Development and validation of a measurement procedure based on ultra-high performance liquid chromatography-tandem mass spectrometry for simultaneous measurement of β-lactam antibiotic concentration in human plasma

Rigo-Bonnin, Raül; Ribera, Alba; Arbiol‐Roca, Ariadna; Cobo-Sacristán, Sara; Padullés, Ariadna; Murillo, Óscar; Shaw, Evelyn; Granada, R.; Pérez-Fernández, Xosé; Tubau, Fé; Alía, Pedro

doi:10.1016/j.cca.2017.03.009

Cited by 61 publications

(55 citation statements)

References 27 publications

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“…To be applied in routine analysis, the method(s) used for TDM must be fast, accurate, and cost effective. In recent years, the use of liquid chromatography–tandem mass spectrometry (LC–MS/MS) has become the method of choice . While most of the available methods focus on the simultaneous analysis of ß‐lactams, none included the concurrent analysis of Sulfamethoxazole/Trimethoprim and Linezolid, the levels of which are also significantly affected in critically ill patients and which are increasingly used against ß‐lactam‐resistant bacteria such as methicillin resistant Staphylococcus aureus (MRSA).…”

Section: Introductionmentioning

confidence: 99%

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

El‐Najjar

Hösl

Holzmann

et al. 2017

Drug Testing and Analysis

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A large variation in the levels of different ß-lactams and other antibiotics used in critically ill patients has been documented. The aim of this study is to establish and validate a fast, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous analysis of ten antibiotics (Meropenem, Cefepime, Ceftazidime, Piperacillin, Benzylpenicillin, Ampicillin, Flucloxacillin, Linezolid, and Sulfamethoxazole/Trimethoprim) in human plasma according to European Medicines Agency (EMA) guidelines. Protein precipitation with ice-cold methanol containing 9 isotopically labeled internal standards was used for sample clean up. Antibiotics were detected, following a 4-minute gradient separation, in multiple reactions monitoring (MRM) using API 4000 instrument equipped with electrospray source operating in positive ion mode. The lower limit of quantification was 0.1 mg/L for Meropenem, Ceftazidime, Piperacillin, Ampicillin, Flucloxacillin, and Sulfamethoxazole; 0.05 mg/L for Cefepime, Benzylpenicillin, and Trimethoprim; and 0.02 mg/L for Linezolid. The method proved to be precise and accurate and applicable for therapeutic drug monitoring and other pharmacokinetic studies.

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Section: Introductionmentioning

confidence: 99%

“…In recent years, the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become the method of choice. 10,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]…”

Section: Introductionmentioning

confidence: 99%

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

El‐Najjar

Hösl

Holzmann

et al. 2017

Drug Testing and Analysis

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“…Pharmacokinetic studies of cefuroxime have been limited to measurements of total concentrations . To our knowledge, only one study is published on the analysis of unbound concentrations of cefuroxime.…”

Section: Introductionmentioning

confidence: 99%

“…2,3 Pharmacokinetic studies of cefuroxime have been limited to measurements of total concentrations. [4][5][6] To our knowledge, only one study is published on the analysis of unbound concentrations of cefuroxime. However, analysis was performed by high-performance liquid chromatography (HPLC) ultraviolet detection.…”

Section: Introductionmentioning

confidence: 99%

Quantification of total and unbound cefuroxime in plasma by ultra‐performance liquid chromatography tandem mass spectrometry in a cohort of critically ill patients with hypoalbuminemia and renal failure

Raaij

Mabelis

Shudofsky

et al. 2019

Clinical Laboratory Analysis

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Background Pharmacokinetic studies of cefuroxime by ultra‐performance liquid chromatography tandem mass spectrometry (UPLC‐MS/MS) have been limited to measurements of total concentrations. Here, we developed a robust method for quantifying total and unbound cefuroxime concentrations using UPLC‐MS/MS and ultrafiltration in critically ill patients with hypoalbuminemia and renal failure. Methods Method validation included accuracy, linearity, precision, repeatability, recovery, and limit of quantification (LOQ). Feasibility of the method was performed on samples obtained from randomly selected intensive care unit (ICU) patients. Total and unbound cefuroxime concentrations were quantified using UPLC‐MS/MS. Sampling times were categorized as trough (180‐1 min prior to administration), peak (10‐30 min after administration), mid (30‐360 min after administration), and continuous (sampling during administration). Pharmacokinetic/pharmacodynamic (PK/PD) targets were unbound cefuroxime concentrations above 4 times the minimum inhibitory concentration (32 mg/L). Results Intra‐assay and inter‐assay precision was <3%. Recovery was 99.7%‐100.3%, and LOQ was 0.1 mg/L. We included 11 patients (median age 72 years (range 54‐77). Median albumin serum concentrations and eGFR were 19 g/L (range 11‐40 g/L) and 48 mL/min/1.73 m2 (range 7‐115 mL/min/1.73 m2), respectively. Median trough and mid concentrations of total cefuroxime were 22.27 mg/L (range 5.42‐54.03 mg/L) and 71.49 mg/L (range 53.87‐73.86 mg/L), and median unbound fraction was 75.42% (range 27.36%‐99.75%). Median unbound cefuroxime concentrations were 11.94 mg/L (range 3.85‐32.39 mg/L) (trough) and 55.62 mg/L (range 10.03‐62.62 mg/L) (mid). Conclusion The method is precise and accurate according to ISO 15189 and within the clinical range of cefuroxime (0.5‐100 mg/L). The method was applied in ICU patients and is suitable for TDM on unbound cefuroxime concentrations.

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“…Numerous simultaneous bioanalytical methods have been developed over the years for beta-lactam antibiotics (14)(15)(16)(17)(18)(19)(20)(21)(22), with evidence of increased interest recently (16,18,20). The number of simultaneously determined drugs varies (maximum 21 (17)) and the required sample volumes range from as little as 20 µL (21) and 50 µL (14,16,18,19,22) up to 1 mL(17).…”

Section: Introductionmentioning

confidence: 99%

Development of a Novel Multipenicillin Assay and Assessment of the Impact of Analyte Degradation: Lessons for Scavenged Sampling in Antimicrobial Pharmacokinetic Study Design

Kipper

Barker

Standing

et al. 2018

Antimicrob Agents Chemother

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Penicillins are widely used to treat infections in children, however the evidence is continuing to evolve in defining optimal dosing. Modern paediatric pharmacokinetic study protocols frequently favour opportunistic, "scavenged" sampling. This study aimed to develop a small volume single assay for five major penicillins and to assess the influence of sample degradation on inferences made using pharmacokinetic modelling, to investigate the suitability of scavenged sampling strategies.2 Using a rapid ultra-high performance liquid chromatographic-tandem mass spectrometric method, an assay for five penicillins (amoxicillin, ampicillin, benzylpenicillin, piperacillin and flucloxacillin) in blood plasma was developed and validated. Penicillin stabilities were evaluated under different conditions. Using these data, the impact of drug degradation on inferences made during pharmacokinetic modelling was evaluated.All evaluated penicillins indicated good stability at room temperature (23 ± 2˚C) over 1 hour remaining in the range of 98-103% of the original concentration. More rapid analyte degradation had already occurred after 4 hours with stability ranging from 68% to 99%. Stability over longer periods declined: degradation of up to 60% was observed with delayed sample processing of up to 24 hours. Modelling showed that analyte degradation can lead to a 30% and 28% bias in clearance and volume of distribution, respectively, and falsely show nonlinearity in clearance.Five common penicillins can now be measured in a single low volume blood sample. Beta-lactam chemical instability in plasma can cause misleading pharmacokinetic modelling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring.

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Development and validation of a measurement procedure based on ultra-high performance liquid chromatography-tandem mass spectrometry for simultaneous measurement of β-lactam antibiotic concentration in human plasma

Cited by 61 publications

References 27 publications

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

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

Quantification of total and unbound cefuroxime in plasma by ultra‐performance liquid chromatography tandem mass spectrometry in a cohort of critically ill patients with hypoalbuminemia and renal failure

Development of a Novel Multipenicillin Assay and Assessment of the Impact of Analyte Degradation: Lessons for Scavenged Sampling in Antimicrobial Pharmacokinetic Study Design

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