many studies (34)(35)(36)(37)(38) have proposed that therapeutic drugs should be monitored and individualized dosing regimen adjusted based on linezolid concentrations and disease progression.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Dosage Optimization of Linezolid in Patients with Liver Dysfunction

Zhang

Zhu

Chen

et al. 2020

Antimicrob Agents Chemother

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Linezolid is the first synthetic oxazolidone agent to treat infections caused by Gram-positive pathogens. Infected patients with liver dysfunction (LD) are more likely to suffer from adverse reactions, such as thrombocytopenia, when standard-dose linezolid is used than patients with LD who did not use linezolid. Currently, pharmacokinetics data of linezolid in patients with LD are limited. This study aimed to characterize pharmacokinetics parameters of linezolid in patients with LD, identify the factors influencing the pharmacokinetics, and propose an optimal dosage regimen. We conducted a prospective study and established a population pharmacokinetics model with the Phoenix NLME software. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and prediction corrected-visual predictive check. A total of 163 concentration samples from 45 patients with LD were adequately described by a one-compartment model with first-order elimination along with prothrombin activity (PTA) and creatinine clearance as significant covariates. Linezolid clearance (CL) was 2.68 liters/h (95% confidence interval [CI], 2.34 to 3.03 liters/h); the volume of distribution (V) was 58.34 liters (95% CI, 48.00 to 68.68 liters). Model-based simulation indicated that the conventional dose was at risk for overexposure in patients with LD or severe renal dysfunction; reduced dosage (300 mg/12 h) would be appropriate to achieve safe (minimum steady-state concentration [Cmin,ss] at 2 to 8 μg/ml) and effective targets (the ratio of area under the concentration-time curve from 0 to 24 h [AUC0–24] at steady state to MIC, 80 to 100). In addition, for patients with severe LD (PTA, ≤20%), the dosage (400 mg/24 h) was sufficient at an MIC of ≤2 μg/ml. This study recommended therapeutic drug monitoring for patients with LD. (This study has been registered in the Chinese Clinical Trial Registry under no. ChiCTR1900022118.)

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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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UPLC–MS/MS method for therapeutic drug monitoring of 10 antibiotics used in intensive care units

Cited by 28 publications

References 38 publications

A statistical approach to optimizing paper spray mass spectrometry parameters

A statistical approach to optimizing paper spray mass spectrometry parameters

Population Pharmacokinetics and Dosage Optimization of Linezolid in Patients with Liver Dysfunction

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

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